1.0 in which it is a Greek term that

1.0  
General
Overview Of Tuberculosis Disease

1.1.History
of Tuberculosis

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Tuberculosis or
best known as TB is a disease that causes by the bacterium, Mycobacterium
tuberculosis. Tuberculosis has been there even in pre-Columbian and early
Egyptian era but it was not a major issue in health until the seventeenth and
eighteenth centuries. The outspread of TB is said to be due to the industrial
revolution causing an extremely crowded living conditions and thus the
spreading of the bacteria. In the olden days, TB was referred as phthisis by
ancient physicians in which it is a Greek term that carries the meaning of
wasting. The common symptoms of TB are cough (3 weeks or longer), weight loss,
fevers, loss of appetite, fatigue, night sweats and hemoptysis. The bacteria
attack the lung primarily but also other parts of the body. The bacteria,
Mycobacterium tuberculosis is said to be infectious from the result of Koch’s
Postulation. Treatment in the olden days consist of isolating the patients by
placing them in hospital for bed rest and fresh air and also away from the
community. As per the advancing technologies in radiographic film, it is known
that pulmonary cavitary lesions are the main causes of the disease. As a
result, pneumoperitoneum, plombage, and thoracoplasty therapies are used to
treat TB.12

After the
discovery certain drugs such as streptomycin, p-aminosalicylic acid, isoniazid,
and rifampicin, the success rate of treating TB has been increased and hope was
there for the ultimate elimination of TB from the community. However, in 1990s,
multidrug-resistant TB (MDR-TB) arised (primarily in United States). In 2000s,
there are the emergence of extensively drug-resistant TB (XDR-TB) and most
recently, the emergence of totally drug-resistant TB (TDR) or super extensively
drug-resistant TB. These destroyed the hope of total elimination of TB from the
community. So, numbers of measurements such as susceptibility testing, rapid
pathogen identification, patient isolation, and appropriate antimicrobial therapy
in individual with high index of suspicion of TB are carried out to halt the
further development of new emergence and spread of drug resistant TB. 1

1.2. Transmission
of Tuberculosis

The transmission
of Mycobacterium tuberculosis is through the air by aerosolized droplet nuclei
from one person (infected) to another person (especially with weak immune
system). The droplet nuclei carry around 1 to 3 mycobacterium tuberculosis
organisms and are about 1 to 5 micron in size which helps them remain intact in
the air for an extended period to eventually reaches the alveoli when inhaled.
However, this bacteria cannot be transmitted through inanimate objects.  There are numerous factors that can increase
the chance of transmission of M. tuberculosis in which include 1 the number of organisms expelled into the
air, the concentration of organisms in the air determined by the volume of the
space and its ventilation, the length of time an exposed person breathes the
contaminated air, and presumably the immune status of the exposed individual.
Family household contacts, especially children, and persons working or living
in an enclosed environment (e.g. hospitals, nursing homes, prisons) with an
infected person are at a significantly increased risk for becoming infected.
Individual with impaired cell-mediated immunity, such as HIV-infected persons
or transplant patients, are more likely to become infected with M. tuberculosis
after exposure than persons with normal immune function. 13

