TUBERCULOSIS (TB)

UNIGOM/2022
 At the end of this presentation the participant
will have;
• Introduction on TB
• Clinical Presentation
• Differential Diagnosis
• Workup
• Management
• References for further readings:
UptoDate and RBC Guidelines on TB

Note: the presentation will only cover pulmonary TB

Introduction
• Tuberculosis (TB), a multisystemic disease with myriad
presentations and manifestations, is the most common cause
of infectious disease–related mortality worldwide. Although
TB rates are decreasing worldwide, the disease is becoming
more common in many parts of the world and in Rwanda. In
addition, the prevalence of drug-resistant TB is increasing
worldwide.

• In Rda(10%) patients died during MDR/RR-TB treatment.

Mortality was higher among HIV-coinfected compared with
HIV-negative TB patients (13.3% versus 7.6%) “pubmed
may-2021”
Definition
• Pulmonary Tuberculosis (TB) is a bacterial (Mycobacterium tuberculosis) infection
spread through inhaling tiny droplets from the coughs or sneezes of an infected
person.(NHS)
• It mainly affects the lungs, but it can affect any part of the body, including the
abdomen, glands, bones and brain.
Signs and symptoms
Classic clinical features associated with active pulmonary TB(elderly
individuals with TB may not display typical signs and symptoms) are:
• Cough
• Weight loss/anorexia (can even go more than 10-20% in a month)
• Fever
• Night sweats
• Hemoptysis
• Chest pain (can also result from tuberculous acute pericarditis)
Pericardial TB can to cardiac tamponade or constriction
• Fatigue

The absence of any significant physical findings does not exclude active
pulmonary TB. Classic symptoms are often absent in high-risk patients,
particularly those who are immunocompromised or elderly.
AETIOLOGY
Pulmonary TB is caused by M tuberculosis, a slow-growing obligate aerobe
and a facultative intracellular parasite. The organism grows in parallel
groups called cords (as seen in the images). It retains many stains after
decoloration with acid-alcohol, which is the basis of the acid-fast stains used
for pathologic identification.
 M tuberculosis, are aerobic, non–spore-forming, nonmotile, facultative,
curved intracellular rods measuring 0.2-0.5 μm by 2-4 μm. Their cell walls
contain mycolic, acid-rich, long-chain glycolipids and phospholipoglycans
(mycocides) that protect mycobacteria from cell lysosomal attack (and also
retain red basic fuchsin dye after acid rinsing (acid-fast stain)).
This barrier is responsible for many of the medically challenging
physiological characteristics of tuberculosis, including resistance to
antibiotics and host defense mechanisms.
The composition and quantity of the cell wall components affect the
bacteria’s virulence and growth rate.
• The peptidoglycan polymer confers cell wall
rigidity and is just external to the bacterial cell
membrane, another contributor to the
permeability barrier of mycobacteria.
• Another important component of the cell wall is
lipoarabinomannan, a carbohydrate structural
antigen on the outside of the organism that is
immunogenic and facilitates the survival of
mycobacteria within macrophages.
Transmission

• Humans are the only known reservoir for M tuberculosis.

