PULMONARY TUBERCULOSIS

Definition

Pulmonary tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. In many

cases, M tuberculosis becomes dormant before it progresses to active TB. It most commonly involves the
lungs and is communicable in this form, but may affect almost any organ system including the lymph
nodes, CNS, liver, bones, genitourinary tract, and gastrointestinal tract. (BMJ Best Practice)

High Risk Group

People Living in
Immunocompromised Substance Abuser &
Close TB Contact Overcrowded
Patients Cigarettes Smokers
Conditions
Household contact DM Drug user (illicit/IV/hard Homelessness
Non household contact HIV drugs) History of incarceration
COPD IVDU Institutionalisation
ESRF Current smoker (homes, shelter)
Malignancy excessive alcohol Prisoner
Malnutrition consumption (>40g of
Use of alcohol/day)
immunosuppresant
drugs

A complete medical evaluation for TB disease includes the following five components:

1. Medical history

2. Physical examination

3. Test for M. tuberculosis infection

4. Chest radiograph

5. Bacteriologic examination of clinical specimens

1. Medical History

I. Typical (Adult) PTB

a. productive cough,
b. haemoptysis Chest symptoms
c. chest pain
 d. loss of appetite
e. unexplained weight loss
f. fever nonspecific constitutional symptoms
nonspecific constitutional symptoms
g. night sweats
h. fatigue
i. **may be absent in immunocompromised patients

II. Unexplained cough >2 weeks

a. ± constitutional symptoms
b. Should be investigated for PTB

III. TB in Children
a. prolonged fever
b. failure to thrive
c. unresolving pneumonia
d. loss of weight
e. persistent lymphadenopathy.
f. symptomatic child having history of contact with active TB.

IV. EPTB
 vary according to the organs involved, may be nonspecific

2. Physical Examination
Accordingly

3. Test of MTB
 There are two methods available for the detection of M. tuberculosis infection ;
o Mantoux tuberculin skin test (TST)
o Interferon-gamma release assays (IGRAs)
 Used to diagnose LTBI as well
 TST should be used as the preferred test in diagnosing LTBI
 IGRA could be used as an alternative test to TST for LTBI especially in certain
situations (refer on subtopic IGRA)

Mantoux Test (TST)

 In this test, a substance called purified protein derivative (PPD), which is derived from
tuberculin, is injected under the skin.
 Reactions to PPD usually begin 5 to 6 hours after injection, reach a maximum at 48 to 72 hours,
and subside over a period of a few days. However, positive reactions often persist for up to 1
week or longer.
 TST is both safe and reliable throughout the course of pregnancy
 TST cross-reacts with BCG and NTM (Non tuberculous mycobacteria), gives rise to false positive
results in some individuals
 The booster phenomenon occurs mainly in previously infected, older adults whose ability to
react to tuberculin has waned over time. When these people are skin tested many years after
they were infected with M. tuberculosis, they may have an initial negative reaction. However,
if they are tested again within a year of the first test, they may have a positive reaction. This is
because the first TST “triggered the memory” of the immune system, boosting its ability to
react to the second TST
Interferon Gamma Release Assay (IGRA)

 IGRAs detect the presence of M. tuberculosis infection by measuring the immune response to
TB proteins in whole blood.
 IGRAs cannot differentiate between LTBI and active TB disease.
 IGRA may be used as an alternative test for TST in all situations for adults
 At the moment, there are two commercial tests available
o T-SPOT.TB (Oxford, Immunotec)
o QFT-GIT Test (Cellestis)
  Theoretically more specific as they do not cross-react with the BCG and most NTM, compared to
TST

 The Development Group suggests that the situations where IGRAs may be used are as the
following:
i. As an alternative to TST for
a. Patients who are not expected to/could not come back for a reading of skin
induration after 48 - 72 hours
b. Patients who had recent BCG vaccination or past NTM

ii. Where a 2-step test is considered (TST followed by IGRA)

a. Close-contacts whose TST is in the range of 5 - 9 mm

b. Patients who are offered LTBI treatment but are not convinced that they have LTBI
c. Individuals who require annual screening of LTBI such as healthcare providers
working in high risk areas)

4. Chest Radiograph/Imaging

 Chest radiography remains the primary imaging modality for PTB in children, adults and even
pregnant women (with abdominal shield).
 Consolidation with cavitation is the hallmark of adult-type PTB but any abnormality in the CXR
has to be considered suspicious when diagnosing PTB
 A severity grading of the CXR :
  CT scan maybe considered in cases of :
o normal chest radiography but with high clinical suspicion
o management of complication of pulmonary tuberculosis.

