Tuberculosis

Bahir Dar University
College of Medicine and Health

Sciences
Tuberculosis
Moderator: Dr.Abebe Shumet
(Internist, Consultant Pulmonologist & Intensivist)
Presenter :Nuru Seid (R2)
Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 1

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Outlines
• Introduction
• Epidemiology
• Pathogenesis and immunology
• Clinical features & Diagnosis Of Tuberculosis
• Treatment of drug susceptible, drug resistant & latent TB

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INTRODUCTION
• Tuberculosis is one of the oldest diseases known to affect humans and the top cause of
infectious death worldwide
• Is caused by bacteria of the Mycobacterium tuberculosis complex
Mycobacterium tuberculosis Mycobacterium bovis Mycobacterium africanum
Mode of transmission: spread via

aerosol droplet nuclei Mode of transmission: common cause of tuberculosis in West,
predominantly via ingestion of Central, and East Africa
contaminated cow's milk
Reservoir: predominantly humans
Reservoir: predominantly cattle
Disease: all forms of tuberculosis

Disease: gastrointestinal tuberculosis in human

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CHARACTERISTICS ORGANISMS
• Acid-fastness
– The ability to withstand decolorization with an
acid-alcohol mixture after coloration with such
stains as carbol fuchsin or auramine O
• Is primarily intracellular pathogens, are obligate
aerobes
• It has the potential to survive in a variety of
environments, including those with low oxygen
tension.
M. tuberculosis is a rod-shaped, non-
spore-forming, thin aerobic
bacterium measuring 0.5 μm by 3
μm

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Epidemiology
• One-fourth of the world's population has latent TB.

• Without treatment, the death rate from Tb disease is high (about 50%)
• With currently-recommended treatments, about 85% of people can be cured

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Epidemiology
• In 2021, there were an estimated increased between 2020 and
1.4 million deaths among HIV- 2021, with 450 000 new cases of
negative people and 187 000 rifampicin resistant Tb in 2021
deaths among HIV-positive
people, for a combined total of
1.6 million
• An estimated 10.6 million people
fell ill with Tb in 2021, an
increase of 4.5% from 10.1
million in 2020.
• The Tb incidence rate rose by
3.6% between 2020 and 2021
• The burden of drug-resistant Tb
(Dr-Tb) is also estimated to have

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Risk factors
• Risk factors for tuberculosis exposure • Risk factors for disease
– Working in the health care industry – Age(increased in infants)
– Migration from countries with a high TB – HIV infection is by far the most potent risk
incidence(≥ 100 cases per 100,000 factor worldwide.
population) – Inhibition of TNF(treatment with a biologic
– Frequent travel to countries with a high TB agent)
burden – Hematologic malignancies, diabetes mellitus,
– Close contact with a patient with active TB uraemia
infection – Genetic risk factors
– Crowded living conditions (e.g., prisons) – Under nutrition( interfere with cell-mediated
– Homelessness responses)
– Vitamin D deficiency
Determined mainly by exogenous factors
Depends largely on endogenous factors

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TRANSMISSION
• M. tuberculosis is transmitted through the air, and – The use of chemotherapy

transmission occurs when a person inhales droplet • Reduce bacillary population in the lungs
nuclei containing M. tuberculosis, and traverse the
respiratory tract, and reach the alveoli of the lungs
• SOURCE CASE Degree of infectiousness
– The severity of coughing
• Severe pulmonary tuberculosis,
tuberculosis laryngitis
• Sputum smear positive
– The number of organisms contained in the
lungs
• Solid nodular lesions ranges from 102 to
104 organisms,cavitary lesions 107 to 109
bacilli)

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TRANSMISSION
Environmental Under standard conditions of temperature and humidity indoors, 60% to 71% of aerosolized M.
tuberculosis organisms survived for 3 hours, 48% to 56% for 6 hours, and 28% to 32% for 9 hours.
factors
Its removal by venting and the death of the organisms from exposure to ultraviolet light
Circumstances Long duration exposure and takes place under conditions that would be associated with a high
concentration of droplet nuclei in the air inhaled by the contact
of exposure
Host factors Susceptibility to acquisition of infection with M. tuberculosis is highly variable. few efforts to
identify the determinants of resistance to acquisition of infection
It is currently unclear whether HIV infection also affects susceptibility to acquisition of infection

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IMMUNITY
Unknown Immunity
• Exposure Infection outcome
• Innate Immune
• Direct or indirect killing via reactive nitrogen intermediates, interferon (IFN)-gamma and
other cytokines, use of toll-like receptors as well as other pattern recognition receptors
for M. tuberculosis molecules

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INNATE IMMUNITY
• Innate Immune Cells

– Macrophages the major reservoirs of the bacteria.
– Dendritic cells serve as the dominant source of the cytokine IL-12, and they transport
tubercle bacilli from the lungs to the local draining lymph nodes, where antigen-
specific T-cell responses are initiated.

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Mycobacterial cell Activation of TLRs
Alveolar
wall contains leads to the
Inhaled macrophages
Entry into pathogen- production of
droplet nuclei recognize M.
associated proinflammatory
reach the macrophage molecular patterns tuberculosis
cytokines (e.g., IL-
terminal s (PAMPs) such as PAMPs via toll-
1, IL-12, TNF-α)
alveoli lipoarabinomannan like receptors
and phagocytosis
and lipomannan. (TLRs)
of mycobacteria.