• Tuberculosis is transmitted from a patient suffering from
pulmonary tuberculosis via micro-droplets loaded with
bacilli which the patient expels into the air when s/he
coughs, spits, sneezes, laughs, sings or speaks.
• These micro-droplets of about 1 to 5 microns in diameter,
may remain in suspension in the air for several days. They
can penetrate as far as the lungs of persons inhaling them
and infect them later on. The infection is generally
asymptomatic at this earlier stage.
• WHO estimates that a third of the world’s population is
infected by the tuberculosis bacillus.
• It is strictly aerobic, that is the reason why it affects the
upper parts of the lungs where oxygen pressure is the
highest.
• M.tuberculosis is very sensitive to heat and to ultra-violet
sunrays. The bacilli exhaled by a patient in the open air die
quickly. On the other hand, bacilli excreted in an enclosed
and poorly ventilated space may remain contagious for a
long period.
• Its multiplication is slow (12 to 24 hours) and that is the
reason why 4 to 6 weeks are required to obtain results from
culture.
• This slow proliferation also explains why it is not necessary
to administer drugs several times a day.
• The bacilli may remain in a latent state for long periods and
re-activate themselves during immune compromising
situations.
Epidemiology
• Globally, an estimated 10.0 million people fell ill with TB in 2018, a number that has been
relatively stable in recent years.
• Despite being a preventable and curable disease, there were an estimated 1.2 million TB deaths
among HIV-negative people in 2018 (a 27% reduction from 1.7 million in 2000), and an additional
251 000 deaths among HIV positive people (a 60% reduction from 620 000 in 2000).
• TB affects people of all age groups
 57% in males (aged ≥ 15 years),
 32% in women and
 11% in children (aged less than 15 years).
• Among all TB cases, 8.6% were people living with HIV (PLHIV).
• Africa accounted for 24% of the world’s cases.
• Drug-resistant TB continues to be a public health threat; In 2018, there were about half a million
new cases of rifampicin-resistant TB of which 78% had multidrug resistant TB (MDRTB).
In Rwanda, the incidence rate of tuberculosis - new cases and relapses- was
estimated at 59 cases per 100,000 inhabitants in 2018, lower than the global average
and that of the AFRO region which were respectively 96 and 231.
• Estimated treatment coverage was 80%. Mortality has been on a consistent
decline since 2010 to the current level of 4.5 per 100,000 population.
• Among the 5,822 incident cases notified in 2018,
• 6%Children(<15 years) ; 65% males; 29% women
• The population of TB patients infected with HIV remain stable between(21-25%)
• MDR-TB burden is relatively low 15% in new cases; 10.7% in previously treated
cases and there is no established resistance to any second line TB agents had
reported “RBC manual tec-2020”
Risk factors
HIV infection
History of a positive purified protein derivative (PPD)
History of prior TB treatment
TB exposure
Travel to or emigration from an area where TB is endemic
Homelessness, shelter-dwelling,incarceration
Others immunocompromising conditions like malnutrition, smoking,
diabetes, corticosteroids longlasting use, severe kidney disease etc
HOST FACTORS
Genetic susceptibility to infection 
Genetic analysis of sibling pairs has been used to evaluate putative genetic markers for enhanced
susceptibility to TB in populations in Africa . Possible markers on chromosomes 15q and Xq were
identified; the investigators speculate that finding a susceptibility gene on an X chromosome may
partially explain the increased incidence of TB in males in some populations.
Acquired susceptibility to infection 
 Investigators examined the interferon (IFN)-gamma response pathway in three patients with severe,
unexplained nontuberculous mycobacterial disease, In all three patients, IFN-gamma was
undetectable following stimulation of whole blood but was detectable when stimulated in the
absence of the patients' own plasma. An autoantibody against IFN-gamma was isolated from the
patients' plasma and was found to be capable of blocking the upregulation of tumor necrosis factor
(TNF)-alpha production in response to endotoxin, in blocking induction of IFN-gamma–inducible
genes, and in inhibiting upregulation of human leukocyte antigen (HLA) class II expression on
peripheral blood mononuclear cells (PBMCs). These acquired defects in the IFN-gamma pathway
may explain unusual susceptibilities to intracellular pathogens, including mycobacteria, in patients
without underlying, genetically determined immunologic defects.
Progression from latent infection to active disease
Pathogenesis of tuberculosis.

TB pathogenesis can be divided in four well-defined events.