5. Bacteriologic Examination of Clinical Specimen

i. Specimen collection, processing, and review

 at least two sputum specimens with at least one early morning

specimen when possible (CPG TB 2012)
 three consecutive sputum specimens are needed, each collected in 8-
to 24-hour intervals, with at least one being an early morning specimen
(CDC, American Thoracic Society 2017)

 4 specimen collection methods for pulmonary TB disease :

 Coughing

 Induced sputum - For patients unable to cough up sputum,

sputum induced by inhalation of an aerosol of warm, sterile,
hypertonic saline (3%– 5%).
  Properly performed sputum induction is the
preferred method over bronchoscopy as the
sensitivities are 96.3% and 51.9% respectively.

 Bronchoscopy - Bronchoscopy might be needed for specimen

collection, especially if previous results have been nondiagnostic
and doubt exists as to the diagnosis
 patients who are smear negative for AFB or who
have difficulty in producing sputum, bronchoscopy can
establish a diagnosis microbiologically or
histopathologically

 Gastric aspiration – for children who often unable to cough up

sputum

ii. AFB smear classification and results

 Smear microscopy is the quickest and easiest procedure that can be
performed
 There are two procedures commonly used for acid-fast staining:
o Direct microscopy: Carbolfuchsin methods which include the
Ziehl-Neelsen and Kinyoun methods
o Fluorescent microscopy: Fluorochrome procedure using
auramine-O or auramine-rhodamine dyes
 Light emitting diode-based fluorescence microscopy (LED FM) has
benefits over conventional FM in terms of being less expensive, having
lower maintenance requirement and not requiring a dark room.

 Many TB patients have negative AFB smears with a subsequent positive

culture. Negative smears do not exclude TB disease.
 5,000 to 10,000 bacilli per milliliter of specimen to allow the
detection of bacteria in stained smears.
 10 to 100 bacilli are needed for a positive culture

iii. Direct detection of M. tuberculosis in clinical specimen using nucleic acid

amplification (NAA)
  Nucleic Acid Amplification Tests (NAAT) provide rapid results within 24 -
48 hours and has greater PPV (>95%) with AFB smear postive
specimens. They have the ability to confirm rapidly the presence of
Mycobacterium in 50 - 80% AFB smear negative, culture positive
specimens.

 CDC recommends that NAA testing be performed on at least one

respiratory specimen from each 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, such as contact
investigations.

iv. Specimen culturing and identification

 Culture remains the gold standard for laboratory confirmation of TB
disease, and growing bacteria are required to perform drug-
susceptibility testing and genotyping.
 Should be done on all diagnostic specimens, regardless of AFB smear or
NAA results.
 The commercially available medium:
o Liquid / broth culture systems (e.g., BACTEC, MGIT, VersaTREK,
MBBACT) - allow detection of most mycobacterial growth in 4 to
14 days
o Conventional solid media eg Lowenstein–Jensen and Ogawa
takes 3 to 6 weeks to culture

v. Drug-susceptibility testing
 For all patients, the initial M. tuberculosis isolate should be tested for
resistance to the first-line anti-TB drugs: isoniazid, rifampin,
ethambutol, and pyrazinamide.
 Conventional growth-based drug-susceptibility test includes :
o commercial liquid medium
o Conventional agar medium.