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M. tuberculosis survives within
Typically, phagocytosed organisms
macrophages because of the
reside within a phagosome to undergo
inhibition of both phagosome
intracellular killing
maturation and phagolysosome fusion
Killing of bacteria by reactive oxygen

Fusion of phagosome and lysosome:
Phagosome maturation: acidification species (ROS), reactive nitrogen
mediated by increased intracellular
using a proton pump system intermediates (RNI), and lysosomal
calcium levels
enzymes

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Virulence factors
Cord factor
(trehalose-6,6'- Sulfatides Lipoarabinomannan Catalase-peroxidase
dimycolate)
A lipoglycan that An enzyme that

Surface glycolipids
induces TNF-α release catalyzes the
that inhibit
from macrophages destruction of ROS
phagolysosome fusion
A surface glycolipid that causes and scavenges ROS and H2O2
serpentine cord-like growth,
inhibits neutrophil migration, and Following replication in the alveolar macrophages, Macrophage lysis and release
induces TNF-α release to of bacteria attack uninfected macrophages to spread infection.
stimulate activated macrophages
Some bacteria enter the bloodstream, causing bacteremia and seeding multiple
to form granulomas
organs.

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Cellular immune response
Dendritic cells present mycobacterial antigens
Activated CD4+ T cells migrate to the focus of infection (type IV HSR) & release IFN-γ
IFN-γ acts on macrophages to enable bacterial killing

• Promotion of phagosome maturation
• Enhanced RNI production
• Autophagy
Granulomatous inflammation and tissue destruction

• IFN-γ-activated macrophages secrete TNF-α.
• TNF-α promotes the aggregation of macrophages and T cells to form granulomas, affecting the lungs and regional
lymph nodes
• Destruction of M. tuberculosis-infected macrophages causes central caseous necrosis and tissue damage.
• Granuloma limits the spread of infection.

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PATHOGENESIS
UNIQUE FEATURES
• INTRACELLULAR TRAFFICKING
– Mycobacteria survive and replicate in host phagocytes (macrophages) by perturbing the normal
pathway of phagosome maturation and killing and digestion of other pathogens
– Which allow M. tuberculosis to survive and replicate intracellularly
• INDUCTION OF TYPE I INTERFERONS
– Type I IFNs play a pathogenic role by enhancing recruitment of mononuclear cells that support
intracellular bacterial replication & Limiting expression of interleukin (IL)-1-β(a cytokine that is essential
for control of M. tuberculosis)

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UNIQUE FEATURES
• BIOLOGICALLY ACTIVE MYCOBACTERIAL LIPIDS
– Acts as a barrier to drugs and other polar molecules
– Mycobacterial lipids interact directly with the host to contribute to pathogenesis
– Trehalose dimycolate (TDM) (an abundant cell wall lipid)
– Modulates innate immune and inflammatory responses to M. tuberculosis
• GRANULOMAS
– Traditionally considered to be host-protective structures, thought to “wall off ” bacteria and keep them
from disseminating(may apply in later stages of fibrotic and calcified granulomas)
– Early granuloma formation actually promotes infection by facilitating cell-to-cell spread within the
macrophage aggregates

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UNIQUE FEATURES
• MODULATION OF APOPTOSIS
– Inhibit apoptosis and prolong the life of infected cells, allowing the bacteria to grow to a larger
population size in each infected cell before spreading to adjacent cells.
– Inhibition of apoptosis of the infected cells minimizes the frequency of CD8 T-cell activation.
• LATENCY/DORMANCY AND REACTIVATION
– The bacteria also possess highly evolved mechanisms that are involved in latency and reactivation

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NATURAL HISTORY OF INFECTION
Inhalation of aerosol droplets

●Immediate clearance of the
organism
●Primary disease: immediate
onset of active disease
●Latent infection
●Reactivation disease: onset of
active disease many years
following a period of latent
infection
CLINICAL MANIFESTATIONS
Primary Disease Post primary (Adult-Type) Disease

• Seen in children and with impaired immunity • Usually localized to the apical and posterior
( malnutrition or HIV infection) segments of the upper lobes & superior
• Distributed to the middle and lower lung zones segments of the lower lobes
• Forms peripheral lesion accompanied by • Nonspecific and insidious, symptoms and
transient hilar or paratracheal signs(mainly of fever, often diurnal and
lymphadenopathy (Ghon focus)
night sweats, weight loss, anorexia, general
• The Ghon focus, with or without overlying
malaise, and weakness)
pleural reaction, thickening, and regional
lymphadenopathy, is referred to as the Ghon • Cough initially non-productive and limited
complex. to the morning and subsequently
• Pleural effusion results from the penetration of accompanied by the production of purulent
bacilli into the pleural space from an adjacent sputum, sometimes with blood streaking
subpleural focus

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Lymph Node TB (Tuberculosis
Lymphadenitis)
• Diagnosis by fine-needle aspiration biopsy (with a yield of up to 80%) or surgical excision biopsy
• Bacteriologic confirmation(granulomatous lesions with or without visible AFBs and cultures are positive
in 70–80% of cases)

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Pleural TB
• Pleural effusion represents a hypersensitivity response to mycobacterial antigens.

