Dr.

NCHINDO PIUS – MARY

INTERNIST MD(Hons), DES.

11/2/2023 1
• Define tuberculosis (TB)

• Cite the clinical signs of pulmonary TB

• List the radiological elemental lesions of pulmonary TB

• Explain the diagnostic procedure during extra pulmonary TB

• State the principles of management of pulmonary TB

11/2/2023 2
• Generalities
• Signs
• Diagnosis
• Treatment
• Conclusion

11/2/2023 3
Definition

• Tuberculosis is a chronic transmissible infectious disease caused

by a mycobacterium of the tuberculosis complex, including:

• Mycobacterium tuberculosis hominis mainly, also called Koch's

bacillus or BK, and more rarely:

• Mycobacterium bovis

• Mycobacterium africanum

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Interest – Epidemiology
• WHO 2014: 9.6 million TB cases worldwide,
• 5.4 million men, 3.2 million women and 1 million children
• 28% lived in sub-Saharan Africa
• 1.5 million TB deaths
In Cameroon
• 26368 cases in 2014
• incidence of about 123 cases per 100,000 inhabitants

11/2/2023 5
Diagnostic interest

• Make every effort to isolate the tuberculosis bacillus

• Usefulness of new diagnostic tests based on gene amplification

• Always look for MDR-TB once suspected

11/2/2023 6
Therapeutic Interest

• Availability of effective anti-TB drugs

• Relatively long course of treatment

• Therapeutic regimen for MDR-TB is available

11/2/2023 7
Prognosis - Interest

• Pulmonary TB often resolves with sequelae

• Acute life-threatening prognosis in disseminated forms and in

cases of massive hemoptysis

• Overall mortality still relatively high of up to 15% in some

centers

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Three stages:

• Airborne transmission from a person with bacilliferous

tuberculosis

• "Aerosol" production of infectious droplets during coughing

• Alveolar deposition of some bacilli (primary focus)

11/2/2023 9
Three stages:

• Primary tuberculosis infection (PTI): most often asymptomatic

responsible for a "latent" tuberculosis infection (LTBI)

• At the level of the "primary focus": phagocytosis of bacilli by

macrophages (with intra-macrophage multiplication)

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• Drainage of bacilli to satellite hilar lymph node

• Primary focus + satellite lymphadenopathy = primary complex,

which may remain visible on chest x-ray several years after the
PTI

• Possible dissemination throughout the body (= secondary foci)

• Development of a cell-mediated immune response in the

following weeks, usually limiting the multiplication of BK

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• Responsible at the level of the primary and secondary foci:

• Influx of epithelioid – like monocytic cells with at times a so-

called "caseous" necrosis in its center:

• Gigantocellular granulomas with caseous necrosis, containing

some quiescent bacilli

• Granuloma = mass of chronically inflamed tissue with

granulations

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Tuberculosis disease (TB)

• At any time during PTBI or after LTBI, multiplication of quiescent

bacilli = tuberculosis-disease: the patient becomes symptomatic
and chest imaging is abnormal

• 5% of patients develop TB within 2 years of PTI

• Approximately 5% of additional patients develop TB beyond 2

years after PTI

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• Three stages

• Primary complex

• Secondary foci

• Tuberculosis disease

11/2/2023 14
Risk Factors of TB
• Extreme Ages,
• Malnutrition,
• Alcoholism/Smoking,
• Low socioeconomic status
• Overcrowded housing/area
• Drug Abuse,
• Diabetes

11/2/2023 15
Risk factors TB:
• Renal failure,

• HIV/AIDS

• Solid tumors and hematologic malignancies,

• Immunosuppressive therapies (long-term corticosteroid therapy,

antimitotics, anti-TNFα),

• gastrectomy

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• No specific symptoms

• Evolution over several weeks to several months, with a generally

insidious onset

• General signs: deterioration of patients general state: asthenia,

anorexia, weight loss, fever with predominance of the night, night
sweats

• Functional signs:

• Cough of >2 weeks duration with or without sputum

• Hemoptysis, Dyspnea, usually late-onset

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Physical signs:

• usually absent

• Possible pleural syndrome (tuberculous pleural effusion) or

alveolar condensation syndrome (acute tuberculous pneumonia)

• Sometimes localized wheezing (bronchial stenosis)

11/2/2023 20
Paraclinical signs: Chest X-ray

• 3 types of elemental radiological lesions

• Single or multiple confluent nodules

• Infiltrates

• Excavated lesion (cavern): from irregular and dense condensation

with early cavitation

• These 3 types of lesions could be found in the same patient

• Lesions usually located in the upper and posterior segments where the
partial pressure of oxygen is highest
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• Right
superior
lobe
infiltrates

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Nodules, infiltrates, and excavation of the right superior lobe

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Isolation of causative agent

• Examination of sputum – ideally three consecutive days

• Gastric washings – very early in the morning before the patient

wakes, as the acid resistant bacterial will still be found inside
the stomach

• Bronchial aspiration/BAL

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Bacteriology

• 1st step:
• Ziehl Nielsen/Auramine staining

• the negativity of direct examination does not rule out diagnosis

• 2nd step:
• culture on enriched media, either solid (Löwenstein Jensen medium, 3 to 4
weeks) or on a liquid medium

11/2/2023 26
Bacteriology

• 3rd Step: M. tuberculosis Identification

• Biochemical and culture features

• Genomic Identification

• Realizable only with AFB+ samples. It permits in 24H the

differentiation between M. tuberculosis ? M. avium ? or another
mycobacteria

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Bacteriology

• 4th step: antibiograme - susceptibility testing (mandatory)

• Consists of culturing bacilli isolated in culture on media

containing different concentrations of antibiotics

• Genetic susceptibility tests

11/2/2023 29
Histo-pathology

• In case biopsy is done, it should be sent for

• Ziehl Nelson coloration and

• Histopathology – epithelioid gigantocellular granuloma with

caseous necrosis: pathognomonic

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Evolution – Early complications

• Pleurisy with or without effusion.

• Spontaneous pneumothorax - rupture of a tuberculous lesion into the

.pleural space.

• Tuberculous empyema - complicating a spontaneous pneumothorax.

• Tuberculous laryngitis - advanced pulmonary disease complication.

• Tuberculous enteritis - swallowing of heavily infected sputum.

• Ischio-rectal abscess and fistula in ano

• Dissemination of tuberculosis via the blood stream.

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Evolution - Late complications:

• Reactivation TB in the lungs (relapse)

• Development of granulomatous or fibrosing mediastinitis.

• Bronchiectasis - hemoptysis due to systemic hypervascularization

• Colonization and infection with atypical mycobacteria in old

tuberculous cavities.

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Evolution - Chronic complications

• Secondary infection of a healed cavity with fungi such as

Aspergillus fumigatus may lead to the development of a
mycetoma or Aspergilloma – erosion into a pulmonary artery is
possible resulting in hemoptysis

• Recurrent pneumonia in an area of destroyed lung tissue.

• Development of “scar cancer”.

• Hemoptysis.
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• TB reactivation = relapse.

• Bronchiectasis

• Superinfection with atypical mycobacteria.

• Aspergilloma or mycetoma in an old tuberculous cavity.

• Broncholithiasis.

• Scar carcinoma

• Secondary infection with pyogenic bacteria.

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• According to the site:
• Pulmonary TB

• Extra-pulmonary tuberculosis

• According to bacteriology:
• bacteriological or non-bacteriologically proven TB

• Pulmonary TB with positive or negative microscopy

• Depending on extra pulmonary location:

• Scrofula (lymph node) - Pleural - Osseous – neuromeningeal …

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Miliary Tuberculosis

• Hematogenous dissemination of bacilli to both lung field and

possible other sites, during either during the initial bacillemic
phase or by vascular erosion from a site of caseous necrosis

• Clinically - deterioration of general condition, often febrile, in a

patient most often dyspneic

• Chest X-ray: bilateral and symmetrical diffuse micronodular

interstitial lung disease ("millet grains") with at times
macronodular lesions in advanced forms
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Acute tuberculous pneumonia