**DETECTS presence of mutations in specific M. tuberculosis genes

 Current guideline incorporates molecular detection of drug resistance,

in order to allow rapid detection of drug resistance. However it is
essential that conventional growth-based drug-susceptibility tests are
done and used in conjunction with molecular results.

o Line Probe Assay (LPA)

 Line Probe Assay (LPA-molecular assay) should
be performed to detect rifampicin and isoniazid
resistance in smear positive sputum specimens or
culture isolates from smear positive and negative
specimens.
 should be carried out in a tuberculosis (TB) risk
level 2 laboratory.

o Xpert MTB/RIF
 simultaneously detects Mycobacterium
tuberculosis complex (MTBC) and resistance to rifampin
(RIF) in less than 2 hours
 The Xpert MTB/RIF assay is a nucleic acid
amplification (NAA) test that uses a disposable cartridge
with the GeneXpert Instrument System
 can be deployed in state laboratories to scale
up the detection of drug resistant tuberculosis for which
a TB risk level 1 laboratory will suffice

 A limitation of molecular testing : clinical relevance of some mutations

remains unknown. Further, not all biological mechanisms of resistance
are known. As a result, if no mutations are detected by the molecular
assay, resistance cannot be ruled out.

 Second-line drug susceptibility testing should be done only in reference

laboratories and generally be limited to specimens from patients who
have the following characteristics:
 o Prior TB disease treatment;
o Contact with a patient with known anti-TB drug resistance;
o Demonstrated resistance to first-line anti-TB drugs; or
o Positive cultures after more than 3 months of treatment.

 Multidrug-resistant TB (MDR TB) - resistant to at least isoniazid and

rifampin, the two most potent first-line anti-TB drugs.
 Extensively drug-resistant TB (XDR TB)-resistant to isoniazid and
rifampin, any fluoroquinolone, and at least one of three injectable
second-line drugs (i.e., amikacin, kanamycin, or capreomycin).
MANAGEMENT OF PTB

 The major goals of treatment for TB disease are to

o Cure the individual patient;
o Minimize risk of death and disability; and
o Reduce transmission of M. tuberculosis to other persons.

 Newly-diagnosed PTB, the standard antiTB treatment :

o 6-month regimen consisting of
 daily 2-month of EHRZ
 followed by daily 4-month of HR

 Most of the bacteria are killed during the first 8 weeks of treatment; however, there are
persistent organisms that require longer treatment.

 Fixed Dose Combinations (FDCs) are preferred to separate-drugs combination for the treatment
of tuberculosis.
 The two FDCs available in MoH Drug Formulary for adults are:-
a. 4-Drug combination: Isoniazid 75 mg, Rifampicin 150 mg, Pyrazinamide 400 mg and
Ethambutol 275 mg tablet
 b. 3-Drug combination: Isoniazid 75 mg, Rifampicin 150 mg and Pyrazinamide 400 mg
tablet
 The recommended dosages for the two FDCs are:
o 30 - 37 kg body weight: 2 tablets daily
o 38 - 54 kg body weight: 3 tablets daily
o 55 - 70 kg body weight: 4 tablets daily
oMore than 70 kg body weight: 5 tablets daily

Intensive Phase
 crucial for preventing the emergence of drug resistance and determining the ultimate
outcome of the regimen.
 Four drugs—EHRZ—should be included in the initial treatment regimen until the results of
drug-susceptibility tests are available.
 Isoniazid and Rifampicin allow for short-course regimens with high cure rates.
 Pyrazinamide has potent sterilizing activity, which allows further shortening of the regimen
from 9 to 6 months.
 Ethambutol helps to prevent the emergence of RIF resistance when primary INH resistance
is present.
 If drug-susceptibility test results are known and the organisms are fully susceptible,
EMB need not be included.
 For children whose clarity or sharpness of vision cannot be monitored, EMB is usually not
recommended except when the risk of drug resistance is high or for children who have
“adult-type” (upper lobe infiltration, cavity formation) TB disease.

Maintenance Phase
 Given for either 4 or 7 months.
 The 4-month maintenance phase should be used in patients with uncomplicated,
noncavitary, drug-susceptible TB, if there is documented sputum conversion within the first
2 months.
 The 7-month continuation phase is recommended only for
 Patients with cavitary or extensive pulmonary TB disease caused by drug-susceptible
organisms and whose sputum culture obtained at the time of completion of 2
months of treatment is positive;
 Patients whose initial phase of treatment did not include PZA; or
 Patients being treated with once-weekly INH and RPT and whose sputum culture at
the time of completion of the initial phase (i.e., after 2 months) is positive.
Treatment Interruption During Intensive Phase

Treatment Interruption During Maintenance Phase

B,A,C,A,D,D
FOLLOW-UP & ADVERSE DRUG EVENTS

 Patients with initial sputum smear positive should have repeat sputum smear at two and
six months of treatment.