• Depending on the extent of reactivity, the effusion may be small, remain unnoticed, and resolve
spontaneously or may be sufficiently large to cause symptoms such as fever, pleuritic chest pain, and
dyspnea
• Fluid
– Straw-coloured and at times haemorrhagic
– An exudate with a protein concentration >50% of that in serum (usually ~4–6 g/dL), a normal to low glucose
concentration, a pH of ~7.3 (occasionally <7.2), and detectable white blood cells (usually 500–6000/μL).
– Neutrophils predominate in the early stage, lymphocyte predominance is the typical finding later
– Mesothelial cells are generally rare or absent
• Adenosine deaminase may be a useful screening test, and TB may be excluded if the value is very low.
• Pleura biopsy
– Is often required for diagnosis and is recommended over pleural fluid analysis
– It reveals granulomas and yields a positive culture in up to 80% of cases.

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Genitourinary TB
• Any portion of the genitourinary tract
• Nonspecific symptoms(urinary tract infection with frequency, dysuria, nocturia and hematuria, and
abdominal or flank pain).
• Delayed diagnosis with irreversible organ damage(a high index of suspicion)
• Up to 75% of patients have abnormalities on CXR(previous or concomitant pulmonary disease)
• Urinalysis( pyuria and hematuria) positive in 90% of cases.
• Urine culture yields a definitive diagnosis in nearly 90% of cases.

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Skeletal TB
• Weight-bearing joints (the spine in 40% of cases, the hips in 13%, and the knees in 10%) are most
commonly affected.
• From the anterior superior or inferior angle of the vertebral body, the lesion slowly reaches the adjacent
body, later affecting the intervertebral disk. With advanced disease, collapse of vertebral bodies results in
kyphosis (gibbus).
Aspiration of the abscess or bone biopsy confirms the tuberculous etiology, as cultures
are usually positive and histologic findings highly typical.

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CNS TB
Cerebrospinal fluid (CSF) reveals a high leukocyte count (up to 1000/μL), usually with a predominance of
lymphocytes but sometimes with a predominance of neutrophils in the early stage; a protein content of 1–8
g/L (100–800 mg/dL); and a low glucose concentration

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Gastrointestinal TB
• Any portion of the gastrointestinal tract may be affected, the terminal ileum and the cecum are the sites
most commonly involved.
• Abdominal pain and swelling, obstruction, hematochezia, and a palpable mass in the abdomen are common
findings at presentation.
• Fever, weight loss, anorexia, and night sweats are also common.

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Tuberculous Pericarditis
• The onset may be sub acute, although an acute presentation, with dyspnea, fever, dull retrosternal pain,
and a pericardial friction rub, is possible.
• An effusion eventually develops in many cases; cardiovascular symptoms and signs of cardiac tamponade
may ultimately appear
• In the presence of effusion, TB must be suspected if the patient belongs to a high-risk population (HIV-
infected, originating in a high-prevalence country); if there is evidence of previous TB in other organs; or if
echocardiography, CT, or MRI shows effusion and thickness across the pericardial space.

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• Pericardiocentesis is required for definitive diagnosis
• The effusion is exudative in nature, with a high count of lymphocytes and monocytes.
• Hemorrhagic effusion is common. Direct smear examination is very rarely positive.
• Culture of pericardial fluid reveals M. tuberculosis in up to two-thirds of cases, whereas pericardial biopsy
has a higher yield.
• High levels of adenosine deaminase, lysozyme, and IFN-γ
• Without treatment, pericardial TB is usually fatal. Even with treatment, complications may develop,
including chronic constrictive pericarditis with thickening of the pericardium, fibrosis, and sometimes
calcification

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• Stages
– Stage 1: fibrinous exudate containing neutrophils and mycobacteria
– Stage 2: serosanguineous effusion with lymphocytes
– Stage 3: absorption of effusion and caseating granulomas
– Stage 4: scarring with calcification
• Types
– Pericardial effusion (rarely, cardiac tamponade)
– Constrictive pericarditis
– Effusive-constrictive pericarditis

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Miliary or Disseminated TB
• Miliary TB is due to hematogenous spread of tubercle bacilli.
• The lesions are usually yellowish granulomas 1–2 mm in diameter that resemble millet seeds (thus the term
miliary, coined by nineteenth-century pathologists).
• Clinical manifestations are nonspecific and protean, depending on the predominant site of involvement.
• Fever, night sweats, anorexia, weakness, and weight loss are presenting symptoms in the majority of cases.
At times, patients have a cough and other respiratory symptoms due to pulmonary involvement as well as
abdominal symptoms
• Physical findings include hepatomegaly, splenomegaly, and lymphadenopathy.
• Eye examination may reveal choroidal tubercles, which are pathognomonic of miliary TB, in up to 30%
cases. Meningismus occurs in fewer than 10% of cases.

