See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/322835066

Pathophysiology of Tuberculosis: An Update Review

Article · January 2018

DOI: 10.29161/PT.v6.i2.2018.15

CITATIONS READS
3 6,949

2 authors, including:

Devender M. Sharma
sanjivani college of pharmaceutical sciences khetri
17 PUBLICATIONS   12 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Influence of GDF-11 in Aging Process : An Review View project

Green tea in green world View project

All content following this page was uploaded by Devender M. Sharma on 31 January 2018.

The user has requested enhancement of the downloaded file.

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 15

Pathophysiology of Tuberculosis: An Update Review

Devender Sharma*, Deepika Sarkar
Hi – Tech College of Pharmacy,
Chandrapur, Maharashtra, India
[email protected]

ABSTRACT
Tuberculosis is a hypersensitive granulomatous infectious disease caused by Mycobacterium Tuberculosis
(M.TB).In India 40% people are affected by T.B. So need of knowledge about T.B. and pathophysiology of T.B. to
people or society. Pathophysiology means, when a human being or animal being suffering from a disease this is
because deranged or change in function on that organ or human body. Infection is caused by air- borne droplets
of organisms person to person. The main object of this review is how to diagnose and how it is cure or treat. It is
diagnosed by PPD, IGRA, Sputum studies, X-rays and Biopsies. Mostly antibiotics are preferred for the first
treatment.

Keyword: Tuberculosis, Sputum studies, Antibiotics, Pathophysiology

INTRODUCTION the burden of TB disease among children have also

Tuberculosis (TB) is an infectious disease caused by been carried out. The figures are 4,90,000s cases and
the bacillus Mycobacterium tuberculosis (Mtb). It is 64,000 deaths among HIV-negative children per year.
the most dangerous bacterial infection responsible TB is one of the leading causes of death among
for severe increase in death cases. The tubercle women. 0.5 millions women succumbed to TB. This
bacillus was discovered by Robert Koch in 1882. includes 3, 00,000 (range, 2, 50,000–3, 50,000) TB
There are several reports indicating that tuberculosis deaths among HIV-negative women. (Kaufman,
(TB) is an age old dreadful disease even from ancient 2014)
times. The disease was called "consumption" in the The burden of TB is highest in Asia and Africa. In
past because of the way it would consume from 2011, largest number of cases was reported from
within anyone who became infected. India, China, South Africa, Indonesia and Pakistan.
Tuberculosis is a chronic granulomatous infectious India and China alone accounted for 26% and 12% of
disease. Infection occurs via aerosol, and inhalation global cases, respectively. Of the 8.7 million TB
of a few droplets containing M. tuberculosis bacilli. incident cases reported in 2011, about 1.2 million
After infection, M. tuberculosis pathogenesis occurs people are also suffering from HIV. In the African
in two stages. The first stage is an asymptomatic region, 39% of TB cases were estimated to be co-
state that can persist for many years in the host, infected with HIV. (Kaufman, 2014)
called latent TB. (Kaufman, 2014) Most cases of TB are caused by M. Tuberculosis and
In the year 1993, World Health Organization (WHO) the reservoir of infection is humans with active TB.
declared TB a global public health emergency. About Most cases of TB are pulmonary and acquired by
one-third of the world’s population (> 2 billion), are person to person transmission of air-borne droplets
infected with TB bacilli. 10% of the people infected of organisms. Oropharyngeal and intestinal TB
with TB bacilli will become sick with active TB in their contracted by drinking dairy milk contaminated with
lifetime.2,3 According to WHO report, global M. Bovis rarely seen nowadays and usually in
population with burden of disease caused by TB from countries with tuberculosis dairy cows and
1990-2011 was 6948 million and total number of unpasturised milk. (Hachart et al., 2016)
Multi-Drug Resistant (MDR) cases from 2005-2011 Tuberculosis is a common disease prevalent through
were 61690.3 In 2011, there were an estimated 8.7 out the world. It is a chronic specific inflammatory
million incident cases of TB (range, 8.3 million–9.0 infectious disease caused by Mycobacterium
million) globally. Highest numbers of incidences were tuberculosis in humans. Tuberculosis usually attacks
reported in Asia (59%) and Africa (26%). Estimates of
How to cite this article: Sharma D, Sarkar D; Pathophysiology of Tuberculosis: An Update Review; PharmaTutor; 2018; 6(2); 15-
21; http://dx.doi.org/10.29161/PT.v6.i2.2018.15 Vol. 6, Issue 2 | magazine.pharmatutor.org
 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 16

