History: Tuberculosis (TB)
History: Tuberculosis (TB)
have already study the old one u have to check the underlined sentences only,&
lets strat:
History:
TB is a very old disease, and this is the chronology of the discovery of tuberculosis
Epidemiology
1/3 of the world population has latent tuberculosis; 8 million cases each year; 3
millions die each year.
TB is the 8th most common cause of death worldwide (3%).
Those in red have very high incidence of TB, the majority (59%) of cases are in
Asia esp. in India and China, Indonesia, Nigeria, and Africa. India has the majority
and Africa has the minority of cases among those countries. (Slide #8, #9)
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Etiology:
Tuberculosis is caused by infection with mycobacterium tuberculosis complex
which includes:
1- Mycobacterium tuberculosis: the commonest & usually infects the lungs.
2- Mycobacterium bovine: rare since the infected cattle (reservoir) have been
eradicated and the milk has been pasteurized, usually infects the GI tract:
terminal ileum and the cecum are the sites most commonly involved.
3- Mycobacterium africanum: the reservoir is human
4- Mycobacterium microti: in immunodeficient.
5- Mycobacterium canetti: in Africa
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Microbiology
M.TB is a small enveloped rod shaped bacillus (2-10 m).It is an acid and alcohol
fast, means that if you stain it by aniline die and then you add acid alcohol to destain it, the stain will not change; it remains the same, and that is due to the high
content of mycolic acid in the cell wall that prevents the de-staining.
M.TB is similar to the gram positive in architecture, but if you stain it with gram
stain, it will take the stain very faintly/weakly due to the presence of mycolic acid;
it is neutral on gram staining.
It is an obligate aerobic organism; it favors high oxygen & high PH environments.
M.TB is a slow growing MO; the generation time is about 20-24 hrs (in contrast to
E coli which takes about 20 mins), thats why TB culture usually takes long time
(about 6-8 weeks). Nowadays & with the advanced procedures, culturing of M.TB
is more rapid; within days rather than weeks.
Transmission:
TB is transmitted through respiratory droplets (0.5-5) so it can be transmitted
through speak, cough and sneezing as well as a single sneeze can generate 40,000
droplets.
Its very easy to get TB because it has a very low infectious dose since 10 bacteria
are enough to cause infection and one untreated patient can infect 10 -15
person/yr.
Risk Factors:
Biological
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-Age (children > young adults < elderly). Aging decreases the immunity.
-Genetic susceptibility (on chromosome 15 q), it's a very weak factor.
- HIV because the immunity is already low.
-Diet:1) Vit D deficiency: A study in Indonesia showed a higher rate of eradication
in those who were treated with anti TB drugs along with vit. D supplements than
those who did not or those who were deficient in vit. D);
osteomalacia/osteoporosis may increase the risk of TB infection,2) Decreased Vit A
intake also increase the risk,3) increase iron intake will increase the risk because
the iron stimulates the growth and multiplication of TB bacilli; haemochromatosis
may increase the risk of TB infection.
-ESRD (End Stage Renal Disease), Diabetes Mellitus (esp. type 1 DM), & Organ
transplantation, Malabsorption diseases (i.e. celiac disease).
-Malignancy: not all types of malignancies only the hematological (leukemia and
lymphoma) and head and neck tumors.
-Drugs: 1)corticosteroids use : depending on the underlying disease, for example,
asthmatics on long term use of corticosteroids are NOT at risk for developing TB,
while patients with connective tissue diseases (SLE) and on long term use of
steroids are at increased risk more than the general population the Dr mean use
of systemic corticosteroids. 2)TNF- inhibitors (infliximab) is a bactericidal product
of macrophages, is used to treat certain rheumatological diseases (e.g.
rheumatoid arthritis). Patients receiving these drugs must be screened regularly
for TB by the history, doing chest X- ray, and by the PPD skin test, because they
are approved to increase the risk. Also 3)cytotoxic drugs are risk factors
Behavioral
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common & important risk factor worldwide, thats why the incidence in poor
countries (Africa and in parts of Asia) is much more than in rich countries.
-Health workers, institutional
Environmental
-Silica, asbestos, solid fuel
-Long term close contact with an active TB patient.
Pathogenesis:
TB is an airborne disease transmitted via droplets and the only reservoir for TB is
the human, other type of TB is transmitted by other ways (mentioned previously),
the initial site of infection is the lungs and then it will be transmitted through the
lymph to the regional lymph nodes (mediastianl).
