Tuberculosis Flashcards
What global areas have the highest incidence of TB?
Sub-Saharan Africa
West Africa
South East Asia and the Pacific
How many people world wide likely have latent TB?
1-2 billions
How many cases of TB are diagnosed annually?
10 million
How many people die each year from TB?
1.6 million
What is the Ro number of TB
<1 - 3 (appears that some people are super spreaders)
What bacterium causes TB?
Mycobacterium Tuberculosis
**ABout 5% of cases are caused by Mycobacterium Bovis
What is the bacteriology of M. Tuberculosis?
Gram Postive
Acid Fast Bacillus
Slow growing (17h) —> difficult to culture
** CAN MAKE IT GROW FASTER BY USING A LIQUID MEDIUM
How does M. Tuberculosis spread?
Aerosol
**Note that only active pulmonary is contagious
What are risk factors for developing active TB?
HIV Co-infection
DM
Smoking
TNF-a
Vitamin D Deficiency
ETOH XS
What is the pathophysiology of TB?
Aerosolised Bacilli enter into the bronchi –> alveoli where they invade into phagocytic cells
Within phagocytic cells two things can happen:
1. Immune system not strong enough to mount a full response against M.Tuberculosis –> active TB
- Immune system has a delayed type response to TB bacteria and causes large amounts of inflammation as phagocytic cells are destroyed. This leads to scarring and granuloma formation. Un-destroyed phagocytes protected within the granuloma are responsible for re-activation disease
**The granuloma illustrates the duality of M. tuberculosis infection: from the host’s perspective, the granuloma is a bacterial ‘prison’ with the potential to ‘wall off’ infection from the rest of the body; however, from the bacterial perspective, it is a growing collection of phagocytic cells to infect and replicate within.
What percentage of people with TB go on to have active infection?
5-10%
How does Classic TB Present?
Chronic productive cough not responding to standard Abx
Weight loss
Pyrexia
Night sweats
Lymphadenopathy (infected macrophages can move through the blood and into lymph nodes)
Fatigue
Haemoptysis
What are common sites of Extra Pulmonary TB (EPTB)?
Neuro
Spinal
Bony
Renal
Skin
What is the difference between TST and IGRA?
TST –> looks for immune response in skin due to secodnary immune response from current or previous TB infection
IGRA –> Blood test looking at serum response to TB by checking IFNy levels
Basically IFNy is released in peripheral t-cells of people who have been exposed to TB; only useful in detecting LTB because there is a high false negative rate of IGRAs in active TB (probably due to general immune changes and therefore low T cell levels in circucating peripheral blood)
should add that IGRA isnt useful in kids <5 and that it was created to try and replace the TST which has many false negatives
How is TB diagnosed?
Sputum Culture and Microscopy (ZN Stained, Fluroscein)
Gene X-pert
Urinary LAM (if HIV +ve)
CXR
IGRA / mantoux test
Gastric Aspirates (paeds)
How can you diagnose latent TB infection (LTBI)
IGRA or TST
What are the standard medications used in uncomplicated TB?
Rifampicin
Isoniazid
Ethambutol
Pyrazinamide
What is the epidemiology of TB + HIV co-infection?
Active TB is 20-40 times higher in HIV +ve people due to early loss of alveolar CD4 cells
9% of global active TB infections are in HIV +ve people
How does DM impact TB outcomes?
Increased mortality
Increased risk of relapse
What percentage of TB cases occur in children?
10%
How has COVID-19 impacted the epidemiology of TB?
Significant reduction in case recogition –> now increasing numbers of diagnoses and deaths from TB due to missed early infections
What are the three main aims of the WHO END TB strategy
- 50% reduction of TB by 2025
- 75% reduction of deaths from TB by 2025
- 0 people living with catastrophic financial burdens due to TB
Are we close to achieving the goals of the WHO END TB strategy by 2025?
NO - not even close
What are the sensitivity and specificity of ZN stained smear microscopy in TB?
Sensitivity = 60-70%
Specificity = >90%
What are the tests of cure in TB?
Negative Smear Microscopy / Culture at month 5 of treatment and at one other subsequent test
What is the definition of treatment failure in TB?