1. Inhalation of the mycobacteria is followed by its interaction with resident
macrophages through cellular receptors and its internalization. Macrophage
bactericidal mechanisms are then activated, including RNI and ROI generation.
The efficient killing of mycobacteria depends on pathogen and host factors.
2. Inflammatory cell recruitment: survived mycobacteria proliferate within
macrophages inducing the production of proinflammatory cytokines. The local
inflammatory environment induces the recruitment of several cell types
including monocytes, neutrophils, and dendritic cells to the site of infection.
High levels of TNF-α contribute to control Mtb growth and granuloma
formation.
3. Control of mycobacteria proliferation: arrival of immune cells to the site of
infection including T cells, which become organized in characteristic structures
called granulomas efficiently stop mycobacteria proliferation and contain the
mycobacteria within the granuloma walls preventing its spread. Characteristic of
this structure is the presence of foam cells resulting from the differentiation of
chronically activated macrophages.
4. Mycobacteria containment eventually becomes stable (latent) infection.
Postprimary TB: mycobacteria persistence associated with a failure in the
immunosurveillance system increases the risk that latent disease becomes
reactivated, inducing the damage of nearby bronchi and conditioning the spreading
of the Mtb to other areas of the lung and the transmission of the disease. See miliary
TB
Chronologically, TB infection happens in 4 stages:

the initial macrophage response,

the growth stage,
the immune control stage,
and the lung cavitation stage.

These four stages happen over roughly one month.

Stage One
• The first stage takes place in the first week after the inhalation of the TB bacillus.
After the bacillus reaches the alveoli, it gets picked up by macrophages. The
following events depend on the amount of TB bacilli and the strength of the
macrophage. If the amount of TB bacilli is too large, or if the macrophage is not
strong enough to resist, the bacilli can reproduce in the macrophage. This
ultimately leads to the destruction of the macrophage and the infection of new,
nearby macrophages that try to swallow emerging TB bacilli.
Stage Two after about a week
• If the macrophage cannot contain the TB bacillus,
The TB bacilli start reproducing exponentially, meaning that for every intial bacillus
two new ones emerge. These two then produce two each, etc. This leads to a rapid
expansion of the intial TB bacillus, and the macrophages cannot contain the spread
anymore. This stage lasts until the third week after initial infection.
Stage Three
• After the third week, the bacilli do not grow exponentially anymore, and the
infection enters its third stage – it seems that at this stage, bacilli growth and
destruction by macrophages are balanced. The body brings in more immune cells
to stabilize the site, and the infection is under control. At least 90% pts infected
with Mycobacterium tuberculosis stop at stage 3 and do not develop symptoms or
physical signs of active disease.

In their lungs, the TB bacilli and macrophages that swallowed them build a round
complex – with TB bacilli and infected macrophages in the middle and healthy
macrophages surrounding them. This is called a Ghon focus, Often TB bacilli also
infect the surrounding lymph nodes. The combination of a complex in the lung
tissue and an infected local lymph node is called the primary complex (also Ghon
complex).
• The TB bacilli are shielded from the lung tissue; however, they can survive for
years in the macrophages. Patients in this stage are not contagious, because the TB
bacilli cannot enter the airways and cannot be coughed out or exhaled. If the
immune system is strong, the primary complex heals and leaves nothing more but
a small cavity and a scar in the tissue. This scar can later be seen on X-rays and
is a sign that the person has had an infection with Mycobacterium tuberculosis.
Stage Four
• In about 5% of cases, the primary complex does not heal and the TB bacilli
become re-activated after a period of 12 to 24 months after the initial infection:
this is stage 4 of the infection. The reactivated TB bacilli reproduce quickly and
form a cavity in the tissue, where the body’s immune system cannot reach them.
From this cavity, the TB bacilli quickly spread through the tissue and the person
develops signs and symptoms of active TB such as coughing.
• In this stage, the person is highly contagious because his or her sputum contains
active TB bacteria. Reactivation is more likely to happen if the immune system is
weakened, such as with HIV infection or malnutrition.
In summary, there are three ways in which the body reacts to an infection
with Mycobacterium tuberculosis:
• If the body’s immune system is strong, lymphocytes manage to contain the
bacteria and the infection does not spread further. This is called asymptomatic
primary TB.

• If the immune system is weak, the lymphocytes cannot contain the TB bacteria
and it rapidly spreads. The infected person develops symptoms and falls ill. This
is called progressive primary TB (stages 1 to 3, but without the final control over
the bacillus).