Most people with TB shed relatively few bacteria (except for those who have
endobrachial,laryngeal, or cavitary tuberculosis). Therefore, a long term of close
contact with the infected patient is required in order the disease to be
transmitted from a person to another, that's why screening of the family
members of the patient is recommended because they are at higher risk than
those who have a casual contact (in the clinic or during taking history) with the
patient, which doesnt lead to infection or transmission of the disease. If a person
is exposed to bacilli for the first time, the response to such an exposure depends
on the immunity of the patient and on the size of the inoculum (how much acid
fast bacilli are present in that droplet). Low immunity and high amount of bacilli
can result in infection/disease.
TB infection begins when the mycobacterium reach the pulmonary alveoli, where
they invade and replicate. The primary site of infection is the lungs and 2/3 of
population who has been exposed to the bacilli will not have the infection
because theyre immunocompetent and the macrophages success in engulfment
of the bacilli so theyll have a ve skin test.
1/3 of population will be infected and will have a +ve skin test but that does not
mean they will develop the disease(symptoms) some will and others will not
because their immunities are not that good; the alveolar macrophages will be
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incapable of controlling the infection so they will burst and more acid fast bacilli
will be released into the alveoli and more alveolar macrophages and monocytes
and neutrophiles will be recruited to the area (due to chemokines and cytokines
release) trying to control the infection.
BUT, the patient will develop cell mediated immunity (CMI) within 2-6 weeks. The
CMI will produce activated macrophages that are capable of engulfing the unactivated macrophages, killing the tubercle bacilli, and damaging the tissue of the
lung leading to caseating necrosis, thus resulting in granuloma formation. The
infection will be contained within this granuloma; the growth & the multiplication
of the bacilli will be inhibited within this necrotic environment by the low oxygen
& low pH (here the acid fast bacilli are not killed only jailed within the granuloma).
And this response is called primary tuberculosis or latent tuberculosis (occur in
90% of cases); in which the patient has been exposed to the bacilli but he didnt
develop the disease hes asymptomatic or mildly symptomatic but has a positive
skin test. His chest x-ray is normal, he developed immunity against the infection
through the formation of the granuloma (via cell mediated immunity) but still
there are acid fast bacilli viable (dormant) within the granuloma and they are
living in synchronization with the body immunity, and the only manifestation in
this patient is the positive skin test>>requires 2-6 weeks to appear).
Primary tuberculosis is common among children & immunocompromised persons
& is not highly infectious. Because most inspired air is distributed to the middle
and lower lung zones, so these areas are the most commonly involved areas in
primary tuberculosis. The granuloma formation usually occurs peripherally and is
usually accompanied by hilar or paratracheal lymphadenopathy; Ghon's complex.
Ghon's complex heals spontaneously by calcification.
Patients with latent TB (called new skin test converters) must receive Isoniazid
(INH) treatment (the so called Treatment of Latent Tuberculosis); it is called
treatment not prophylaxis, because prophylaxis means the prevention of the
infection before happening but here infection is already present. In contrast to
the disease, the infection is an asymptomatic condition but with a +ve skin test.
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In conclusion: 2/3 of the population who is exposed to the bacilli, all cases
attempt an immediate clearance of the organisms because of the excellent
immunity. And 1/3 will get the disease but 90% of cases will get latent infection
which is controlled within 2-6 wks via CMI, 5% of cases will have primary
progressive disease, 5% will have reactivation of the disease after the first 2 yrs of
primary exposure.
To differentiate:
-Primary pulmonary TB: infection of a previously uninfected individual.
-Post primary pulmonary TB: exogenous (new infection) or endogenous
(reactivation of a dormant primary lesion) infection in a person who has been
sensitized by earlier exposure.
-Latent TB: the person infected with mycobacterium TB but does not develop a
disease i.e. without symptoms.
Primary TB
Secondary TB reactivation
Location
Infection
More infectious
Clinical presentation:
Tuberculosis is classified as pulmonary, extra-pulmonary, or both. Most HIV
patients have both or extra-pulmonary alone.
TB disease is a sub-acute or chronic illness, it doesn't present acutely like
pneumonia.
Those who have latent TB will pass un-noticed (asymptomatic), in which,
they might have flu like symptoms for few days and nobody will care about
them.