1.3. Epidemiology
of Tuberculosis

In epidemiology
studies of TB, there are about 2 billion people are infected with M.
tuberculosis. In fact, TB 1 is one of
the most common causes of death from an infectious disease in the world. In
the year 2009, approximately 9.4 million new cases of TB have found and when
compared to the year 2000, there is an increment of 1.1 million cases. The
countries with the highest increment were India – two million, China – One
million and three hundred thousand, and South Africa, Nigeria, Indonesia, and
Pakistan all carry about half million each. About twelve percent from the new
cases in 2009 were found in HIV patients in which African region accounting
most of the cases. There are about 4700 deaths in a day due to TB itself. Moreover,
it is found that Asians are the most prone to TB disease followed by
non-Hispanic blacks, Hispanics, and finally Caucasians. In the case of MDR-TB,
in which it is defined as resistance to both rifampicin and isoniazid, there
were about four hundred thousand cases found where they were mostly reported
from China, India, Russia, and South Africa. There is also studies claim that
the risk of getting MDR-Tb is about five times greater for patients with previous
history of TB. In the case of XDR-TB which defined as resistance to rifampicin
and isoniazid among first-line agents, resistance to any fluoroquinolone, and
resistance to second-line injectable drug (kanamycin, capreomycin, amikacin),
there are no correlation with previous TB history of patient and almost all
patients diagnosed with XDR-TB died with a median survival period of sixteen
days after collection of the first sputum specimen. However, the mortality of
XDR-TB is closely associated with HIV infected patient.  Besides that, there are also increasing
chance to get XDR-TB for patients with alcohol use, previous treatment of TB,
and homelessness. It was also documented in a retrospective study that the
emergence of XDR-TB is associated with the baseline chronic disease and
non-adherence to MDR-TB therapy. The success rate of getting recover fully from
XDR-TB is very less in comparison to MDR-TB. Luckily, later generation of
fluoroquinolones have shown some significant improvement on XDR-TB patient even
the bacteria show resistance to the drug in susceptibility testing. 13

1.4.Etiology
of Tuberculosis

In etiology study
of TB, it is caused by 1 M.
tuberculosis, an aerobic, non-spore-forming acid-fast bacillus. M.
tuberculosis replicates slowly in which it replicates one every 24 hours. This
bacillus grows best in places with high oxygen level, for example the lungs.
1

1.5.
Pathogenesis of Tuberculosis

The pathogenesis of tuberculosis starts when the
bacillus M. tuberculosis cells in droplets nuclei form from an active TB
patient are inhaled and enters the lungs. At the site of alveolar, there will
be macrophages engulfing the bacillus cells but are unable to destroy due to
the mycolic acids in the cell wall which prevent fusion of the phagosome with
lysosomes. The bacillus cells then leave the phagosome and replicate within the
cytoplasm of the alveolar macrophages. This in turn causes inflammatory
response and more macrophages are recruited to the site providing the bacillus
cells more host cells to replicate in. Few of the macrophages will fuse
together to form giant multi-nucleated cells while the others accumulate large
numbers of oil droplets and become foamy macrophages. The lipids also help the
bacillus cells survive within the macrophages. Then, lymphocytes are collected
around the macrophages, causing the infected are to wall off from the
surrounding tissue. This forms a granuloma (also called as tubercles since they
are granulomas of tuberculosis) in which it is the body’s characteristic
response to microbes and foreign substances are unable to be destroyed and
removed by phagocytosis. Inside the granuloma, effector, helper T cells will
release cytokines to activate macrophages to destroy the bacteria infecting
them. A fibrous layer will form around the macrophages, preventing the
lymphocytes from entering the tubercle. Through X-rays, the fibrous tissue can
be seen as Ghon foci. It will be called as Ghon complex if the adjacent lymph
nodes are involved. Few of the bacillus cells will survive in the Ghon
foci/complex but their replication are halted by the condition in the tubercle
(low O2 level and acidic pH). The bacillus cells remain in this
state for years thus causing latent TB infection. Patients with latent TB
infection are non-infectious and in multiple cases, the infection is cured.

In
active TB disease in which it results from the inflammatory response failed to
contain and destroy the bacillus cells of the mycobacteria. This status can
occurs both during primary infection as well as patient with latent TB
infection (the reactivation of TB). The reactivation of TB can be caused by
aging, stress, and AIDS. Inside the tubercle, the macrophages containing the
bacillus cells die and erupted causing the release of the bacillus cells, enzymes,
and cytokines. This resulted to formation of caseous necrosis in the center of
the tubercle. After that, the tubercle ruptures which in turn causing the
bacillus cells to be freed into the airways and causes a large lung defect
called tuberculous cavity. The bacillus then starts to spread to other parts of
the lungs. If this persist, the cavity will slowly enlarge for months to years
and then the bacillus cells will shed into the bronchi. Active form of TB are
infectious through airborne droplets. There are other systems that can be
affected by reactivation of TB. They include the lymph nodes, bones, pleura,
pericardium, kidneys, joints, and the CNS. 14

 

 

 

 

 

 

 

 

 

 

2.0   Strategies For The
Management Of Tuberculosis (National and International Guidelines)

*The standards for strategies will be attached at the
end of the assignment.