the lungs but it can also affect any parts of the body. d. Aerobic and non motile.
(Alexander et al., 2015) e. Multiplies slowly.
f. Can remain dormant for decades.
Etiology of tuberculosis (Alexander et al., 2015)
Mycobacturium tuberculosis–most common cause How is TB Transmitted (Hachart et al., 2016)
Other than tuberculosis-includes: a. Person-to-person through the air by a
a. M. aviumintracellulare person with active TB disease of the
b. M. kansasi lungs.
c. M. scrofulaceum b. Less frequently transmitted by:
d. M. marinum 1. Ingestion of Mycobacterium bovis
e. M.ulcerence found in unpasteurized milk
f. M. fortuitum products or autoingestion.
g. M. chelonei 2. Inoculation (in skin tuberculosis).
3. Transplacental route (rare route).
Sites involved (Hachart et al., 2016)
a. Pulmonary tb-85% of all tb cases PATHOGENESIS OF TUBERCULOSIS (ALEXANDER ET
b. Extrapulmonary sites. AL., 2015)
c. Lymph node 1. M.tuberculosis starts a IV
d. Genito-urinary tract hypersensitivity immune reaction inside
e. Bones & joints the lung which damages the lung tissue
f. Meninges while killing the foreign microorganism.
g. Intestine 2. Pathologic manifestation of tuberculosis
h. Skin like caseating granuloma and cavitation
are result of hypersensitivity that
Characteristics of m. Tb (Alexander et al., 2015) develops in concert with the protective
a. Rod shape, 0.2-0.5 in D, 2-4 in L. host immune response.
b. My colic acid present in its cell wall, makes it 3. Macrophages are the primary cells
acid fast, infected by M.tuberculosis.
c. So it resists decolourization with acid &
alcohol.

Morphology of Tb
Primary tuberculosis: (Alexander et al., 2015)
1. Form of disease that develops in a previously unexposed person.
2. Almost always begins in lungs.

Vol. 6, Issue 2 | magazine.pharmatutor.org

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 17

3. Inhaled bacilli implant in the distal airspaces of lower part of upper lobe or upper part of lower lobe.
4. It forms a small sub pleural parenchymal lesion in the mid zone of the lung (ghon focus inflammation
+caseous necrosis )
5. Tubercle bacilli drain to the regional lymph node which also often undergo caseous necrosis.
6. Parenchymal lung lesion + Nodal involvement= Ghon’s complex.

Histologically:
Granulomatous inflammation forms both caseating and non caseating tubercles. Tuberculous Granuloma has
the following characteristics:
1. Central caseous necrosis.
2. Transformed macrophages called epithelioid cells.
3. Lymphocytes, plasma cells, and fibroblasts
4. Langhans giant cells

Pathophysiology of T.B. (Hunter et al., 2014)

The Three Distinct Stages Hypothesized (Hachart et al., 2016)