• If the immune system is initially strong and contains the TB bacteria, but
subsequently weakens and cannot control it any longer, the bacteria first go into a
dormant state but then get reactivated and subsequently spread aggressively (stage
4). This is called secondary TB or reactivation TB. It can also be triggered by a
new infection with TB bacteria, which leads to the reactivation of the initial
infection.
Differential Dx

 Actinomycosis
 Aspergillosis
 Bronchiectasis
 Constrictive Pericarditis
 Fungal Pneumonia and other forms
 Histoplasmosis
 Lung Abscess
 Nocardiosis
 Non-Small Cell Lung Cancer (NSCLC)
 Pott Disease (Tuberculous [TB] Spondylitis
 List Not limited ???
INVESTIGATIONS
1. History collection
2. Physical examination , respiratory system special focus
3. Paramedical investigation
2. Physical Examination associated with TB

• Patients with pulmonary TB

have abnormal breath sounds,
especially over the upper lobes
or involved areas.
• Rales or bronchial breath signs
may be noted, indicating lung
consolidation.
The absence of any significant physical findings
does not exclude active TB. Classic symptoms
are often absent in high-risk patients,
particularly those who are
immunocompromised or elderly.
3. Paramedical investigation
a) Imaging
1. CXR lungs infiltrate with or not cavitations
The following patterns may be seen on chest radiographs:
• Cavity formation - Indicates advanced infection and is associated with a high bacterial load
• Noncalcified round infiltrates - May be confused with lung carcinoma
• Homogeneously calcified nodules (usually 5-20 mm) - Tuberculomas; represent old
infection rather than active disease
• Miliary TB - Characterized by the appearance of numerous small, nodular lesions that
resemble millet seeds on chest radiography
Primary TB
• In primary active TB, radiographic features of pulmonary tuberculosis are nonspecific,
sometimes even normal. The chest radiograph typically shows a pneumonialike picture of
an infiltrative process in the middle or lower lung regions, often associated with hilar
adenopathy and/or atelectasis.
Primary TB is more likely to mimic the appearance of routine community-acquired
pneumonia (CAP) on chest radiography than is reactivation TB. Studies have shown
that primary TB and CAP may be associated with pleural effusion and cavitation.
Reactivation TB
• In classic reactivation TB, pulmonary lesions are located in the posterior segment
of the right upper lobe, the apicoposterior segment of the left upper lobe, and the
apical segments of the lower lobes. Cavitation is most common; healing of
tubercular regions results in the development of a scar, with loss of lung
parenchymal volume and calcification.
• TB and HIV infection
• In patients with HIV infection or another immunosuppressive disease, lesions are
often atypical. Up to 20% of HIV-positive patients with active TB have normal
chest radiographic findings.
2. CT-scan is the preferred imaging modality if lymphadenopathy(mullet seeds in
lungs would be
3. MRI is the preferred modality in tuberculous spondylitis 
b) Laboratory studies
The primary screening method for tuberculosis (TB) infection (active or latent) is
the Mantoux tuberculin skin test with purified protein derivative (PPD).
An in vitro blood test based on interferon-gamma release assay (IGRA) with
antigens specific for Mycobacterium tuberculosis can also be used to screen for
latent TB infection. IGRA assays offer certain advantages over tuberculin skin
testing.

Obtain the following laboratory tests for patients with suspected TB:
1. Acid-fast bacilli (AFB) smear and culture
HIV serology in all patients with TB and unknown HIV status
There are two main types of AFB tests:
• AFB smear. 
In this test, your sample is "smeared" on a glass slide and looked at under a
microscope. It can provide results in 1–2 days. These results can show a possible or
likely infection, but can't provide a definite diagnosis.
• AFB culture. 
In this test, your sample is taken to a lab and put in a special environment to
encourage the growth of bacteria. An AFB culture can positively confirm a
diagnosis of TB or other infection. But it takes 6–8 weeks to grow enough bacteria
to detect an infection.
This AFB may also be used to help diagnose other types of AFB infections like
leprosy and or other opportunistic lung infections
Blood cultures
• Blood cultures using mycobacteria-specific, radioisotope-labeled systems help to
establish the diagnosis of active TB. However, mycobacterial bacteremia
(bacillemia) is detectable using blood cultures only if specialized systems are
used; these bacilli have specific nutrient growth requirements not met by routine
culture systems.
• Such blood cultures should be used for all patients with HIV infection who are
suspected of having TB, because bacillemia is particularly prevalent in this
population. If available, in fact, these cultures should be used for any patient
highly suspected of having active TB
Sputum Smear