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Miliary or Disseminated TB
• A high index of suspicion is required for the diagnosis of miliary TB. Frequently, CXR reveals a miliary
reticulonodular pattern (more easily seen on underpenetrated film), although no radiographic abnormality
may be evident early in the course and among HIV infected patients.
• Other radiologic findings include large infiltrates, interstitial infiltrates (especially in HIV-infected patients),
and pleural effusion.
• Sputum-smear microscopy is negative in most cases

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DIAGNOSIS OF PULMONARY TUBERCULOSIS
• DIAGNOSTIC EVALUATION, PATIENT HISTORY • PHYSICAL EXAMINATION
– Clinical suspicion is by the presence of – In most cases, physical findings are not
symptoms and by awareness of comorbidities particularly helpful. Crackles may be heard in
and epidemiologic circumstances that the area of involvement, along with bronchial
increase the risk of tuberculosis in an breath sounds, when lung consolidation is
individual patient. close to the chest wall.
– The most commonly reported symptom of – Findings such as lymph node enlargement,
pulmonary tuberculosis is persistent cough suggestive of extra pulmonary tuberculosis,
that generally, but not always, is productive may also indicate concurrent pulmonary
of mucus and sometimes blood. The cough is involvement.
often accompanied by systemic symptoms,
such as fever, night sweats, and weight loss
Three main reasons for delays in diagnosing tuberculosis
The affected person not seeking or not having access to care;
The provider not suspecting the disease
The lack of sensitivity of the most commonly available diagnostic test,
sputum (or other specimen) smear microscopy
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TB Diagnostic Methods
• The diagnosis of TB may be reached using bacteriologic confirmatory techniques including
microscopic examination, rapid molecular diagnostic tests such as Xpert MTB/RIF assays
and culture.
• Additional supportive investigations (imaging techniques, histopathology or biochemical
analysis of body parts/fluids) may be used to assist clinicians to diagnose TB in cases
where the bacilli are not detected by bacteriologic techniques.

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BACTERIOLOGIC EVALUATION
• Isolation of tubercle bacilli in culture or specific nucleic acid sequences is needed for definitive diagnosis
• Sputum is the initial specimen of choice.
• Patients who are not producing sputum
– Inducing sputum production by the inhalation of a hypertonic (3% to 5%) saline mist generated by an
ultrasonic nebulizer
– Sampling of gastric contents via a nasogastric tube has a lower yield than sputum induction
• If the sputum is negative or cannot be obtained, the next diagnostic step is usually fiberoptic bronchoscopy
with Bronchoalveolar lavage, and in some instances trans bronchial lung biopsy.

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Smear Microscopy
• It is a direct identification of mycobacterial TB bacilli to make a diagnosis and monitor treatment responses.
• Two staining methods can be used to identify acid-fast bacilli: Ziel-Neelsen staining (ZN) or
fluorescent auramine staining (LED FM).
• Generally specific for mycobacteria, the sensitivity is relatively low (25-75% compared to culture); the level
of detection is approximately 10,000 bacilli per milliliter of secretions
• Light emitting diode (LED) microscopy has been used to save time required to perform a test and improve
the sensitivity by 10% over ZN technique

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Mycobacterial Culture
• Culture in liquid media is considered the current diagnostic gold standard and can detect as few as 10 to
1000 viable mycobacteria/mL.
• Is not used as a primary diagnostic test because of the cost, infrastructure requirements and long time
required to generate results
• Solid media
– Löwenstien-Jensen (LJ) media is culture media which with ease of preparation, low cost, and low contamination
rate. May take several weeks, 21-42 days, to detect growth and produce results.
• Liquid media
– Mycobacterial Growth Indicator Tube (MGIT) is highly enriched media for growing mycobacteria with added 10 %
more sensitivity than LJ media, and can produce positive results rapidly.
– Enable M. tuberculosis growth to be detected in 10 to 14 days.
– Have higher rate of contamination with other bacteria or with nonmycobacteria.

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Drug Susceptibility Testing
Phenotypic DST
• Culture-based phenotypic DST using liquid or solid media
• Phenotypic DST of M. tuberculosis can be determined either by observation of growth or metabolic inhibition in a
medium containing antituberculosis drug.
• is time-consuming (taking from weeks to months to generate results), primarily because of the slow growth rate of
M.tuberculosis
• Requires sophisticated laboratory infrastructure, qualified staff and strict quality control
Genotypic/ Molecular DST techniques
• Recommended
• Employs molecularthat
DNA PCR technologies DSTare
inspecifically
Ethiopia designed to detect/confirm genetic mutations associated with drug
resistance.
– Xpert MTB/RIF Assay
• Produce rapid results if DST is performed directly from sputum samples but may take weeks if done from culture
– Xpert MTB/RIF Ultra assays,
isolates.
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• The techniques
– Xpert MTB/XDR Assay as
may not detect a follow on
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which of additional
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is not designed; hence, are not
definitive test to exclude resistance in some patients.

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Rapid molecular tests
• Innovative rapid molecular tests to diagnose both pulmonary and extra pulmonary TB in all populations are
strongly recommended
• Nucleic acid amplification technology
– Xpert MTB/RIF assay
• Rapid diagnosis with high specificity and sensitivity (approaching that of liquid culture)
• Can simultaneously detect TB and rifampin resistance in <2 h and has minimal biosafety and
training requirements
• The WHO recommends its use worldwide as the first line diagnostic test in all adults and children
with signs or symptoms of active TB.
• In the diagnosis of pulmonary TB, it has an overall sensitivity of 85% reaching 98% among AFB-
positive cases and ~70% among AFB-negative specimens; its specificity is 98%