• Acute form related to massive seeding of BK into healthy

parenchyma from an excavated lesion, associated with an
intense inflammatory reaction

• Radiological picture comparable to that of acute community-

acquired pneumonitis with sometimes small excavations within
the pneumonitis site

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Tuberculous pleural effusion

• Secondary to break-in of sub-pleural infra radiologic parenchymal focus

• Effusion usually unilateral

• Exudative and lymphocytic pleurisy

• Clinical and radiological manifestations are non specific appearance

• Assessment:

• Bacteriology: AFB + in <10% of cases, culture of pleural fluid or pleural

biopsy positive in about 30% of cases

• Anatomical pathology of pleural biopsies positive in more than 90% of

cases++

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Extrapulmonary TB - Less common than pulmonary forms

• Virtually all organs can be affected, particularly:

• Lymph node tuberculosis (50% of extra-pulmonary locations)

mainly cervical and mediastinal (HIV+ subject, or not HIV but

from sub-Saharan Africa or Asia)

• Gneito urinary TB, neuromeningeal TB, peritoneal TB

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Osteoarticular tuberculosis
• Vertebral localization is most common = tuberculous
spondylodiscitis or Pott disease
• Thoraco-lombar pains, mechanical or mxed, at times associated
with general signs
• Clinicallly – spinal and radicular syndrome, and neurologic
deficit
• Biology – urinary TB Lamp
• Confirmation – bone biopsy for AFB and histopathology
11/2/2023 43
Osteoarticular - TB – X ray

• Destruction of at least 30%

needed, 2 to 6 weeks to achieve
this

• Erosions and destruction of the

cortex of the bone

• Mirror image – erosion at anterior

edge of the plateau and bottom of
two apposed vertebrae

11/2/2023 44
• Reduced intervertebral space
• Swollen soft tissue
• Sub chondral geodes
• Osteolysis
• Vertebral compaction
CT same but early images,
demineralization

11/2/2023 45
• Latent tuberculosis infection is by definition an asymptomatic
Primary Tuberculosis Infection (PTI)

• Sometimes PTI can be "patent" and is accompanied by:

• Landouzy's typhobacillosis, cough and dyspnea

• Alteration of general condition, erythema nodosum, phlyctenular

keratoconjunctivitis, cervical lymphadenopathy,

• Chest X-ray may show mediastinal lymphadenopathy with or

without parenchymal inoculation chancre.
11/2/2023 46
• Suspect TB in case of the following situations:

• Functional signs evolving for several weeks to several months

• An evocative context: notion of contact with a TB patient, low

socio-economic profile, immigration, poor housing conditions,
no prior BCG vaccination, history of TB, immunosuppression
and HIV infection...

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• Physical signs usually depends on the affected organ
• Infiltrates, nodules or caverns in the upper lobes and posterior
segments - chest radiography
• Diagnosis of TB = evidence of BK
• In case of military TB, there is need for additional respiratory
samples, blood cultures on isolator medium (specific medium for
mycobacteria), urocultures (three consecutive days) and possibly
myeloculture in case of leuconeutropenia

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• Other samples will depend on the infectious focus.

• With extra-pulmonary tuberculosis:

• Lymph node TB: Excision lymph node biopsy (do not puncture
- risk of fistulization to the skin)

• Genitourinary tuberculosis: urine samples taken 2 days in a

row

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• For TB meningitis or meningoencephalitis, CSF analysis
shows:
• Cloudy fluid on macroscopy

• Lymphocytic pleocytosis on cytology

• Hypoglucorachia, hyperproteinorachia and hypochlororachia

on biochemistry

• AFB or molecular technics are frequently negative

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• Tuberculosis is a great deceptive disease, as it can simulate

multiple pulmonary pathologies or can occur at the same time

as other pulmonary pathologies.

• Other infections, sarcoidosis, cancer, connective tissue disease

and other systemic diseases.