+ve smear microscopy/culture at month 5 of rx
What is the Treatment Success rate calculated?
The number of patients who have successful TB Cure and Completion of TB treatment (without test of cure)
What medication should be given to mitigate the side effects of Isoniazid?
Pyridoxine 50mg OD as prophylaxis to prevent peripheral neuropathy
What things should you discuss/ tests you should complete with patients prior to starting TB management?
- Adherence
- Contraception
- Side effects of medicines
- Visual acuity assessment
- LFTs
What percentage of TB cases present with pulmonary disease?
85%
57% of these are smear positive –> smear positive are most likely to be contagious
According to the WHO, who should be tested for LTBI?
HIV +ve people
Household contacts of people with confirmed Pulmonary TB
People awaiting the following:
- initiation of Interferon Alpha meds
- Dialysis
- pre organ transplant
- New diagnosis of Silicosis
Who should receive TB preventative therapy?
All HIV +ve people, including infants, children, pregnant women and adults
All household contacts of +ve PTB cases with negative TB screening
What are the options of treatment of latent TB (in all patient populations, including HIV +ve individuals)
6H / 69: 6 months daily Isoniazid or 9 months daily isoniazid
4R : 4 months of daily rifampicin
3RH: 3 months of daily rifampicin and isoniazid
3H + Rifapentine: 3 months of weekly Isoniazid + Rifapentine
What is the preventative therapy recommendation for people with HIV in a highly endemic TB area, with confirmtion of NO TB infection?
Isoniazid OD for 36 months
Who should be screened regularly for active TB infection?
- Systematic screening in populations where TB prevelance >0.5%
- HIV patients at each medical encounter
- Household contacts of +ve PTB
- Prisoners
How can you screen for TB?
Symptom check
CXR
RDTs
How should you screen HIV +ve patients for possible PTB?
Symptom screen
±CXR
±RDT
±CRP <5
What are the 4 components of the WHO symptom screen for TB?
- Cough
- Weight Loss
- Fever
- Night Sweats
What is the gold standard diagnostic test in TB for HIV -ve people?
Gene X-pert (sputum, or elsewhere depending on symptoms)
TrueNat can also be used
Children are notoriously hard to get sputum samples from - where else could you get samples in kids for Gene X-pert for TB testing?
Gastric aspirate
LN biopsy
Nasopharyngeal Aspirate
Stool
How do you diagnose TB meningitis?
Gene X-pert CSF
When should you use Urinary Lam for TB diagnosis?
In all HIV patients with:
- Serious illness - ?TB
- CD4 <100
- patients with symptoms of TB
What is the TB diagnostic algorithim in HIV -ve patients?
- Gene X-pert
- Drug susceptibility testing (RIF)
What is the TB diagnostic algorithm in HIV +ve patients
- Symptom Screen
- Urinary LAM
- Gene Xpert
- RIF resistance testing
what is the management of HR-TB (isoniazid resistant TB)
Rifampicin + Ethambutol + Pyrzinamide + Levofloxacin
For 6/12
How soon should TB+ve patients with a new HIV diagnosis be started on ART?
Within 8/52
In regards to MDR-TB/RR-TB, what drugs make up the Group A treatment drug class?
Group A:
Linezolid
Levofloxacin / Moxifloxacin
Bedaquilline (Bdq)
In regards to MDR-TB/RR-TB, what drugs make up the Group B treatment drug class?
Group B:
Clofazimine
Cycloserine
In regards to MDR-TB/RR-TB, what drugs make up the Group C treatment drug class?
Group C:
Ethambutol
Pyrazinamide
Amikacin
Meropenem
How often and how should treatment progress be measured in patients recieving treatment for MDR/RR - TB?
Monthly
Sputum Culture
What surgical procedure can sometimes be recommended in MDR/RR-TB?
Lung resection - lobectomy or wedge resection
Is DOT still recommended in MDR/RR-TB
Yes
Ideally virtually or through CHV/community personnelle, rather than family or daily clinic visits
What Treatment regime is recommended in uncomplicated TB in paediatrics (3m-16y)
4 months:
2RHZE/2RH
What treatment regime is recommended in paediatrics with TB Meningitis?