1.     
Investigations/Diagnosis

A patient is said
to have TB only if series of diagnosis have shown the positive results for TB.
First, the laboratory investigations are done in which the 5 diagnosis of TB is based on the detection of
the presence of acid fast bacilli on smears and cultures for clinical
specimens. Patients that are suspected to be contacted with PTB (pulmonary
tuberculosis) should provide at least 2 sputum specimens (best to collect the
sputum in early morning as this time has the highest yield) for observations
under microscope.  Conventionally, the
microscopic test is carried out with light microscope but the sensitivity is
relatively low. Thus, Fluorescence microscopy (FM) is instead used in many
cases which is about 10% higher in sensitivity than conventional light
microscope. Since FM is costly, a modified version of FM which is LED FM (light
emitting diode-based fluorescence microscopy) has replaced FM. 56

Next, the molecular
method in which the specimen is being send into Nucleic Acid Amplification
Tests (NAAT) to confirm the presence of M. tuberculosis. This method is a lot
faster than simple culturing method as rapid results can be given within 24 to
48 hours. Besides NAAT, rapid methods (serology assays) can also be used to
determine the presence of M. tuberculosis. One of the rapid methods is Anda-TB
IgG test. However, WHO stated that commercial serological tests for TB do not
give consistent and precise results, thus they are not recommended. After that,
the drug susceptibility testing or optimal methods to rapidly detect
drug-resistant TB are carried out. For example, the Line Probe Assay (LPA)
which is used to test MDR-TB (both rifampicin and isoniazid or rifampicin
alone). Since LPA can only be done in laboratories with sophisticated
equipment, WHO has suggested a fully integrated and automated on-demand
molecular diagnostic system (Xpert MTB/RIF) for the rural area. This system
must have the following characteristics which are near the patient, fully
automated, have a robust system, technically simple that it can be operated by
untrained operator, result can be made within 2 hours and has high sensitivity
range (98% to 100%) and specificity of 100%. The difference between LPA and
Xpert MTB/RIF is that LPA should only be carried out in TB risk level 2
laboratory while Xpert MTB/RIF can be carried out in TB risk level 1
laboratory. 56

Then, the imaging
testing, in which a chest radiography is taken to also used in support of
microscopic test. However, imaging cannot provide a clear result as many other
diseases mimic the radiologic characteristics of TB. This kind of radiologic
imaging can be divided into three plus two categories in which the first three
can be used on both PTB and EPTB (extrapulmonary tuberculosis) while the latter
two are used mainly for EPTB detection. First, the Chest X-Ray (CXR) in which
this is the primary imaging modality for PTB although it has lower sensitivity
than the other two but relatively less costly. Second, the Computerized
tomography (CT) or most people called it as CT scan in which it has higher
sensitivity in picturizing endobronchial spread, lymphadenopathy and pleural
complication. Third, Magnetic Resonance Imaging (MRI) in which this is only
used under special circumstances especially for paediatrics and pregnant women
due to the absence of ionising radiation. MRI is not used widely due to its
high cost and limited accessibility but it is definitely better in
demonstrating soft tissue characteristics. The fourth category is the
ultrasonography (US) in which it is only used to do the imaging of EPTB to show
the collection of pleural and put guidance on diagnostic or therapeutic procedures.
The fifth category is intravenous urography (IVU) in which it is used to
characterize the “moth-eaten” calyx for the evidence of renal TB. 56

There are also
additional diagnostic tests can be done to diagnose a TB case for example in
PTB, sputum induction with nebulised hypertonic saline, gastric lavage, and
fibreoptic bronchoscopy with bronchoalveolar lavage can be used in patients who
cannot expectorate enough sputum specimens spontaneously. In EPTB, since
microscopy and culturing of M. tuberculosis give relatively low proportion of
cases with positive result, procedures like thoracocentesis, biopsy,
colonoscopy, cystoscopy, fine needle aspiration, and lumbar puncture can be
done to support the diagnosis of EPTB. 56

 