Patients suspected of having TB should submit sputum for AFB smear and culture.
should be collected in the early morning on 3 consecutive days.
In hospitalized patients, sputum may be collected every 8 hours. [53] Early-morning
gastric aspirate may also produce a good specimen, especially in children.
• In patients without spontaneous sputum production, sputum induction with
hypertonic saline should be attempted. 
•  Fiberoptic bronchoscopy with bronchoalveolar lavage (and perhaps
transbronchial biopsy) can be used if other attempts at obtaining sputum
specimens are unsuccessful.
Ziehl-Neelsen staining of sputum is a simple 5-step process that takes
approximately 10 minutes to accomplish. While highly specific for mycobacteria,
however, this stain is relatively insensitive, and detection requires at least 10,000
bacilli per mL; most clinical laboratories currently use a more sensitive auramine-
rhodamine fluorescent stain (auramine O).
Staining in TB detection
• Ziehl-Neelsen staining of sputum is a simple 5-step process that takes approximately 10
minutes to accomplish. While highly specific for mycobacteria, however, this stain is
relatively insensitive, and detection requires at least 10,000 bacilli per mL; most clinical
laboratories currently use a more sensitive auramine-rhodamine fluorescent stain (auramine
O).
2. Nucleic Acid Amplification Tests
a. Deoxyribonucleic acid (DNA) probes specific for mycobacterial ribosomal RNA identify
species of clinically significant isolates after recovery.
- In tissue, polymerase chain reaction (PCR) amplification techniques can be used to
detect M tuberculosis
 - specific DNA sequences and thus, small numbers of mycobacteria in clinical specimens.
b. Ribosomal RNA probes and DNA PCR assays allow identification within 24 hours
The CDC recommends performing one of these nucleic acid amplification tests when the
diagnosis of pulmonary TB is being considered but has not yet been established, and when the
test result would alter case management or TB control activities, such as contact investigations.
The CDC recommends performing the test on at least 1 respiratory specimen. CDC 2021
2. Nucleic Acid Amplification Tests
a. Deoxyribonucleic acid (DNA) probes specific for mycobacterial ribosomal
RNA identify species of clinically significant isolates after recovery.
- In tissue, polymerase chain reaction (PCR) amplification techniques can be
used to detect M tuberculosis
 - specific DNA sequences and thus, small numbers of mycobacteria in clinical
specimens.
b. Ribosomal RNA probes and DNA PCR assays allow identification within 24
hours
The CDC recommends performing one of these nucleic acid amplification tests
when the diagnosis of pulmonary TB is being considered but has not yet been
established, and when the test result would alter case management or TB control
activities, such as contact investigations. The CDC recommends performing the test
on at least 1 respiratory specimen. CDC 2021
3. Tuberculin skin test OR Mantoux tuberculin skin test
The primary screening method for TB infection (active or latent) is the Mantoux tuberculin skin
test with PPD.
Tuberculin sensitivity develops 2-10 weeks after infection and usually is lifelong. Tuberculin skin
testing is based on the fact that TB infection induces a strong, cell-mediated immune response that
results in a measurable delayed-type hypersensitivity response to intradermal inoculation of tuberculin
PPD.
The PPD test involves an intradermal injection of 5 units of PPD (0.1 mL), preferably with a 26-, 27-,
or 30-gauge needle.
The results should be read between 48 and 72 hrs.
a. In immunologically intact individuals, induration of less than 5 mm constitutes a negative result.
b. Population-based criteria for PPD positivity are as follows:
• Cutoff of 5 mm or more induration - Patients who are HIV positive, have abnormal chest radiographic
findings, have significant immunosuppression, or have had recent contact with persons with active
TB
• Cutoff of 10 mm or more induration - Patients who are intravenous drug users, residents of nursing
homes, prisoners, impoverished persons, or members of minority groups
• Cutoff of 15 mm or more induration - Patients who are young and in good health
TB Treatment & Management
Special Considerations
1. Hospitalizing pt In isolation setting
• Isolate patients with possible tuberculosis (TB) infection in a private room with
negative pressure (air exhausted to outside or through a high-efficiency particulate
air filter).
• Medical staff must wear high-efficiency disposable masks sufficient to filter the
tubercle bacillus. Continue isolation until sputum smears are negative for 3
consecutive determinations (usually after approximately 2-4 wk of treatment).
• Unfortunately, these measures are neither possible nor practical in countries where
TB is a public health problem including Rwanda.
2. Drug therapy