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Rapid molecular tests
• In the diagnosis of extra pulmonary TB
– Xpert MTB/RIF and Ultra should be the initial test applied to CSF from patients in whom TB meningitis is suspected
as well as a replacement test (preferable to conventional microscopy, culture, and histopathology) for selected
nonrespiratory specimens—those obtained by gastric lavage, fine needle aspiration, or pleural or other biopsies
– Sensitivity varies according to specimen type being the lowest in pleural fluid (50% with Xpert MTB/RIF and 71%
with Ultra) and the highest in synovial fluid (97%) and lymph node biopsy (100% with Ultra).
• HIV-associated TB
– The Xpert MTB/RIF assay is the preferred rapid diagnostic test because of its simplicity and increased sensitivity
(~60–70% among AFB-negative, culture positive cases and 97–98% among AFB-positive cases)
– A test based on the detection of mycobacterial lipoarabinomannan antigen in urine has emerged as a potentially
useful point-of-care test
– The WHO recommends this assay to assist in the diagnosis of TB in HIV-positive adults who have signs and
symptoms of TB and a CD4+ T-cell count of ≤100 cells/μL or in HIV-positive patients who are seriously ill regardless
of CD4+ T-cell count or with an unknown CD4+ count.

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Additional supportive methods
• Histo-Pathological Examination
– Pathology plays a complementary role in confirming the diagnosis of TB.
– Multiplication of tubercle bacilli in any site of the human body causes a specific type of inflammation, with
formation of characteristic granuloma that can be found on histo-pathological examination.
• Samples
- Fine needle aspiration from accessible mass like peripheral enlarged lymph nodes
- Aspiration of effusions from serous membranes
- Tissue biopsy from any body tissues such as serous membranes, skin, endometrium as
well as bronchial, pleural, peritoneal, colonic, gastric or liver tissue.

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RADIOGRAPHIC FEATURES
• Pulmonary tuberculosis nearly always causes detectable abnormalities on the chest radiograph(with HIV
infection, Findings nonspecificity
• In primary tuberculosis, resulting from recent infection, the process is generally seen as a middle or lower
lung zone opacity, often associated with ipsilateral hilar adenopathy
• Tuberculosis that develops at a time remote from the original infection(endogenous reactivation) usually involves the
upper lobes of one or both lungs. Cavitation is common in this form of tb
• The most frequent sites are the apical and posterior segments of the right upper lobe and the apical-posterior segment
of the left upper lobe .
• With more advanced HIV disease, the radiographic findings become more “atypical”: cavitation is uncommon, and
lower lung zone or diffuse opacities and intrathoracic adenopathy are frequent

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Diagnosis of M. tuberculosis
Infection
• Measure host immunological response to TB antigens.
• Tuberculin Skin Testing
– It probably measures the response to antigenic stimulation by T cells that reside in the skin rather than
the response of recirculating memory T cells.
– The test is of limited value in the diagnosis of active TB because of its relatively low sensitivity and
specificity and its inability to discriminate between TB infection and active disease.
– False-positive reactions may be caused by infections with nontuberculous mycobacteria and by BCG
vaccination

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TUBERCULIN SKIN TEST
False Negative
• The reaction to the test should be read by Errors in application or reading of the test result
inspecting and palpating the area where the Disease states, especially HIV infection, interfere with
tuberculin was injected. cell-mediated immune responses.
• The reaction size is determined by measuring the Malignancies(Hodgkin disease) suppressors of cell-
mediated immunity.
diameter of any induration with a ruler.
Corticosteroids and immunosuppressive drugs
• The amount of erythema should not be taken into (decrease tuberculin reactivity)
account; only the extent of induration is important. Advancing age Malnutrition
• Readings must be recorded accurately in mm. A Pleural tuberculosis and overwhelming tuberculosis
reading of 10 mm or more is considered indicative may cause diminished or absent tuberculin
of infection with M. tuberculosis responsiveness
A negative tuberculin test result cannot be used to exclude tuberculosis as a diagnostic

possibility

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Interferon-γ release assays
• Higher specificity and greater availability of resources, IGRAs have usually replaced the TST for TB infection
diagnosis in low-incidence, high-income settings.
• IGRAs require that blood be drawn and testing be performed by specially trained technicians in a laboratory
setting.
• However, in high-incidence TB and HIV settings and population groups, evidence about the performance
and usefulness of IGRAs is still limited, and cost considerations may currently limit wider use
Advantages over TST

Can be performed in one patient visit
Are more specific in the presence infection with
nontuberculous mycobacteria,
Are not subject to reader variability, and do not
stimulate waned immunity
Are not affected by BCG vaccination
Neither the TST nor IGRAs have value for the diagnosis of active tuberculosis in adults
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Interpretation of results
• IGRA
– Positive: TB infection is likely
– Negative: TB infection is unlikely, but cannot be
excluded
• TST
– Depending on patient characteristics, a TST can
be positive with an induration ≥ 5 mm, ≥ 10
mm, or ≥ 15 mm.
– For healthy individuals with no risk factors, an
induration < 15 mm is considered negative for
TB.