Vol. 6, Issue 2 | magazine.pharmatutor.org

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 18

Act I - The War of Attrition mostly due to tobacco smoking, but may also occur
1. MTB try to multiply while the host attempts from atmospheric pollution (either due to cooking or
to contain them within granulomas heating fires or in some places due to industrial
2. With no or little immunity, there is greater pollution). (Hachart et al., 2016)
lymphatic or hematogenous spread.
3. Control is through cell mediated Immunity. General Symptoms: (Hachart et al., 2016)
Act II-The Sneak Attack 1. Loss of weight.
1. Act II Post-primary bronchogenic TB begins 2. Fever and sweating.
asymptomatically in the apices of the lung, 3. Loss of appetite.
at some distance from the site initial 4. Breathlessness.
infection
2. It is part of latent TB since there are no Respiratory Symptoms:
clinical symptoms 1. Cough
3. Few numbers of MTB in modified alveolar 2. Sputum.
macrophages drive accumulation of host 3. Blood-spitting.
lipids and mycobacterial antigens in an 4. Tiredness.
isolated section of lung in preparation for a 5. Amenorrhea.
sudden necrotizing reaction sufficient to 6. Arrhythmia
produce a cavity further evolution of 7. Hoarseness.
necrotic caseous pneumonia .
Act III-The Fallout Diagnosis (Hunter et al., 2014)
1. It is either coughed out to form a cavity or Clinical Clues
becomes surrounded by epithelioid cells and 1. Cough > 2 weeks
fibrosis. 2. Fever > 2weeks
2. This produces granulomatous inflammation 3. Exposure to TB
and most clinical disease 4. Chronic immune suppression
3. Cavities form when caseous stage 5. Endemic country
encompasses the pneumonia softens, 6. Abnormal physical exam
fragments and is coughed out of the body
leaving a hole. LABORATORY TESTS (Hunter et al., 2014)
4. Pneumonia that is not coughed out remains TB test is the Mantoux skin test (PPD) - a small
to induce inflammation. It dries to become amount of fluid (called tuberculin) is injected into the
fibrocaseous TB. forearm just under the skin. –A health professional
should read the test 48 to 72 hours after it is
Symptoms of tuberculosis (Hunter et al., 2014) administered to check for a reaction. –If there is a
If a patient has any of the following, consider him a reaction (swelling), more testing is done. –The Tine
'Tuberculosis Suspect': test (which uses a 4-pronged device) is no longer
1. Cough for over 3 weeks. recommended because it is not as effective in
2. Haemoptysis. delivering the proper amount of tuberculin under
3. Pain in the chest for over 3 weeks. the skin. (Harries et al., 2016)
4. All these can be due to some other diseases but Mycobacterial Examination-
sputum must be tested if any of the symptoms are Mycobacterial examination has 6 stages:
present. Cough and sputum is very common 1. Proper specimen collection
everywhere. Much of this is due to acute respiratory 2. Examination of acid‐fast bacilli (AFB) smears
infections and lasts only a week or two. 3. Direct identification (NAAT‐
nucleic acid amplification test)
There is also much chronic cough due to chronic 4. Specimen culturing and final identification
bronchitis (sometimes called 'Chronic Obstructive 5. Drug susceptibility testing
Pulmonary Disease' (COPD or other names). This is 6. TB genotyping

Vol. 6, Issue 2 | magazine.pharmatutor.org

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 19

Specimen Sources (Harries et al., 2016)

1. Sputum(primary)
2. Pulmonary aspiration (secondary)
3. Body fluids (CSF, pleural, peritoneal, etc)
4. Tissue biopsy
5. Blood
6. Urine
7. Gastric aspirate
8. Stool (special request)

Acid‐fast Bacilli (AFB) smear (Harries et al., 2016)

1. Least sensitive of all AFB Tests (20‐ MTD-Hologicand Gene Xpert-Cepheid are the only
75% positivity) FDA approved methods.
2. Requires 10,000 AFB/ml to be positive
3. Positive slide does not differentiate TB from
atypical mycobacteria (i.e. M. avium)
4. Reported within 24 hours of receiving the sp
ecimen in the laboratory.

Fluorescent AFB Smear Using Auramine‐O Staining

1. Very sensitive, takes minutes to read
2. Not all that is fluorescent is AFB (need a care
ful eye)
3. Chemical fluorescence, notan immune stain
or Direct Fluorescent Antibody
4. Can be confirmed with Ziehl Neelson (ZN) NAA tests are available that are not FDA approved,
smear. such as real time PCR assays. MDHHS performs a real
5. “NAA testing should be performed on at time lab developed PCR test to detect Mtband MAC
least one respiratory specimen from each using the ABI 7500 Fast DX.
patient with signs and symptoms of
pulmonary TB for whom a diagnosis of TB is
being considered but has not yet been
established, and for whom the test result
would alter case management or TB control
activities”
6. NAAT should be performed on all
new AFB+ sputum specimens

AFB Culture Test

1. More sensitive than AFB smear
2. 10 AFB/ml can produce a positive result, whereas
AFB smear needs 10,000 AFB/ml
3. Culture may be AFB positive even if smear was
negative for AFB.

Vol. 6, Issue 2 | magazine.pharmatutor.org

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 20

Tests Performed on Growth in Mycobacteria 4. Second‐lineMDDR to detect XDR‐TB

Culture 5. GYRA (Fluoroquinolones)
1. Accuprobe DNA test (not amplified) 6. EIS (Kanamycin)
2. HPLC (high performance liquid chromatography) 7. TLYA (Capreomycin)
3. MALDI‐TOF 8. PNCA (Pyrazinamide)
4. Biochemical Identification Confirmation 9. EMBB (Ethambutol)
5. Drug Susceptibility
TB DNA Genotyping (Hachart et al., 2016)
Susceptibitility Testing of M. tuberculosis 1. Universally Offered by CDC
1. Repeat after 90 days of therapy, if specimens 2. DNA “Fingerprint” of each isolate
continue to produce M. tb 3. Michigan Department of Health & Human Services
2. Relapse or failed therapy laboratory runs genotype on all TB cultures in United
Additional Molecular Tests for TB States and territories.