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Aim

• Sterilize the focus of infection

• Prevent and treat complications

11/2/2023 52
• Anti-tuberculosis drugs: 1st line/2nd line

• Adjuvant drugs

Indications

• Sensitive TB : Quadruple therapy

• MR/XDR TB: Dedicated protocol

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• Early Detection and Treatment

• Addressing Risk Factors

• BCG Vaccination

11/2/2023 54
• For AFB+ patients

• Anti-TB drugs

• Implementation

• Associated measures

• Multidrug-resistant TB – particular protocols

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• Three populations of AFB to be eliminated

• Extracellular bacilli (95% of bacilli): responsible for

contagiousness and symptomatology. Active TB drugs:
isoniazid, rifampicin and streptomycin

• Very slow-multiplying intracellular bacilli: -inside macrophages.

Active TB drugs: pyrazinamide and rifampicin

• Extracellular bacilli within the caseus granuloma *Responsible

for the risk of future relapse * Active TB drug: Rifampicin

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5 Major:

• Isoniazid

• Rifampicin

• Pyrazinamide

• Ethambutol

• Streptomycin

11/2/2023 57
• Classic abbreviation INH

• available orally (50 and 150 mg tablets) and injectable form

• Dose: 3 to 5 mg/kg/24h (depends on whether slow or fast

acetylor, possibility of initial dosages to have kinetics)

• Active against extracellular forms of AFB

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Side effects:

• digestive disorders (nausea)

• hepatitis (from simple transaminase elevation to severe drug-induced

hepatitis that may require discontinuation of treatment: monitoring
liver enzymes

• Sensory-motor polyneuropathy in case of vitamin B6 deficiency

• Rarely neuropsychiatric disorders, skin reactions or algodystrophies

(shoulder-hand syndrome)

• monitoring = liver enzymes

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Classic abbreviation: RMP
• available orally (300 mg capsule, syrup) and parenteral form
• dose: 10 mg/kg/day, not to exceed 600 mg/day
• Strong enzyme inducer
• Beware of drug interactions, especially with oral anticoagulants
(INR monitoring), COC pills (change contraceptive methods),
antiretrovirals (protease inhibitors), corticosteroids, digitalis,
and may increase the hepatotoxicity of INH and PZA

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Side effects:

• Immunoallergic phenomena (toxiderma, thrombocytopenia,

haemolysis, acute renal failure, cholestatic hepatitis)

• Digestive disorders (nausea),

• Caution: orange coloring of tears, semen, urine, etc. (notify the

patient)

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• Classic abbreviation EMB available orally and injectable

• Dose: 20 mg/kg/day (15 mg/kg/day in case of moderate renal

impairment)

• Side effects: retrobulbar optic neuritis, especially in case of high

dosage, chronic alcohol or renal failure, Requires an ophthalmological
consultation before starting treatment and then every month for the
duration of treatment (color vision, visual acuity, visual field).

• Acute gout attack

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• Classic abbreviation: PZA

• available only orally (500 mg tablet)

• dose 25 to 30 mg/kg/day

• Precautions in case of hepatocellular and renal failure

• side effects:

• Hepatic cytolysis (later than INH, transaminase monitoring)

• Hyperuricemia (usually asymptomatic, more of a marker of

good drug intake)

• Toxiderma - Digestive disorders...

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• Intramuscular administration

• Dose: 15 mg/kg/day (not to exceed 1 g/day)

• The cumulative dose should not exceed 120 g

• rather used as a 2nd line treatment

• Renal and auditory toxicity

11/2/2023 64
Fluoroquinolones: -
• bactericidal on intra- and extracellular bacilli, prefer
moxifloxacin (Izilox®)
• avoid treating a lung infection with fluoroquinolones if
tuberculosis is suspected (risk of negative samples)
• to be used in case of documented resistant tuberculosis
• Kanamycin: aminoglycosides, IM, IV
• Other anti-tuberculosis drugs: PAS: para-amino salicylic acid,
ethionamide, cycloserine, thiacetazone, clofazimine
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• Rifater®: in the same tablet 50 mg INH, 120 mg RMP and 300
mg PZA