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TREATMENT
• The treatment regimen of choice for virtually all forms of drug susceptible TB in adults consists of a 2-
month initial (intensive) phase of isoniazid, rifampin, pyrazinamide, and ethambutol followed by a 4-month
continuation phase of isoniazid and rifampin
• This regimen can cure TB in >90% of patients
• Efforts have been made to develop effective shorter regimens to treat DS-TB.
In the intensive phase, tubercle bacilli are rapidly killed to prevent disease progression and
transmission, and the development of drug-resistance. In the continuation phase, dormant
bacilli are eliminated to effect cure and prevent relapse

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WHO recommendations
• 6-month regimen
– New patients with pulmonary TB should receive a regimen containing 6 months of rifampicin:
2HRZE/4HR (strong recommendation, high certainty of evidence). The recommendation also applies to
extra pulmonary TB – except TB of the central nervous system, bone or joint for which some expert
groups suggest longer therapy.
– Wherever feasible, the optimal dosing frequency for new patients with pulmonary TB is daily
throughout the course of therapy (strong recommendation, high certainty of evidence).
– In all patients with drug-susceptible pulmonary TB, the use of thrice-weekly dosing is not recommended
in both the intensive and continuation phases of therapy, and daily dosing remains the recommended
dosing frequency (conditional recommendation, very low certainty of evidence).

023
– The use of fixed-dose combination (FDC) tablets is recommended over separate drug formulations in
treatment of patients with drug-susceptible TB (conditional recommendation, low certainty of
evidence).
– In new pulmonary TB patients treated with the regimen containing rifampicin throughout treatment, if
a positive sputum smear is found at completion of the intensive phase, the extension of the intensive
phase is not recommended (strong recommendation, high certainty of evidence).
The presence of one or more sputum smear results that are still positive after 2 months usually
indicates the presence of dead bacilli. If the patient is not improving clinically and radiologically, and
drug-resistance or potential failure is suspected, rapid diagnostic testing

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WHO recommendations
• 4-month regimens
– People aged 12 years or older with drug-susceptible pulmonary TB may receive a 4-month regimen of
isoniazid, rifapentine, moxifloxacin and pyrazinamide (2HPMZ/2HPM) (conditional recommendation,
moderate certainty of evidence) – new recommendation.
Eight weeks of daily isoniazid (H), rifapentine (P), moxifloxacin (M) and pyrazinamide (Z) ,
followed by nine weeks of daily isoniazid, rifapentine, and moxifloxacin 2HPMZ/2HPM). The
dose of rifapentine used is 1200 mg daily

023
• A conditional recommendation, rather than a strong one.
• Resources
– Further research is needed on resource implications (e.g. patient and health system savings) and cost-
effectiveness of the 4-month regimen.
• Equity:
– Increased pill burden (due to the lack of fixed-dose combinations for the 4-month regimen
• Acceptability and feasibility:
– The pill burden and the potential need for fluoroquinolone DST in some settings with a high
background prevalence of fluoroquinolone resistance.

023
• Eligibility • children and adolescents aged under 12 years;
• Adults and children aged 12 years or older with a and
body weight of more than 40 kg and affected by • pregnant, breastfeeding and postpartum women
pulmonary DS-TB are eligible for this regimen,
including those who are also HIV-positive with a
CD4 count of more than 100 cells/mm3 and
patients with diabetes.
• Exceptions
• patients weighing less than 40 kg;
• patients with severe extra pulmonary TB (e.g.
tuberculous meningitis, disseminated TB,
osteoarticular
TB or abdominal TB);
• PLHIV with a CD4 count of less than 100
cells/mm3;

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WHO recommendations
• 4-month regimens
• In children and adolescents between 3 months and 16 years of age with non-severe TB (without suspicion or
evidence of MDR/RR-TB), a 4-month treatment regimen (2HRZ(E)/2HR) should be used (strong
recommendation, moderate certainty of evidence) – new recommendation.

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WHO recommendations
• Use of adjuvant steroids
– In patients with tuberculous meningitis, an initial adjuvant corticosteroid therapy with dexamethasone
or prednisolone tapered over 6–8 weeks should be used (strong recommendation, moderate certainty of
evidence).
– In patients with tuberculous pericarditis, an initial adjuvant corticosteroid therapy may be used
(conditional recommendation, very low certainty of evidence)
Corticosteroids for patients with constrictive pericarditis and patients at high risk of constrictive tuberculous pericarditis(large
effusions, high levels of inflammatory cells in the pericardial fluid. For adults, prednisone 60 mg/day (the equivalent dose)
given for four weeks, followed by 30 mg/day for four weeks, 15 mg/day for two weeks, and 5 mg/day for one week
To prevent isoniazid-related neuropathy, pyridoxine (10–25 mg/d) should be added to the regimen
given to persons at high risk of vitamin B6 deficiency (e.g., alcoholics; malnourished persons;
pregnant and lactating women; and patients with conditions such as chronic renal failure, diabetes,
and HIV infection).

023
Treatment of DS-TB in PLHIV
• All three regimens can be initiated in PLHIV, the 6-month regimen is a preferred option in those with a CD4
count of less than 100 cells/mm3.
• The 4-month regimen with rifapentine and moxifloxacin has been shown to perform well in patients who
are also HIV-positive. The evidence is only for a CD4 count of above 100 cells/mm. For PLHIV with a CD4
count above that threshold, both regimens can be used.