SHORT:
6HRZEthionamide
LONG:
12 months of
2RHZE/10RH
Give examples of sites for EP-TB
§ Pleural
§ Lymph node
§ Bone and spine
§ Gastrointestinal
§ Genitourinary
§ Skin
§ Central nervous system
§ Pericardial
§ Disseminated and miliary
— pretty much anywhere
What risk is associated with concurrent introduction of ART and Anti-TB drugs?
IRIS
When should you suspect pleural TB?
Pleural disease in any endemic country (about 2/3rd of effusions are caused by TB in these areas)
Is Gene-Xpert of pleural fluid recommended in Pleural TB?
No - usually paucibacillary transudate, so you are unlikely to have a positive result
How do you diagnosed Lymph Node TB?
Aspirate –> histology and culture of nodal fluid
Which lymph nodes are usually involved in lymph node TB?
Cervical
Which patient groups are most likely to present with lymph node TB?
Children
HIV + with mycobacteraemia / disseminated TB
When should you suspect spinal TB?
Unexplained neurological symptoms suggestive of cord disease
New #
Gibbus deformity (kyphosis due to several vertebral #)
*** Note in anyone with TB with new neurology suspect a paraspinal abscess
What are common findings on X-ray in spinal TB?
Wedge Fractures
Skipping lesions (i.e. some vertebrae are spared)
Vertebral abscess
How do you manage spinal TB?
Standard 6/12 TB regime is fine
2RHZE/4RH
Which other form of TB is assocaited with GI Tract TB?
Mycobacterium Bovis
** Consider extending treatment to 9RH
When are steroids recommended in EPTB?
- Pericardial TB
- Severe IRIS
- TB Meningitis
Consider in large pleural effusions, large ascites etc.
How do you diagnose disseminated / miliary TB?
Blood Culture
Sputum Smear (likely -ve) and Culture (likely +ve)
CXR
Smear Microscopy in TB should be graded according to how many specimen are found. What is the grading chart?
A patient was admitted last night from OPD and has been started on TB treatment.
However he doesn’t have any sputum smear results. His CXR looks like this.
Would you continue his TB treatment?
Severe cavitary pneumonia
Answer: Yes
Continue treatment
But need more information, clinically (history but also parameters / weight loss / unwell / cachectic / moribund). Probably unwell.
Radiological features could be many things (gram negative pneumonia, TB, aspergillus, other pneumonia) but TB may be most likely
radio < microbiology as micro more specific than CXR
Take samples (AFB positive and culture)
A 30 yr old woman who is living with HIV has been on TB treatment for 6 weeks.
Presented to the ward after being told to see the doctor by her treatment supporter.
She is jaundiced, has a poor appetite and is slightly nauseated.
a) What do you think has caused her symptoms?
b) What would you next?
a)Most likely hepatotoxicity
b)Stop TB meds and other hepatotoxic drugs and check LFT
Key learning point – Hepatotoxicity common side effect of TB treatment. Jaundice and symptoms = likely significant / severe hepatotoxicity, so appropriate to stop treatment, whilst the cause is investigated and liver dysfunction improves.
Less hepatotoxic regimens may be used and drug introduced sequentially so that the culprit drug can be identified.
What TB drugs are most likely to cause Hepatotoxicity?
Pyrazinamide > Isoniazid > Rifampicin
In a patient with TB-drug induced hepato-toxicity, which would you consider re-starting treatment?
wait until ALT/AST <2x ULN and then reintroduce drugs
80% of time when you reintroduce RHZE it is successful but might want to do it stepwise.
20% of the time you usually find its 1/2 of the drugs
pyrazinamide >isoniazid>rifampicin
So if severe, you could argue not to reintroduce pyrazinamide.
A 25 year old woman was admitted from OPD yesterday with breathlessness and dry cough. She has lost ~5 kg in
weight in the last few months. She appears distressed and her BP is 95/60.
a) what other signs may be relevant?
b) what would you do next ?