• Rifinah®: in the same tablet 150 mg INH and 300 mg RMP

• Fixed generic combinations: RHEZ, RHE, RH

11/2/2023 66
• Long doubling time (20H): single daily dose
• Bacilli persistent in foci of necrosis: prolonged treatment
• Risk of emergence of resistant mutants (in the initial inoculum of
a patient with "susceptible" tuberculosis, presence of bacilli
naturally resistant to ATBs Especially in the case of
"monotherapy"): poly-antibiotic therapy
• Need for action on the 3 BK populations: Combination
antibiotic therapy

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• New case: patients who have never been treated before for
more than a month.

• Retreatment – received treatment before for at least a month

• Relapse: disease re-occurs after a first complete successful

treatment

• Failure: positive microscopy after at least 5 months of effective

treatment

• Resumption of treatment: return after treatment discontinuation

of more than 2 consecutive months
11/2/2023 68
• Standardized Treatment (PNLT)

• Classic Regimen New cases: quadruple therapy, with

• INH+ RMP+EMB+PZA for 2 months followed by INH+RMP

dual therapy for 4 months

• 2RHEZ/4RH

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• Alternative regimen (less used, may be proposed in case of

contraindication to PZA like pregnancy):

• triple therapy with INH+RMP+ EMB for 2 to 3 months

followed by dual therapy with INH+RMP for 6 months

• Case of retreatment : 2RHEZS/1RHEZ/5RHE

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• DOT strategy recommended but sometimes difficult to
implement in some countries

• Outpatient treatment or hospitalization during the intensive

phase

• Bacteriological control for AFB+ forms - M2, M5, M6 (or M8)

• Clinical and imaging control for extrapulmonary forms and AFB-

- forms

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• Take anti-tuberculosis drugs once daily on an empty stomach at a
distance from meals (about 1 hour before and 2 hours after) (better
absorption of RMP)

• Emphasize the importance of good adherence and the possibility of

therapeutic adaptation in the event of significant adverse reactions

• Warn the patient of the orange-red discoloration of the various

secretions (risk of contact lens staining, orange urine...)

• Ineffectiveness of the estrogen-progestin pill and therefore the need

for another effective method of contraception

11/2/2023 72
• The following conditions require association with corticosteroids

• Miliary TB

• TB meningitis

• TB pericarditis

• Dose: 1mg/kg/day in the morning for 28 days – with adjuvant

therapy

11/2/2023 73
• Isolation of patient during the contagious phase

• Duration of isolation not fixed +++

• it is generally considered that after 15 days of full treatment

isolation can be lifted

• In clinical practice, when a patient is contagious at the time of

diagnosis of tuberculosis, he or she has generally already been
contagious for 3 months

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• Importance of isolation is to be emphasized, especially if
contact with children, elderly or immune depressed patients is
eminent

• Mandatory notification and reporting of all cases

• The case source should always be investigated: screen contacts

with a CXR

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• Man is responsible, by either inappropriate untimely

monotherapies, stock shortages, or incompliance to treatment

• MDR (multidrug-resistant) tuberculosis: strain resistant absolutely

to RMP, with or without a concomitant INH resistance

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• High prevalence in Southeast Asia, sub-Saharan Africa and
Eastern Europe

• XDR (extensively drug-resistant) tuberculosis:

• strain resistant to INH, RMP, all fluoroquinolones and at least

one of the 3 second-line antibiotics: Capreomycin, Amikacin,
Kanamycin

• Very high mortality ++

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Screening for LTBI

• Objective: To diagnose LTBI patients at high risk of progression

to tuberculosis disease

• Who is concerned by the search for LTBI?

• During the investigation of a case,

• contact subjects: any person (adults, children) who have had

repeated and close contact (same room or who have stayed, in
the same space defined by the distance of a conversation) with
the patient
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The risk of infection after LTBI depends on:

• The contagiousness of the index case: high contagiousness =

positive direct examination and cavities on chest x-ray.