CDC –Molecular Detection of TB Drug Resistance TREATMENT (Hachart et al., 2016)

(MDDR) The standard four medications (yes, all at once) for
1. Rapid testing for DNA mutations associated with starting treatment for TB in the US are:
drug resistance • Isoniazid(INH)
2. NAAT (+) sputum specimens or culture isolates • Rifampin
(prior approval) •Pyrazinamide(PZA)
3. Must meet the following criteria: • Ethambutol
4. Known Rifampin resistance Ok, so you take your pills –For 6-8 months.
5. Known MDR
6. High risk of Rifampin resistance or MDR‐TB Antibiotics used to treat “TBs” of all kinds
7. High profile patient (e.g. daycare worker, nurse) • Rifampicin.
8. Mixed or non‐viable culture • Rifabutin.
9. Drug Adverse reaction (e.g. Rifampin allergy) • Ciprofloxacin.
• Amikacin.
CDC MDDR (Harries et al., 2016) • Ethambutol.
1. First‐line MDDR to detect MDR‐TB • Streptomycin.
2. rpoB(Rifampin) • Clarithromycin.
3. inhA and katG(Isoniazid) • Azithromycin.

Drug Adverse Reactions Comments

Izoniazid Hepatitis, drug interactions, numbness, tingling, Raises Dilantin and INH blood serum levels
pain in extremities, fatigue if taken together; this may lead to toxicity

Rifampin Stomach upset, Symptoms of Flu, If you are taking other drugs (such as birth
Bleeding, Rashes, Hepatitis control pills) consult your doctor. Rifampin
can turn body fluids orange but this is
temporary.

Pyrazinamide Joint aches, Hepatitis, Rashes, Stomach upset, Avoid in pregnancy

Gout (rarely)

Ethambutol Visual Problems Should not be used in young children

whose vision can't be tested unless
there is drug resistant TB

Vol. 6, Issue 2 | magazine.pharmatutor.org

 PharmaTutor PRINT ISSN: 2394-6679 | E-ISSN: 2347-7881 21

CONCLUSION
Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). Tuberculosis
is a chronic granulomatous infectious disease. Infection occurs via aerosol, and inhalation of a few droplets
containing M. tuberculosis bacilli. Most cases of TB are pulmonary and acquired by person to person
transmission of air-borne droplets of organisms. It can be diagnosed by PPD, IGRA, Sputum studies, X-rays and
Biopsies.
Some antibiotics such as
•Isoniazid(INH)
•Rifampin
•Pyrazinamide(PZA)
•Ethambutol are therapeutically used.

Acknowledgement: The authors are thankful to the Principal of Hi-Tech College of Pharmacy, Chandrapur (Maharashtra),
India for providing necessary facilities to carry out this work.

↓ REFERENCES
1. Alexander J. adami, Jorge L. Cervantes, themicrobiome at pulmonary alveolar niche and its role in
mycobacterium tuberculosis infection, tuberculosis, 2015, 95(6), 651-658
2. Hachart .B. Pamela, “Tuberculosis Pathogenesis and Transmission, Oakland Country Michiga Health Division ,
2016, Page no. 6,8,12,14,20-28
3. Harries, Anthony D. and Kumar, Ajay M.V. and Sataynarayana, Srinath and Lin, Yan and Zachariah, Rony and
Lonnroth, Khut and Kapur, Anil, Addressing diabetes mellitus as part of strategy for ending TB. Trans R Soc TRop
Med Hyg, 2016,110: 173-1.
4. Hunter, R. L. Actor, J.K, Hwang, S.A., Karew, V and Jagannath,(2014). Pathogensis of Post Primary tuberculosis,
Immunity and hypersensitivity in the development of cavities. Ann. Clin Lab. Sci., 44, 365-387.
5. Kaufman S, Introduction, Seminar in Immunology, 26(6), 429-430.

Vol. 6, Issue 2 | magazine.pharmatutor.org

View publication stats