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TUBERCULOSIS
Learning Objectives
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At the end of the session students will
able to:
Describe the unique features of mycobacterium
tuberculosis bacillus
Describe the risk factors as well as signs and
symptoms of TB
Distinguish between the diagnostic tests used for
patients potentially infected with TB
Design an appropriate therapeutic plan for
pulmonary and extrapulmonary TB as well as LTBI
Assess the effectiveness of therapy in TB patients
What is Tuberculosis
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(TB)?
TB is a communicable infectious disease caused by
Mycobacterium tuberculosis that is spread from person
to person through air droplet
TB most commonly affects lungs, causing a condition
known as pulmonary TB
But can affect almost any part of the body
Extrapulmonary TB: sites most commonly involved in
TB are lymph nodes, pleura, genitourinary tract, bones
and joints, meninges, peritoneum, pericardium, and
skin.
What makes M. Tuberculosis unique??
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Mycobacterial TB is the most difficult of all bacterial
infections to cure:
Mycobacteria grow slowly and dormant in the host for long
periods (a portion reside inside macrophages)
Many anti-bacterials do not penetrate mycobacterial CW, and
CW contain mycolic, acid-rich, long-chain glycolipids and PG
that protect mycobacteria from cell lysosomal attack
It is agile in developing resistance to single chemotherapeutic
agents
Consequently
Effective therapy requires a prolonged course of multiple
drugs
Patient compliance, drug toxicity, drug interactions,
Epidemiology
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Globally, approximately 2 billion people are infected by M.
tuberculosis
In 2021, an estimated 10.6 million people affected with TB
worldwide. 6 million men, 3.4 million women and 1.2 million children.
About 90% of those infected with M. tuberculosis have
asymptomatic (latent TB infections)
TB is present in all countries and age groups.
TB is curable and preventable
A total of 1.6 million people died from TB in 2023
In 2021, about 208,000 people died of HIV-associated TB
126 cases per 100,000 people in Ethiopia
Countries in the three high-burden country lists
for TB, TB/HIV and MDR-TB during the period
2016–2020, and their areas of overlap
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Risk Factors for Active Tuberculosis Among Persons Who Have
Been Infected With Tubercle Bacilli
9 Factor Relative
Risk/Oddsa
Recent infection (<1 year) 12.9
Comorbidity
HIV infection 21–>30
Chronic renal failure/hemodialysis 30
10–25
Diabetes
2–4
IV drug use 10–30
Immunosuppressive 30–60
treatment 20–70
Post-transplantation period
(renal, cardiac)
Tobacco 2–3
smoking
Malnutrition and severe underweight 2
Pathophysiology
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How does Tuberculosis develop?
Tuberculosis develops in the human body in two
stages.
1. Individual who is exposed to micro-
organisms from an infectious case
becomes infected (Tuberculous infection)
Most (probably (80-90%) will never
become ill unless their immunity is
seriously compromised.
2. Infected individual develops the disease.
What Happens after
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infection?
About 5% are likely to develop disease in the period
immediately following infection
Overall, it is estimated that up to 10% of infected
persons will eventually develop active TB in their
lifetime-half of them during the first 18 months after
infection.
HIV STATUS LIFETIME RISK OF
DEVELOPING TB
Negative 5-10 %
Positive 50%
Cont.………
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Primary infection usually results from inhaling
droplet nuclei that contain M. tuberculosis.
Alveolar implantation of organisms in droplet nuclei
that are small enough (1 to 5 mm) to escape the
ciliary epithelial cells of URT
The progression to clinical disease depends
on three factors:
Number of M. tuberculosis organisms inhaled
(infecting dose),
The virulence of these organisms and
The host’s cell-mediated immune response
Cont.….
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The organisms multiply and are ingested by
pulmonary macrophages, where they continue
to multiply, albeit more slowly.
Tissue necrosis and calcification of originally
infected site and regional lymph nodes may
occur, resulting in formation of a radiodense
area called Ghon complex
Pathophysiology
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Large numbers of activated macrophages surround
the solid caseous (cheeselike) tuberculosis foci
(necrotic area) as a part of cell-mediated immunity.
Delayed-type hypersensitivity also develops through
activation and multiplication of T lymphocytes.
Macrophages form granulomas to contain the
organisms.
Successful containment of M. tuberculosis requires
activation of a subset of CD4 lymphocytes
Occasionally, a massive inoculum of organisms
may be introduced into bloodstream, causing widely
disseminated disease and granuloma formation
known as miliary tuberculosis.