Pericardial Effusion: Raised JVP, muffled heart sounds, pleural rub, Pulsus paradoxus
b. Echo/USS
Consider pericardial aspiration if temponade
Start TB rx
Steroids recommended
A man was admitted five weeks ago with severe weight loss, anaemia, fever and
lymphadenopathy. He tested HIV+ and was treated for disseminated tuberculosis.
Shortly after he started on ART. He now says that he has a burning numb sensation in both feet and is having trouble mobilising despite an improvement in his appetite.
What is the likely cause?
What do you do next?
ART/TB related peripheral neuropathy (older ART including zidovudine / stavudine / isoniazid for TB treatment without pyridoxine replacement) / alcohol / HIV-related peripheral neuropathy / vit b12 and
thiamine deficiency / heavy metal poisoning / diabetes
Add pyridoxine 50mg OD
A patient with HIV-associated pulmonary tuberculosis remains smear positive after two months on treatment.
a) Are you concerned?
b) What further questions might you ask?
a) Yes
b) How is the patient? What was the baseline disease status? Are there any risk factors for acquired resistance?
Learning point: Sputum smear status at 2 months is a key indicator in treatment monitoring
A 32 yr old man presented to OPD with breathlessness increasing over the last few weeks. Hix CXR showed a
pleural effusion but there wasn’t time to do a pleural aspiration. He was started on
TB treatment a week ago but is still breathless on exertion and has vague discomfort on the left side of this chest.
What could you do to help his symptoms?
Pleural TB
May require pleural aspiration/drainage
May require steroids
A patient has come for final follow-up
after six months of treatment. He has been taking treatment six days per week directly supervised by a community health worker. On closer examination of the treatment card 21 doses of treatment have not been
signed for, scattered randomly throughout treatment.
a) Has he completed his treatment ?
b) What else might you do ?
No - has missed nearly a month of doses
Full hx from patient
Full hx from clinic
Pill count if possible
Check clinically and re-check re symptoms / weight etc / smear and culture results throughout treatment (Xpert if possible!)
Consider extending treatment or extending follow-up of patient (where possible)
A colleague is finishing their operating list in theatre and phones you after completing an excision biopsy of a lymph node.
He asks if you can come and look at the specimen and advise whether the patient should start TB treatment.
What do you recommend?
?Lymph node TB
Send FRESH (not formalin) sample to the labs for histology and confirmation
Consider starting TB meds
Test for HIV
A 33 year-old man attends Outpatients with back pain, which has stopped him working on his farm. Further questioning
identifies symptoms of weight loss and night sweats for several months.
a) What is the likely diagnosis?
b) What do you do next?
Spinal TB (Pott’s disease)
Key point: clinical sign of gibbus
Full history re previous TB diagnosis/contact and neurological examination
Risk factors for EPTB e.g. HIV status must be assessed and investigated
Spinal imaging may help.
- X-ray in first instance and MRI if available
- Risk of instability/neurological damage. - - - May require surgical input to stabilise if neurological symptoms/signs.
What is the ‘golden age’ of TB epidemiology in children?
Ages 6-9
What is the most common presentation triad in children with TB?
FTT
Cough
Fever
HIGH INDEX OF SUSPICION IF:
*** Enlarged non tender lymph nodes in the neck (with or without
fistulation)
* Abdominal swelling with hard painless swelling with or without
free fluid
* Painful swelling of joint or bone which has arisen slowly over
time
* Audible wheeze not responding to bronchodilators
* An angular deformity of the spine
* Signs of meningitis
When would you consider a TST to be positive?
- ≥10mm in anybody regardless of BCG vaccination
- ≥5mm in children with HIV / malnutrition
** indicates latent infection; not useful in active TB
What bedside examination could be performed in Tuberculosis?
Fundoscopy
Shows retinal tuberculomas
What is XDR-TB?
TB caused by MTB strains that fulfil the definition of MDR/RR-TB and which are also resistant to
- any fluoroquinolone AND
- at least one additional Group A drug
(Group A drugs – bedaquiline, linezolid, moxifloxacin, levofloxacin)
What are the Group A drugs of MDR-TB treatment regime?
bedaquiline, linezolid, moxifloxacin, levofloxacin
Which three countries have the highest rate of MDR-TB?