2.     
Treatment

The treatment of
TB is to cure and reduce the risk of transmission of the disease itself. There
are few criteria for the determination of the risk of TB infection
post-exposure which are the nature and duration of the contact, infectiousness
of the index case, and the immune status of the individual. Pulmonary and
laryngeal TB are infectious and EPTB are said to be non-infectious. The most
infectious TB is from the patient which shows positive result in sputum smear
or multiple pulmonary cavities are imaged in the chest radiograph. Besides
that, the risk of infection is also determined to the physical distance, degree
of co-ventilation, and duration of exposure between the index case and the
contact. In the treatment of TB, health education must be given to both the
patients and their family members or those who live with them at the beginning
of the therapy in which aspects such as;5 nature
of the disease, necessity of strict adherence with the prolonged treatment,
risks of defaulting treatment, side effects of the medication, risks of
transmission and need for respiratory hygiene as well as cough/sneeze etiquette.
TB treatment regimen/therapy must be standardized to control the disease. A
good TB treatment must include appropriate regiment, right duration of
treatment, and patient adherence to the treatment to make sure the treatment is
effective enough to cure, prevent death, decrease the rate of transmission, and
prevent the rise of drug resistant TB. 15

Treatment of
tuberculosis is divided into two phases, which are intensive and maintenance
phase. The regimen for each phase is as below:

–         
Intensive phase: 2SHRZ or 2EHRZ or 2HRZ or
2Akurit-4

–         
Maintenance Phase: 4H2R2
or 4S2H2R2 or 4HR or 4H3R3
or 4S3H3R3

*(H: Isoniazid, R: Rifampicin, Z: Pyrazinamide, E:
Ethambutol, S; Streptomycin, Akurit-4: H 75mg + R 150mg + Z 400mg + E 275mg)

                        The
number preceding the treatment regimen refers to the treatment duration in
months and he subscript below the drug symbol refers to the frequency of doses
per week.

 

 

a)      Common
Antituberculosis Drugs Regimen.

Bil

Regimen

INTENSIVE PHASE
(Duration: 2 months)

MAINTENANCE PHASE
(Duration: 4 months)

1

Akurit-4 & RH

Akurit-4 (daily)

R (daily)

H (daily)

2

Akurit-4 & RH

Akurit-4 (daily)

R (2 times per week)

H (2 times per week)

3

Akurit-4 & RH

Akurit-4 (daily)

R (3 times per week)

H (3 times per week)

4

EHRZ & RH

E (daily)

H (daily)

R (daily)

Z (daily)

R (daily)

H (daily)

5

EHRZ & RH

E (daily)

H (daily)

R (daily)

Z (daily)

R (2 times per week)

H (2 times per week)

6

EHRZ & RH

E (daily)

H (daily)

R (daily)

Z (daily)

R (3 times per week)

H (3 times per week)

 

b)      Doses
of First Line Antituberculosis (Individual Drugs)

Drug

Recommended Dose
 

Daily
 

2 times per week

3 times per week

Dose and range
(mg/kg body weight)

Max
(mg)

Dose and range
(mg/kg body weight)

Daily Max
(mg)

Dose and range
(mg/kg body weight)

Daily Max
(mg)

Isoniazid (H)
100 & 400mg

5 (4-6)

300

15-20

1200

10 (8-12)

900

Renal dose:
N/A
 

Rifampicin (R)
150 & 300mg

 
10 (8-12)

600

15-20

600

10 (8-12)

600

Renal dose:
N/A
 

Pyrazinamide (Z) 500mg

25 (20-30)
 

50

2000

35 (30-40)

Renal dose:
ClCr 70

5 tablet daily

5 tablet daily

 

                        The
treatment for previously treated TB patient is different from normal regimen as
this can be considered as failure, relapse or return after default. WHO
recommends regimen for this case consisting of first-line drugs
2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR-TB.
To the patient, a drug sensitivity test must be done to ensure that the M.
tuberculosis bacilli did not mutate. 
Whenever there is an interruption in the drug therapy, the physician
needs to decide whether the patient needed to restart the whole course of the
therapy or continue from the last dose or just exit from the treatment. In
intensive phase. If the interruption is more than or equal to 14 days then the
patient should restart the whole drug therapy, if less than 14 days then the
patient can continue from the last dose. In maintenance phase, if interruption
happens after patient taken 80% of the total planned doses, the drug therapy
can be exited if the sputum AFB smear was negative but if the sputum smear was
positive, then the treatment should be continued until the total number of planned
doses is achieved. For patient who receives less than 80% of total planned
doses, restart the whole regimen from the start if the interruption lapse is
more than or equal to 2 months but if less than 2 months, the patient can
continue the regimen from the day it stops until the full course is completed.
15