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Clinical Presentation
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Diagnosis
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Mantoux ,Tuberculin Skin Test/ TST- is
often used to screen people at high risk
for TB
In this test, tuberculin is injected into skin
Tuberculin (purified protein derivative
(PPD) is protein derived from tubercle bacilli
that have been killed by heating
In most people who have TB infection, the
immune system will recognize the
tuberculin
Diagnosis
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The test is read 48 to 72 hours after injection by
measuring the diameter of the zone of
induration.
Symptomatic Disease
Confirmatory diagnosis of a clinical suspicion of
TB must be made via chest x-ray and
microbiologic examination of sputum or other
infected material to rule out active disease.
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• Chest X-ray -doesn't give a
definitive diagnosis
– Could be normal in the
presence of + smear
Smear microscopy
20 AFB (shown in
AFB smear- a microscopic red) are tubercle
bacilli
examination of a person's
sputum or other specimen that
is stained to detect acid-fast
bacteria.
It is a rapid test used to
provide presumptive results
within one to two days
Should be done for all cases
of TB suspect
Cough >3 weeks
Chest x-ray suggestive of
pulmonary TB
GeneXpert—MTB/RIF
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Xpert MTB/RIF assay is a new
test that is revolutionizing TB
control by contributing to
rapid diagnosis of TB
disease and drug
resistance.
The test simultaneously
detects Mycobacterium
tuberculosis complex (MTBC)
and resistance to rifampin
(RIF) in less than 2 hours.
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TB culture and sensitivity
-It takes up to 6 weeks to yield results.
Itis required for drug sensitivity testing.
Not routinely practiced.
PCR
FNA/Biopsy can play a role in the confirmation
of Extrapulmonary TB.
Not routinely practiced.
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TREATMENT & FOLLOW-
UP OF TB
Basic Principles of TB Treatment
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Desired Outcome:
To cure the patient
To decrease disease transmission
To prevent death from active TB
To prevent relapse
To prevent development of drug
resistance
Cont.…
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General Principles
Drug treatment is the cornerstone of TB
management.
A minimum of two drugs, and generally four drugs,
must be used simultaneously.
Drug treatment is continued for at least 6 months
and up to 2 to 3 years for some cases of MDR-TB.
Measures to assure adherence, such as directly
Antimicrobial agents
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First-line agents (in approximate order of
preference)
Isoniazid 300 mg/d
Rifampin 600 mg/d
Pyrazinamide 25 mg/kg/d
Ethambutol 15–25 mg/kg/d
Streptomycin 15 mg/kg/d
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First line drugs are:
Safe
Effective
Given to patients free of charge
Serious side-effects are rare
The principles of treatment are the same in all
patients (adults & children).
Treatment schedule/DOTS/
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Intensive Phase:
4 drug regimen for 2 months
RHZE/S
Continuation Phase:
Extends from 4-6 months.
4 months if H and R are used or 6 months
if H and E are used
TB treatment regimen in
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Ethiopia
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Patients aged 12 years or older with
pulmonary DS-TB may receive a 4-month
regimen of isoniazid, rifapentine,
moxifloxacin and pyrazinamide
(2HPMZ/2HPM). (Conditional
recommendation, moderate certainty of
evidence) – new recommendation
TB and HIV co-infection
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Treatment of TB should
1,2 million people have both infections
always get a priority
ART should be considered HIV TB
Infection Infection
according to the national 2.2
million 35 million
Guidelines
The Dual Epidemic in Ethiopia
WHO estimates, 1997–2000
Cont.…..
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INH and rifampicin are the two most active drugs,
backbone of TB treatment.
Drugs available in FDC in Ethiopia:
Rifampicin, Isoniazid, Pyrazinamide and
Ethambutol (RHZE)
275/150/75/400 mg
Rifampicin, Isonizid and Pyrazinamide (RHZ)-
150/75/400 mg
Ethambutol and Isoniazid (EH) – 400/150 mg
Rifampicin and Isoniazid (RH) – 150/75 mg
1. Isoniazid (INH)
INH is the most active drug for treatment of
tuberculosis
It is bactericidal for actively growing tubercle bacilli.
INH is able to penetrate into phagocytic cells and
thus is active against both extracellular and intracellular
organisms.