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Diagnosis
Clinical features (primary, latent, reactivation) not specific
Tuberculin Skin tests (Mantoux test): It is used primarily for the detection of
M. tuberculosis infection in persons without symptoms; it is used in
screening for latent TB. It doesnt diagnosis or exclude TB but tells you that
this patient has been exposed to acid fast bacilli and he might have a
disease or a latent infection; it is neither specific nor sensitive. It is not
diagnostic because some patients may have actual disease but they still
have -ve skin test (this occurs esp. in Miliary TB, sarcoid, lymphoma,
malnourished, or immuno-suppressed patients) and some patients may
have +ve skin test even without having the disease. So, negative PPD skin
test in a patient with symptoms of TB makes the likelihood of TB less likely,
but it doesn't exclude the infection because some patients might have a
negative PPD skin test in spite they are having active diseases.
The interpretation of the skin test depends on the immunological status and
the age of the patient.
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For young people and those who have no risk factors and healthy (low risk
group), >15 mm indurations after injecting 5 units of tuberculin interadermally
inside the skin (not subcutaneously) is considered as a +ve PPD skin test.
For people above age of 30 and those who have associated risk factors (e.g.
ESRD on dialysis, diabetes, Leukemias, lymphomas, Silicosis, Underweight
10% ideal body weight etc.) but non-HIV (moderate risk group), 10 mm
indurations is considered as a +v skin test.
For those patients with HIV infection, with close contact with a TB active
patient, Immunosuppression, Organ transplant, Chemotherapy , Old TB on
chest X-ray, TNFa inhibitors and those who are their disease is about to be
reactivated (high risk group), >5 mm indurations is considered as a +ve skin
test.
Two step skin test; as we said we do this test because some patients have been
infected many years ago and the T-cells will be dormant, so we will give two doses
of PPD, the first dose is a booster dose that will sensitize the dormant T-cells .
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interferon release assay :We can use interferon gamma release assay to
diagnose latent TB ; in this test we stimulate the pre-existing T-cells by
specific antigens unique to M. tuberculosis quantiferon test then we
measure the level of interferon gamma in the blood ; if it is elevated , latent
infection is present(+).
Radiology
Early in the disease (latent TB), the chest x-ray may be completely normal.
Chest x-ray is important in determining the presence and the extent of the
disease. Pulmonary TB has different radiographic patterns which are:
a- Primary parenchymal lesion and mediastianl node (Ghon complex)
b- Apical pleural scarring
c- Cavitary disease
d- Lobar consolidation
e- Miliary (diffuse) disease
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Cavitary disease
This is a cavitary TB, it is
multiple cavities present here
(usually it is single cavity but it
might be multiple, it might
occur as a part of primary
disease
or
reactivation).
Cavitation is not specific for TB
because staph. Infection or
fungal
infection
(e.g.
histoplasmosis) can result in
cavitations.
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Microbiology
Specimens:
Patients with symptoms suggestive of pulmonary TB must do a chest x ray, and
usually we can see an abnormality in the chest x-ray but sometimes the chest x
ray might be normal early in the disease. Also we might do CT scan to
demonstrate the lesion but again it might be normal. If there is an abnormal chest
x ray with typical symptoms of pulmonary TB, we have to confirm our diagnosis
by the microbiological tests. So we must take a specimen or a sample first by
taking/doing:
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Histopathology:
To reach a presumptive diagnosis for TB we need to isolate the
Mycobacterium tuberculosis and this is done by:
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Rapid diagnostic test: Gene Xpert MTB/RIF: this test can diagnose TB in less
than two hours; also it measures the resistance of TB against RIF.
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Treatment:
Previously in the 19th century, the aim of the treatment of TB was to create an
anaerobic environment in the infected part of the lung since the acid fast bacillus
is obligate aerobic bacteria, thus killing the MO. In the 20th century,
chemotherapy was introduced as a treatment of choice of TB. Till now, no better
treatment of TB is available than chemotherapy
Herman Brehmer introduced sanatoria and 1st sanatoria opened in 1859 in
Sokolowsko Poland and sanatoria means isolation of infected patients
(from the community) and putting them in certain areas and giving them
good nutrition and rest and healthy atmosphere (good ventilation and sun
exposure)).
Carlo Forlanini introduced artificial pneumothorax in 1882 because the
bacilli are strictly aerobic, decreasing the O2 by collapsing the lungs will kill
the acid fast bacilli & stopped in 1946 because it causes deformity in chest
wall.
Thoracoplasty in the early decades of 1900s (by removing the upper ribs
and then collapsing the lungs, it also causes deformity of chest wall)
Plombage: by inserting balls composed of inert substances -instead of
removing the ribs- inside the chest to obliterate the area (to create an
anaerobic environment) which is infected) started in 1930 using air, oil,
paraffin wax, gauze, and Lucite balls in 1946. It doesn't cause chest wall
deformity; the mediastinum remains in the middle.