3.     
Direct Observed Therapy (DOT)

DOT is a practice where both the health care
provider or other responsible person are in-charge in observing as the patient
ingest and swallows the TB medications. DOT management strategy is used in all
patients with TB. DOT aims to ensure adherence to TB therapy and reduce the
risk of the emergence of drug-resistance TB. Thus, it can greatly decrease the
risk of transmission of TB in the community. DOT can be administered to
patients in the office/clinic/home/school/work settings with daily or 2 to 3
times per week regimens.

3.0 Own Strategies for
the Management of Tuberculosis

            First of all, the
management of tuberculosis starts with the risk assessment by categorizing the
risk in category of low, medium, and potential ongoing transmission. Secondly,
the risk control which includes environmental controls, administrative
controls, and personal protective equipment. Environmental control is the
separation of certain room with high risks in which the cleanliness can be
aided by various ventilation and filters such as HEPA filter and UVGI
(ultraviolet germicidal irradiation). Administrative controls include starting
a TB Infection Control Committee to train and educate patients and health care
workers on the information of TB. Patients should undergo various tests once they
are suspected to have contacted TB disease. Once found to be infected with
infectious TB (PTB), the patients should be put into quarantine room and away
from other non-TB patients. Personal protective equipment includes wearing the
protective gear such as N95 disposable mask/respirator. 7

As a civilian, if we have non-stopping cough for
more than 2 weeks should check ourselves into clinics or hospital for
diagnostic test for TB. If our family members are infected with TB, protective
measure should also be carried out even after the patient has been sent to the
hospital. For example, cleaning the house especially calling some specialist to
help clean the air in the house. Family members are also better to do some
quick tests in clinics or hospitals to ensure that they are not contacted with
TB. As the patient, we should also adhere to the drug therapy regimen to reduce
the risk of transmission and also prevent the emergence of drug-resistance TB
which is more deadly.

 

REFERENCES

1.      Alldredge
Brian K., Corelli Robin L., Ernst Michael E., Guglielmo B. Joseph, Jacobson
Pamala A., Kradjan Wayne A., Williams Bradley R. Koda-Kimbel & Young’s
Applied Theraputics: The Clinical Use of Drugs. 10th ed.
Philadelphia, USA: LIPPINCOTT WILLIAMS & WILKINS; 2013.

2.     
MedlinePlus Internet. United States;
Tuberculosis; cited 2017 Dec 6; about 1 screen. Available from: https://medlineplus.gov/tuberculosis.html

3.      World
Health Organization (WHO). Tuberculosis Internet. Specialized agency of the
United Nations; 2017 cited 2017 Dec 6. Available from: http://www.who.int/mediacentre/factsheets/fs104/en/

4.      Nester
Eugene W., Anderson Denise G., Roberts C. Evans Jr., Nester Martha T.
Microbiology: A Human Perspecitive. 7th ed. USA: The McGraw-Hill
Companies Inc; 2012.

5.      author
unknown – Group of Development from Ministry of Health Malaysia, Academy of
Medicine Malaysia, and Malaysian Thoracic Society. MANAGEMENT OF TUBERCULOSIS.
3rd ed. Putrajaya, Malaysia: Malaysia Health Technology Assessment
Section (MaHTAS) Medical Development Division, Ministry of Health Malaysia;
2012.

6.      TB
Care I. International Standards for Tuberculosis Care. 3rd ed. TB
CARE I, The Hague, 2014.

7.      Occupational
Health Unit Disease Control Division Ministry of Health Malaysia. GUIDELINES ON
PREVENTION AND MANAGEMENT OF TUBERCULOSIS FOR HEALTH CARE WORKERS IN MINISTRY
OF HEALTH MALAYSIA. Ministry of Health Malaysia; 2012.

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