• Contagious period = three months before diagnosis and 15

days after starting treatment

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• The type of contact: degree of proximity, confinement and
duration of close contact: people sharing the same closed space
for several hours a day (family, class, office, cell, etc.); regular
contact: people who regularly share the same closed place
(home, canteen, workshop, sports club, etc.); Casual contact:
people who occasionally share the same closed place (dinner,
etc.).

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• The risk of developing tuberculosis disease after infection then
depends on the specific characteristics of the people exposed.

• Systematic screening only concerns people in close or regular

contact

• People in occasional contact are only screened if they are

fragile, immunocompromised, etc.

• At the time of diagnosis of HIV infection

• Health professionals

• Epidemiological survey of LTBI prevalence

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• Intradermal tuberculin reaction (IDR) also known as tuberculin
skin reaction (RCT)

• Evidence of a skin reaction after local injection of mycobacterial

antigens, evidence of the acquisition of cell-mediated immunity

• Non-specific to M. tuberculosis, also reacts with M. bovis

antigens (i.e. with BCG) and with antigens of certain atypical
mycobacteria

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• May be negative despite LTBI or TB (= tuberculin anergy) in
particular during certain viral infections, malignat haemopathy,
solid tumor, long-term corticosteroid therapy, severe
immunosuppression (and therefore during an HIV infection),
immunosuppressive treatment, or anticancer chemotherapy....

11/2/2023 83
Technic

• Inject 0.1ml tuberculin(Tubertest®) intradermally

• Reading the reaction: 72 hours later, assess the induration

around the puncture site (ruler graduated in mm)

• Do not take into account the dimensions of the erythematous

reaction

• At 3 month intervals (=tuberculin shift)

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Interpretation of tuberculin IDR:

• Based on history (tuberculosis, PIT, immunosuppression, serious

progressive pathology, etc.) and vaccination status (BCG and

results of previous IDRs)

• Difficult to interpret within 10 years of BCG vaccination

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• Negative IDR = induration diameter < 5 mm

• Positive IDR = ≥ 5 mm diameter

• Suspected LTBI when the diameter is greater than 10 mm in the

absence of previous BCG vaccination or when the diameter of

induration increased by more than 10 mm between two IDRs

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• Apart from the IDR, in vitro interferon detection can also b used

• It looks for evidence of interferon production (IFNƔ) by a patient's

lymphocytes in the presence of specific M. tuberculosis antigens

• Practical advantages:

• Easy to perform (blood test) not operator dependent.

• Interpretation is fast, single visit, fewer false positives with BCG

• Disadvantage – it is expensive

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Interferon Assays

• 2 main tests: QuantiFERON® and T-SPOT. ® TB.

• 4 main indications:

• patients > 15 years of age about to be initiated anti-TNF treatment,

• for health professionals at the time of recruitment and for those working in

a high-risk department,

• to help diagnose extrapulmonary TB

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• Indications for interferon assays: when TB is suspected in any of

the following:

• Non- BCG vaccinated children under 5 years of age,

• Unvaccinated individuals who have recently become tuberculin

positive

• Immunosuppression (eg HIV infection)

• INH alone for 6 or 9 months OR INH + RMP for 3 months

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Objectives – reduce the risk of developing severe forms of TB

• Limit the risk of TB meningitis - 90% protection

• Limit the risk of military tuberculosis - 70% protection

• Limit the risk of pulmonary TB by 50%

NB: The immunity conferred by BCG vaccination wanes in 10

to 15 years

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• Indications: Given at birth in countries of high prevalence like
in Cameroon

• Complications are exceptional:

• Local inflammatory reaction – apply INH-soaked compresses

• Inflammatory axillary adenopathy

• Disseminated BCGitis

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• Contraindications to BCG vaccination:

• HIV infection: children with HIV/AIDS or born to an HIV+

mother until proven not to be infected

• Any other immune suppression: congenital or acquired immune

deficiencies

• Immunosuppressive therapies..

• Extensive progressive dermatoses

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• Frequent

• Major public health problem

• Diagnosis sometimes difficult

• Effective and well-tolerated treatment exist

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