China
India
Russia
What is Primary Drug Resistance?
A person becomes infected with an organism that is already drug resistant
What is Acquired Drug resistance?
A person becomes resistant to a drug after inadequate treatment
What are risk factors for developing MDR-TB?
Individual level
* Prior TB treatment
* Treatment not completed
* Poor adherence (Addiction disorders, Side effects, Social barriers, costs,
homelessness)
* Malabsorption
* Originating from a country with
high prevalence of drug resistance among
TB programme level
* Non-implementation of DOTS strategies
* Lack of treatment monitoring/non standard treatment
* Interrupted drug supply
* Poor drug quality, not using fixed-dose
combinations
* Dominant private sector
* Poor infection control in health facilities
What is the GOLD STANDARD TEST in TB diagnosis?
Sputum Culture
- 26 year-old lady, Born in UK presents with a Cough for 2 months, fever, weight loss
- Contact of boyfriend who had INH resistant TB 1 year ago
- At the time of screening:
- CXR normal, IGRA positive
- Declined chemoprophylaxis
What treatment would you give?
A. RIF, EMB, PZA
B. RIF, EMB, PZA, LEVO
C. RIF, EMB, PZA, MOXI, AMK
D. RIF, INH, EMB, PZA,LEVO
E. Something else
B or D are correct. B once you have confirmation of Isoniazid resistance
Treatment of Isoniazid Resistant TB =
6(H)REZ-Lfx
Conditions
Rifampicin resistance ruled out
Try to exclude fluoroquinolone resistance
Can extend duration in cavitatory TB or
persistent smear positive / slow progress
What are side effects of linezolid treatment?
Myelosuppression
Peripheral Neuropathy
What are the symptoms of TB meningitis in adults?
Adults/older children
* Subacute onset (1-3 weeks)
* Headache (50-80%)
* Fever (60-95%)
* Vomiting (30-60%)
* Weight loss/anorexia (60-80%)
* Photophobia (5-10%)
* Neck stiffness (40-80%)
* Confusion/coma (30-60%)
* Seizures (5% adults;)
* Cranial nerve palsy (30-50%)
* Hemiparesis (10-20%)
*symptoms are vague - you should consider even in HEADACHES
What is the presentation of TB meningitis in children?
Teenager/children/adolescents
* Failure to thrive/Weight loss
* Irritability/Sleep disturbance
* Vomiting/abdominal pain
* Seizures (50%)/Focal neurology
* History of TB contact (50-90%)
How do you diagnosis TB Meningitis?
LP with CSF
- Gene expert
- smear microscopy
- culture
*****Note: notoriously hard to diagnose; you need at least 6mL of CSF
MRI
Consider diagnosis og TB elsewhere –> CXR, sputum microscopy, Urinary LAM if HIV +ve
What clinical scoring system can you use to determine the liklihood of TB meningitis?
Marais Score
Takes into account clinical symp, imaging, CSF and TB exposures
What does CSF in TB Meningitis look like?
- Raised opening pressure
- Clear appearance (can be slightly cloudy)
- Moderately raised cell count (10 – 500/ul)
- Lymphocytic predominant (>50%)
- Protein conc. > 1g/L
- CSF/Plasma Glucose ratio <0.5 (CSF glucose conc. <2.2 mmol/L)
What is the management of TB Meningitis?
4 drugs (HRZE) for 2 months followed by 2 drugs (HR) for at least 10 months
+
Corticosteroids to all TBM patients
What are complications of Tb Meningitis?
- Cranial nerve entrapment
- Hydrocephalus (up to 80% children)
- Cerebral infarction
- Enlargement of tuberculomas
- Adhesive arachnoiditis/spinal block
- Hyponatraemia
- Paradoxical reactions (~30%)
How can you manage hydrocephalus secondary to TB Meningitis?
Mannitol
Therapeutic LP
Neurosurgery
When should you start co-trimoxazole in HIV as chemoprophylaxis?
CD4 <350
WHO HIV Severity 3 or 4
What are key indicators of TB control from a POV of public health campaigns?