MoA: INH inhibits synthesis of mycolic acids, which
are
33 essential components of mycobacterial cell walls.
Pharmacokinetics
INH is readily absorbed from GI, and it diffuses readily
into all body fluids and tissues.
Metabolism of INH, especially acetylation by liver N-
acetyltransferase, is genetically determined.
INH metabolites and a small amount of unchanged drug
are excreted mainly in the urine.
The dose need be adjusted in severe hepatic insufficiency.
34 Clinical Uses: Used in the treatment and prevention
of tuberculosis.
Adverse Reactions
INH-induced hepatitis: risk of hepatitis greater in old age,
alcoholics, during pregnancy and immunocompromised
patients.
Peripheral neuropathy: is more likely to occur in slow
acetylators and patients with predisposing conditions such
as malnutrition, alcoholism, diabetes, AIDS, and uremia.
Neuropathy is due to a relative pyridoxine deficiency.
INH promotes excretion of pyridoxine, and this toxicity is
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readily reversed or can be prevented by administration of
pyridoxine.
2.Rifampicin
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Rifampicin binds strongly to bacterial DNA-dependent
RNA polymerase and thereby inhibits RNA synthesis.
It is well absorbed after oral administration and excreted
mainly through liver into bile.
Rifampin is distributed widely in body fluids and tissues.
It is relatively highly protein bound, and so adequate
cerebrospinal fluid concentrations are achieved only
in presence of meningeal inflammation.
Rifampin is used in the treatment of mycobacterial
infections.
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Rifampicin is administered together with INH,
ethambutol, or another anti-tuberculous drug in
order to prevent emergence of drug
resistant mycobacteria.
Rifampicin is an alternative to INH for
prophylaxis in patients who are unable to take
INH or who have had close contact with a case of
active tuberculosis caused by an INH-resistant,
Adverse Reactions
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Rifampin causes a harmless orange color to urine,
sweat, and tears.
Rashes, thrombocytopenia, nephritis, cholestatic
jaundice and occasionally hepatitis.
Rifampin induces microsomal enzymes (cytochrome
P450), which increases elimination of
anticoagulants, AED, and contraceptives.
Administration of rifampin with ketoconazole, or
chloramphenicol results in significantly lower serum
levels of these drugs.
3. Ethambutol
Ethambutol inhibits synthesis of
mycobacterial cell wall.
Ethambutol is well absorbed from gut and
accumulates in renal failure.
Ethambutol crosses BBB-only if meninges
are inflamed.
Ethambutol given in combination with INH
or rifampin
Serious adverse event: is optic neuritis
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causing loss of visual acuity and red-green
color blindness is a dose-related side effect.
4. Pyrazinamide
Pyrazinamide (PZA): is taken up by macrophages and
kills bacilli residing within this acidic environment.
PZA is well absorbed from the gut and widely
distributed in body tissues, including inflamed meninges.
Tubercle bacilli develop resistance to pyrazinamide fairly
readily.
Major adverse effects: of pyrazinamide include
40 hepatotoxicity, nausea, vomiting, drug fever, and
hyperuricemia(provoke acute gouty arthritis).
5. Streptomycin
Most tubercle bacilli are inhibited by streptomycin.
Streptomycin penetrates into cells poorly, and thus it
is active mainly against extracellular tubercle bacilli.
Streptomycin crosses BBB and achieves therapeutic
concentrations with inflamed meninges.
It is employed principally in individuals with severe,
possibly life-threatening forms of tuberculosis
(meningitis and disseminated disease), and in treatment
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of infections resistant to other drugs.
Adverse Reactions: Streptomycin
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Ototoxic and nephrotoxic.
Vertigo and hearing loss /may be permanent/.
the risk in the elderly.
the dose must be adjusted according to renal
function
Toxicity can be ↓ by limiting therapy to no
more than 6 months whenever possible.
Second-line agents
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Amikacin Aminosalicylic
acid
Capreomycin Ciprofloxacin
Clofazimine Cycloserine
Ethionamide Levofloxacin
Rifabutin Rifapentine
Moxifloxacin Kanamycin
Drugs for MDR-TB (generally 18-
24 months)
Drugs Possible ADRs
Fluoroquinolones** Generally well-tolerated
Injectables (e.g. amikacin) Hearing loss, nephrotoxicity, balance,
Cycloserine Central nervous system toxicity
Ethionamide Nausea/vomiting
Linezolid BM toxicity, peripheral neuropathy
Clofazimine** Skin discoloration
Para-aminosalicylic acid GI toxicity, hypersensitivity, drug-induced
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lupus
ART and TB Similarities Between
Rx of TB and HIV
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Extended therapy needed
Multiple drugs required
Adherence essential for optimal outcome and
to prevent resistance
Drugs individually have serious toxicities
Drugs in combination have further toxicities
and problematic interactions
National Recommendation
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When to start ART??