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Thoracoplasty
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Chemotherapy
1st line drugs:
In Jordan, we give these four standard drugs as first line drugs. Streptomycin was
considered as the 1st line treatment but because of increase incidence of
resistance, it is now used in the 2nd line treatment. The TB center in Jordan is
doing a very good job because they are distributing these drugs for free. If the
patient didnt come by the end of the month to take his medication, the health
workers will contact the patient and go to his home and make sure that he takes
the drugs.
Directly Observed Therapy (DOT) therapy is a policy adopted by the WHO which
means that the health workers go to the infected patient 3 times per week (but
they have to increase/adjust the dose) to give him his medication. DOT therapy is
successful in India and other parts of the world but not in Jordan, because if you
see a health worker coming every week 3 times to a family or a neighbor of you,
you will start asking why he is coming, they will answer we come to treat a TB
INFECTION, so the whole area will not talk to him or will not probably marry
his/her daughters, so, actually TB is considered as a stigma. Rather, we give the
patient 20-30 JDs every month if he comes to the hospital in order to let him buy
these drugs.
3. Ethionamide
4. Cycloserine
5. Paraaminosalicylic acid
6. Fluoroquinolones
These are reserved for multi drug resistance TB. Fortunately the multi drug
resistance of TB is a rarity in Jordan but in other counties, it is more common. The
term 'Multi Drug resistance' denotes that there bacilli resistance to INH and RIF.
Any Multi drug resistance patient MUST BE SENT to Al-Noor hospital in Mafraq,
because these 2ed line drugs are only available there.
Steroids are the treatment of choice in TB meningitis or TB pericarditis.
In TB meningitis we use RIF, INH, PZA and streptomycin rather than EMB as first
line treatment because streptomycin can cross the blood brain barrier as well as
the steroid.
New Drugs
Two drugs in research pipeline could be available in 2013:
Bedaquiline ,Delaminid.
Standared treatment:
We start the initial treatment by RIF, INH, PZA, and EMB daily for 2 month and
continue with RIF, INH daily for another 4 months.
-Rifampicin causes a change in the color of all body fluids to orange/red. This
color may stain the contact lenses resulting in blurring/blocking of vision.
-Ethambutol is associated with reversible (once the drug is discontinued) optic
neuritis, which can cause color blindness and other visual disturbances.
-PZA can cause hyperuricemia (rare).
Patients should be warned about all these side effects; if he developed optic
neuritis and visual disturbances, he should stop the drug right away. Similarly for
abdominal pain and vomiting (hepatitis) and red urine and tears.
Prevention: BCG vaccine will protect from miliary TB only and the response
or the protection is variable from 0% to 80%. We give the vaccine in the first
month of life.
Monitoring:
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-Before starting any patient on anti TB drugs, the patient has to do Base line tests:
Liver Function Test (RIF + INH + PZA are hepatotoxic), CBC, visual acuity and color
vision.
-Monthly you have to check the patient for side effects and adjustment of dose if
necessary.
-Every patient must have monthly sputum for smear and cultures until two
consecutive specimens are negative on culture then we stop it monthly. If the
patient is still +ve, he might have a resistance organism; so, change your
treatment/drugs. Usually, after 2-3 months, all become -ve.
So it is recommended that smears and cultures be reassessed after 3 months of
therapy to monitor for possible infection with drug resistant bacilli.
Smear +ve recheck smear at 2 months, if +ve repeat at 3 months & if +ve do
culture & sensitivity so after 3 months of treatment and the smear +ve this
is mean resistance or therapy failure
Smear ve at 2 months repeat at end
Smear +ve at 5 or 6 months this is treatment failure, do culture & sensitivity
In treatment monitory we must do both smear test and culture ; because
sometimes the smear will be positive for TB due to the presence of dead
bacilli but when we do culturing it will be negative.
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Drug Resistance
Primary vs Secondary
Drug resistant (any first line drug)
Multidrug-resistant MDR (resistant to at least INH & RIF)
Extensively drug-resistant XDR (resistant to INH, RIF, Quinolone, and and at
least one of the following second-line anti-TB injectable
drugs: kanamycin, capreomycin, or amikacin.)
Totally drug-resistant TDR(resistant to all locally tested drugs)
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Definition of cure:
Smear or culture ve at last month and on other previous occasion
TB & Pregnancy
We use the same treatment but no Streptomycin
Its safe to continue breast feeding
W akeed B2
Good Luck
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