023
Treatment of DS-TB in PLHIV
• The interactions of rifampicin with antiretroviral therapy (ART) are of concern in HIV-associated TB.
• Standard, rifampicin containing anti-TB treatment was recommended in combination with efavirenz-based
ART.Drug combinations of rifampicin with nevirapine and protease inhibitors is contraindicated .
• In patients receiving these drugs, rifabutin (where available) was suggested as a suitable substitute for
rifampicin
• Rifampicin is known to lower plasma concentrations of the HIV medication dolutegravir. WHO guidelines
recommend adjusting the dose by offering 50 mg of dolutegravir twice per day (instead of a single daily dose
of 50 mg)

023
Treatment of extrapulmonary TB
• Adults with extrapulmonary TB are eligible for the 6-month 2HRZE/4HR regimen, except for those
with TB of the central nervous system, bone or joint, for which some expert groups suggest longer
therapy (i.e. 9–12 months).
• The 4-month 2HPMZ/2HPM regimen was not studied in extra pulmonary TB and thus cannot be
recommended at this time.
• Furthermore, extra pulmonary TB evaluation of its outcomes can be more challenging because of the
absence of bacteriological evidence in most patients and the need for cross-sectional imaging; hence, there
is little quality evidence on this type of TB

023
DS-TB in special situations
• Diabetes
– Diabetes has a negative effect on the pharmacology of some anti-TB drugs (e.g. rifampicin), with
higher risk of development of drug-resistance
– A higher proportion and sometimes a greater severity of adverse events has been described in TB
patients with diabetes (e.g. peripheral neuropathy due to isoniazid and ocular neuropathy due to
ethambutol)
• Pregnancy
– Pregnant women are usually treated with the standard 6-month 2HRZE/4HR regimen.
The preferred initial treatment regimen is INH, rifampin (RIF), and ethambutol (EMB) daily for 2 months,
followed by INH and RIF daily, or twice weekly for 7 months (for a total of 9 months of treatment). CDC
– Evidence on the use of the 4-month 2HPMZ/2HPM regimen during pregnancy is lacking

023
• Chronic renal failure
– Dose adjustments in adults with creatinine clearance below 30 mL/minute
– Pyrazinamide: 25–35 mg/kg per dose, three times per week after dialysis.
– Ethambutol: 15–25 mg/kg per dose, three times per week after dialysis.
– Rifapentine and moxifloxacin do not require renal dose adjustment

023
• Chronic liver disease may
• Isoniazid, rifampicin or pyrazinamide may cause be restarted with ethambutol;
hepatotoxicity. – after 3–7 days, after checking
• If aminotransferase are five or more times higher aminotransferases, isoniazid may be
than the upper limit of normal (with or without reintroduced, with subsequent
symptoms), or three or more times higher in the rechecking of liver enzymes; and
presence of symptoms or jaundice (i.e. bilirubin >3 – if symptoms recur or aminotransferases
mg/dL-1), the treatment should immediately be increase again, the last drug added should be
withdrawn. stopped
• The drug reintroduction should be performed one and replaced with another from the list of the
drug at a time, starting with the drug considered to recommended drugs
be the least hepatotoxic
– when aminotransferases return to less than
two times the upper limit of normal, rifampicin

023
MONITORING TREATMENT RESPONSE
AND DRUG TOXICITY
• Bacteriologic evaluation with liquid-culture systems (or through smear microscopy) is essential in
monitoring the response to TB treatment.
• In addition, the patient’s weight should be monitored regularly and the drug dosage adjusted with any
significant weight change
• Patients with pulmonary disease should have their sputum examined monthly until cultures become
negative to allow early detection of treatment failure.
• Molecular tests such as Xpert MTB/RIF are not used to monitor response to treatment

023
• Clinical examination
– Persistent fever, weight loss or recurrence of any of the classic symptoms of TB should prompt
investigation for possible treatment failure, undetected resistance to one or more drugs in the
current treatment regimen or untreated comorbidities.
– The recurrence of TB symptoms after sputum conversion may be the first sign of treatment failure
• Chest radiography
• No formal recommendations
• It is prudent to undertake CXR at baseline, at the end of the second month of treatment and at the end of
treatment, to document progress and to use for comparison if the patient’s clinical condition changes at any
time after the achievement of treatment success
• A chest radiograph at the end of treatment is also useful to optimally manage TB pulmonary sequelae after
treatment

023
023
Drug toxicity
• The most common adverse reaction of significance is hepatitis.
• All adult patients should undergo baseline assessment of liver function (e.g., measurement of serum levels
of hepatic aminotransferases and bilirubin). Routine biochemical monitoring is not recommended,
• Older patients, those with concomitant diseases, those with a history of hepatic disease (especially
hepatitis C), and those using alcohol daily should be monitored especially closely (i.e., monthly), with
repeated measurements of aminotransferases, during the initial phase of treatment.

023
023
• Individuals who develop autoimmune thrombocytopenia secondary to rifampin therapy should not receive
the drug thereafter.
• Similarly, the occurrence of optic neuritis with ethambutol is an indication for permanent discontinuation of
this drug.
• Other common manifestations of drug intolerance, such as pruritus and gastrointestinal upset, can
generally be managed without the interruption of therapy.

023
TREATMENT FAILURE
• Treatment failure should be suspected when a patient’s cultures (or sputum smears, when cultures are not
available) remain positive after 3 months of treatment.
• The treatment approach should start with molecular testing for—at the least— resistance to rifampin and
isoniazid. Because results are expected to become available within a few days, changes in the regimen can
be postponed until that time.
• However, if the patient’s clinical condition is deteriorating rapidly, an earlier change in regimen may be
indicated.
• A cardinal rule is always to add more than one drug, preferably two or three, at a time to a failing regimen;
in practice, starting an empirical regimen for MDR-TB is warranted. The patient may continue to take
isoniazid and rifampin along with these new agents pending the results of susceptibility tests.