§ Numbers infected (e.g. latent TB infection, LTBI)
§ Numbers with disease (prevalence)
§ Numbers treated for disease (case notifications)
§ Number of TB deaths
§ Numbers registering for treatment
§ Numbers completing treatment
What are the 6 main components of the WHO End TB+ Policy
- D irect Smear Microscopy
- O bserved Therapy
- T reatment monitoring
- S hort course of treatments
5 ! NGO and governemnt support - MDR-TB management
What are the 2035 End TB Milestones?
95% reduction in TB deaths
90% reduction in TB incidence
0 families/people facing catastrophic costs due to TB health costs
What are recommended Regimes for TB preventative therapy in high-risk groups?
Recommended treatment regimens include
6-9H, 3HR, 3HP, 4R (Consider 36m in HIV+ve patients)
- 6 months of isoniazid
- 9 months isoniazid
- 3 months rifampicin & isoniazid
- 3 months weekly / 1 month daily rifapentine & isoniazid
- 4 months rifampicin
Can you give the BCG vaccine to HIV+ patients?
NO
contraindicated
Can cause IRIS or disseminated TB
What are the main side effects of rifampicin?
Reddish discolouration of urine, sweat, sputum, tears.
Gastrointestinal: Anorexia, nausea, vomiting, heartburn.
Hepatic: Transient increases in LFTs.
Flu-like syndrome.
What are contraindications to using Rifampicin?
Hypersensitivity: To rifampicin or other rifamycins.
Liver Disease: Avoid if jaundiced.
Drug Interactions: Avoid concomitant use with saquinavir or ritonavir.
What are the side effects of ethambutol?
Optic Neuropathy and colour blindness
High serum urea
N+V
What are contraindications to Ethambutol?
Optic neuritis undelrying
What are the side effects of Isoniazid?
Peripheral Neuropathy
Can be mitigated with pyridoxine
Who is most at risk of peripheral neuropathy from isoniazid?
Patients with other underlying RFs for peripheral neuropathy
e.g. ETOH xs, DM
What is the 4 month new treatment regime for TB?
4/12 of:
Rifapentine + Moxifloxacin + Isoniazid + Pyrazinamide
What is the pathophysiology of TB Meningitis
After the release of bacilli and granulomatous material into the subarachnoid space, a florid gelatinous exudate forms, which may impair CSF circulation and cause hydrocephalus, cranial nerve palsies and vasculitis. Vasculitis is the most serious complication of tuberculous meningitis and may lead to cerebrovascular accidents.
What is the DDx of TB Meningitis?
Bacterial Meningitis
Cryptococcal meningitis
What are the 4 key pillars for diagnosing TB meningitis?
- Clinical Criteria
-Symptom duration > 5 days
- Systemic symptoms suggestive of tuberculosis
- History of close contact with an individual with pulmonary tuberculosis or a positive tuberculin skin test within the past year
- Focal neurological deficit
- Cranial nerve palsy (from raised ICP)
- Altered consciousness - CSF Criteria
- Clear appearance
- Leukocytes: 10–500/μL
- Lymphocytic predominance (> 50%)
- Protein concentration > 1 g/L
- CSF to plasma-glucose ratio < 50% or absolute CSF glucose concentration < 2.2 mmol/L - Neuroimaging Criteria Hydrocephalus
Basal meningeal enhancement
Tuberculoma
Infarct
Pre-contrast basal hyperdensity - Evidence of TB Elsewhere
- Chest radiography suggestive of active TB
- Evidence for TB outside the CNS on CT, MRI or ultrasound
- AFB identified or M. tuberculosis cultured from another source (sputum, lymph node, gastric washing, urine, blood culture)
- Positive commercial M. tuberculosis-PCR from extraneural specimen
How do you manage TB Meningitis?
The WHO recommends treatment with the same regimen as any form of tuberculosis starting with isoniazid, rifampicin, ethambutol and pyrazinamide.
Usually, treatment is for 9 to 12 months.
Corticosteroids seem to improve clinical outcomes and are currently recommended; however, their effects may vary in different clinical settings.
How can you diagnose TB?
Gene xpert MTB/RIF
TB LAMP Assay
Urinary LAM (HIV+ve)
IGRA
Sputum Microscopy
Sputum Culture