Complete TB therapy prior to beginning ARV
Consider ART if there is high risk of HIV disease
progression and death during the period of TB
treatment (within 2-8 weeks)
the presence of disseminated TB.
Initiate treatment as soon as the patient
Latent TB infection
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At least 30% of the world population is
latently infected with TB worldwide
The risk of active TB disease is greatly elevated in
HIV+ persons
TB accounts for up to 40% of all AIDS deaths
IPT reduces risk of TB in PLWH by 33-67%,
reduces risk of death by 26%;
Prevent further transmission of TB in the community
LTBI chemoprevention summary (new)
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Drug Resistance
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Drug resistance should be suspected in the
following situations:
Patients who have received prior therapy for TB
Patients from geographic areas with a high
prevalence of resistance
Patients who are homeless, institutionalized, and/or
infected with HIV
Patients who still have AFB-positive sputum
smears after 2 months of therapy
Patients who still have positive cultures after 3 to 4
months of therapy
Patients who require retreatment
Special Populations
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Tuberculous Meningitis and
Extrapulmonary Disease
In general, isoniazid, pyrazinamide, ethionamide, and
cycloserine penetrate the cerebrospinal fluid readily.
Patients with CNS TB are often treated for longer
periods (9–12 months)
Extrapulmonary TB of the soft tissues can be
treated with conventional regimens.
TB of the bone is typically treated for 9 months,
occasionally with surgical debridement
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Children
TB in children may be treated with regimens
similar to those used in adults, although some
physicians still prefer to extend treatment to 9
months.
Pediatric doses of drugs should be used
Pregnant Women
The usual treatment of pregnant women
is isoniazid, rifampin, and ethambutol for
Prevention
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By far the best way to prevent tuberculosis is
to diagnose and isolate infectious cases
rapidly and administer appropriate treatment
until patients are rendered non-infectious and
the disease is cured.
BCG vaccination and treatment of persons
with LTBI who are at high risk of developing
active disease
Public health campaigns
Case
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AF is a 56-year-old HIV-positive man who
presents to the medical clinic complaining of a
1-month history of a persistent cough that has
become productive over the past 2 weeks. He
also complains of malaise and a 6-kg weight
loss over the past 2 months.
PMH: HIV positive; last CD4+ 28%; T2DM -well
controlled; HTN × 5 years-well controlled
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FH: Mother and father died in an MVA 10 years
ago; one brother, age 54, lives with the patient;
one sister, age 50, is alive and has had breast
cancer
SH: Single, one daughter. He reports IV drug use
but last use was 20 years ago. He had a 20-year
history of alcohol abuse but has been sober for
10 years.
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Vs: BP 126/78, P 90 beats/min, RR 18, T 38.7°C
(99°F), O2
Neck: Supple; no lymphadenopathy, bruits, or JVD;
no thyromegaly
Chest: Diffuse rhonchi, decreased breath sounds
on left
CVS: no murmurs, rubs, gallops
Abd: (+) BS; nontender, nondistended
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CXR: Bilateral upper lobe infiltrates with cavitation
on left; small left pneumothorax
Clinical Course: The patient was admitted and
placed on respiratory isolation. Three separate
sputum AFB stain specimens were reported to
contain 3+ AFB. Sputum samples were sent for AFB,
fungi, and bacterial cultures and sensitivities. After
48 hours, the PPD skin test was read as a 5-mm area
of induration
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Assessment: Active pulmonary TB in an HIV-
positive patient
1. What information is suggestive of TB?
2. 2. What factors place this patient at increased risk for
acquiring TB?
3. Which signs, symptoms, and other findings are
consistent with active TB infection?
4. Based on the information provided, what are the goals
of therapy for this patient?
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5. Select and recommend a therapeutic plan for
treatment of this patient’s TB infection. What
drugs, dose, schedule, and duration of therapy
are best for this patient?
6. Should any contacts infected by this patient
be evaluated and treated?
7. Who else should be tested and how should
they be treated?
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