023
DRUG-RESISTANT TB
• Drug resistant TB continues to be a global public health threat with 3.4% of new TB cases and 18% of
previously treated cases having multidrug resistant TB or rifampicin-resistant TB (MDR/RR-TB).
• According to 2020 Global TB Report, Ethiopia is among the 30 High TB and TB/HIV burden countries, with
new TB incidence
annual estimated previously
of 140/100,000 populations and death rate of 19 per 100,000 populations.
treated TB
RR-TB 1.1% 7.5%
MDR 1.03% 6.52%

INH 6.16% total
XDR Not detected in
this survey.
Pre-XDR 2.7%)
The third drug resistance surveys (DRS) (2019)

DRUG-RESISTANT TB
Rifampicin-resistant TB (RR-TB): resistant to rifampicin. may be susceptible or resistant to isoniazid (i.e. MDR-TB), or
resistant to other first-line or second-line TB medicines.
Pre-XDR-TB: fulfil the definition of MDR/RR-TB and are also resistant to any fluoroquinolone.
XDR-TB: fulfil the definition of MDR/RR-TB and that are also resistant to any fluoroquinolone and at least one additional
Group A drug
Rifampicin-susceptible, isoniazid-resistant TB (Hr-TB): TB caused by M. tuberculosis strains resistant to isoniazid and

susceptible to rifampicin

023
023
DRUG-RESISTANT TB

023
Current WHO recommendations on
drug-resistant TB

023
023
Shorter MDR-TB Regimen

023
Longer MDR-TB Regimen
• Suspected additional resistance (fluoroquinolones)
• Severe pulmonary or extra pulmonary disease
• Previously treated with second-line drugs

023
Longer regimens

023
023
Duration of longer
MDR/RR-TB regimens

023
Extra pulmonary forms of DR-TB
• The national recommendations on longer MDR-TB regimens apply also to patients with
extra pulmonary disease. Adjustments may be required depending upon the specific location of
disease
MDR/RR-TB meningitis
Levofloxacin and
moxifloxacin penetrate well
Ethionamide/
prothionamide,
cycloserine/terizidone,
linezolid and imipenem-
cilastatin.
High-dose isoniazid and
pyrazinamide can also
reach therapeutic levels in
the cerebrospinal fluid

023
MDR/RR-TB Regimens in Ethiopia

023
023
023
87
Adjuncts to MDR-TB treatment
• Surgery in treatment of M/XDR-TB
• Use of corticosteroids
– Same as non-MDR-TB

023
Pregnancy
• Pregnant women should receive counseling

concerning the risk because of the known and
unknown risks of second-line antituberculosis drugs
• Individualized longer regimen be is recommended
• Amikacin, streptomycin, prothionamide and
ethionamide are usually contraindicated during
pregnancy

023
PREVENTION
• BCG VACCINATION
– BCG vaccine is recommended for routine use at birth in countries with high TB prevalence
– Contraindicated in
• HIV-infected adults and children
• Infants whose HIV status is unknown but who have signs and symptoms consistent with HIV
infection or who are born to HIV-infected mothers

023
TB PREVENTIVE TREATMENT (TPT)
• Goal
– Prevent reactivation to active TB
• Indication
– Positive IGRA or TST
– Active TB excluded
TPT Regimens

023
REFERENCES
• MURRAY & NADEL’S TEXTBOOK OF RESPIRATORY MEDICINE, SIXTH

EDITION
• HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 21ST EDITION
• THE NEW ENGLAND JOURNAL OF MEDICINE
• WHO CONSOLIDATED GUIDELINES ON TUBERCULOSIS, 2022
• GUIDELINES FOR CLINICAL AND PROGRAMMATIC MANAGEMENT OF TB,
TB/HIV, DR-TB AND LEPROSY IN ETHIOPIA,7th EDITION
• UP-TO-DATE 2022
03/22/2023 93
THANK YOU!!!
03/22/2023 94

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Bahir Dar University

College of Medicine and Health

Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 1

Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 2

Mycobacterium tuberculosis Mycobacterium bovis Mycobacterium africanum

Mode of transmission: spread via

Disease: all forms of tuberculosis

Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 3

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• One-fourth of the world's population has latent TB.

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• M. tuberculosis is transmitted through the air, and – The use of chemotherapy

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• Innate Immune Cells

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Killing of bacteria by reactive oxygen

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A lipoglycan that An enzyme that

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Dendritic cells present mycobacterial antigens

IFN-γ acts on macrophages to enable bacterial killing

Granulomatous inflammation and tissue destruction

Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 15

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Inhalation of aerosol droplets

Primary Disease Post primary (Adult-Type) Disease

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Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 21

• Pleural effusion represents a hypersensitivity response to mycobacterial antigens.

Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 22

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Wednesday, March 22, 2 E-mail: cmhs@bdu.edu.et Website: www.bdu.edu.et/cmhs 44

A negative tuberculin test result cannot be used to exclude tuberculosis as a diagnostic

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Advantages over TST

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