a. For initial empiric treatment of TB, start pts on a 4-drug regimen:

isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin.
Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin,
if it is used as a fourth drug) can be discontinued.

b. After 2 months of therapy (for a fully susceptible isolate),

pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or
intermittent therapy for 4 more months.

If isolated isoniazid resistance is documented, discontinue it and continue T 3 with

rifampin, pyrazinamide, and ethambutol for the entire 6 months.
Therapy must be extended if the patient has cavitary disease and remains culture-
positive after 2 months of treatment.
Note; Medical concerns
- Patients diagnosed with active TB should undergo sputum analysis
for Mycobacterium tuberculosis weekly until sputum conversion is documented.
Monitoring for toxicity includes baseline and periodic liver enzymes, complete
blood cell (CBC) count, and serum creatinine.
- Patients with TB who are receiving pyrazinamide should undergo baseline and
periodic serum uric acid assessments, and patients with TB who are receiving long-
term ethambutol therapy should undergo baseline and periodic visual acuity and
red-green color perception testing.
The latter can be performed with a standard test, such as the Ishihara test for color
blindness.
-
Seizures or; from isoniazid overdose
• A special regimen exists for patients with TB who are actively seizing or who
have overdosed on antimycobacterial medication.
In these pts, overdose with isoniazid should be suspected.
T3/ IV diazepam can be attempted to control seizure activity,
but IV pyridoxine is the drug of choice, in a gram-for-isoniazid-ingested-gram
dose.
If the ingested dose is unknown, 5 g of pyridoxine can be used empirically.
For patients who are awake and alert, an oral dose of activated charcoal (1 g/kg)
with sorbitol can be administered.
During Pregnancy
Pregnant women with active TB should be treated, even in the first stage of pregnancy.
Isoniazid, rifampin, and ethambutol are recommended.
then, pyrazinamide is reserved for women with suspected multidrug-resistant TB (MDR-
TB).
manytimes, pyrazinamide is commonly used in pregnant women with TB. Streptomycin
should not be used, because it has been shown to have harmful effects on the fetus.
Preventive treatment is recommended during pregnancy, especially in the following
types of patients:
• Pregnant women with a positive tuberculin skin test result who are HIV
seropositive or who have behavioral risk factors for HIV infection but who decline
HIV testing
• Pregnant women with a positive tuberculin skin test result who have been in close
contact with a patient who is smear-positive for pulmonary TB
• Pregnant women who had a documented tuberculin skin test conversion during the
previous 2 years
HIV-Infected Patients
• Treatment regimens for active or latent TB in patients with HIV infection are similar
to those used in HIV-negative patients, but dose adjustments may be necessary.  
•  The most significant differences involve the avoidance of rifampin in patients who
are on protease inhibitors. Rifabutin should be used in place of rifampicin in such
patients.

Subsequent studies found that starting ART early (eg, within 4 weeks after the start
of TB treatment) reduced progression to AIDS and death
Note;
Patients with HIV and TB may develop a paradoxical response (immune
reconstitution inflammatory syndrome [IRIS]) when starting antiretroviral therapy.
This response has been attributed to a stronger immune response to M tuberculosis.
Clinical findings include fever, worsening pulmonary infiltrates, and
lymphadenopathy.