 Patients with initial sputum smear negative should have repeat sputum smear at two
months of antiTB treatment. If still negative, no further sputum sample is required.

 Patients who remains sputum positive at two months should be referred to specialist with
experience in tuberculosis (TB) management.
.
 Follow-up may not be conducted routinely after completion of antiTB treatment.
o Patients should be well-informed on symptoms of TB recurrence.
.
ADVERSE DRUG REACTION
Drug-Induced Hepatitis (DIH)

 Risk factors for DIH include:

o slow acetylators
o old age
o extensive TB disease
o malnutrition
o alcoholism
o chronic viral hepatitis B and C infections
o pregnancy until 90 days postpartum
o HIV
o organ transplant recipients.

 DIH is usually caused by pyrazinamide, isoniazid and rifampicin; pyrazinamide being the
most hepatotoxic and rifampicin the least.

PYRAZINAMIDE>ISONIAZID>RIFAMPICIN
More hepatotoxic

 It has been recommended to stop antiTB drugs when

o the serum transaminase level reaches three times the upper limit of normal for
patients with symptoms suggestive of hepatitis or
o five times upper limit for those without symptoms.

 Subsequently, if the TB disease is of low severity in terms of radiographic extent,

bacillary load and infectiousness, antiTB treatment can be withheld until liver chemistry
recovers and patients symptoms resolve.

 Timing of restarting treatment also depends on whether hepatotoxicity sets in during

the initial or the continuation phase of treatment, and the amount of treatment
received prior to the onset of such toxicity.

 The patient can then be retreated with a regimen containing fewer potentially
hepatotoxic drugs

 Retreatment regimen can contain fewer potentially hepatotoxic drugs such as

streptomycin, ethambutol and isoniazid.
 If symptoms recur or liver function tests become abnormal as the drugs are
reintroduced, the last drug added should be stopped.

 Rifampicin can be introduced first as it is less likely than isoniazid or pyrazinamide to

cause hepatotoxicity and is the most effective drug.

 In patients who have DIH but tolerate the reintroduction of rifampicin and isoniazid, it is
advisable to avoid pyrazinamide.

 After 3 - 7 days, isoniazid may be reintroduced. If pyrazinamide is not included in the

intensive phase, the total duration of treatment should be extended to nine months
 LATENT TB INFECTION (LTBI)

Definition
Latent TB is defined as infection with Mycobacterium tuberculosis complex, where the
bacteria may be alive but in the state of dormancy and not currently causing any active
disease/symptoms.

 High risk individuals of acquiring LTBI or developing TB reactivation should be investigated,

which include
1. Recent close contacts (<2years)
2. Residents and employees of high risk congregate settings (such as correctional facilities,
nursing homes, homeless shelters, hospitals and other health care facilities)
3. HIV-infected persons
4. Organ transplant recipients
5. Persons who are receiving immunosuppressant drugs
6. Recent immigrants (<2years) from high prevalence countries
7. Injecting drug users
8. Persons with fibrotic changes on CXR consistent with old TB (patients with calcified
lesions should be excluded)
ISONIAZID FOR LTBI
 The recommended treatment regimen for LTBI is nine months of daily isoniazid.
 The shorter course of six month is an acceptable alternative.
 Very effective and preferred for HIV-infected people taking antiretroviral treatment (IPT) and
children aged 2 - 11 years of age.

TB IN SPECIAL GROUP - RX

TB IN PREGNANCY  Isoniazid, rifampicin, ethambutol and pyrazinamide are safe

to be used in pregnancy.

 no increased risk of congenital abnormalities in babies after

their mothers receive treatment with isoniazid and other
antiTB drugs.

 Streptomycin should be avoided in pregnancy due to foetal

ototoxicity.

 Pyridoxine (25 mg daily) should be given to all pregnant

women on isoniazid to prevent foetal neurotoxicity.

LACTATION  Breastfeeding mothers with TB should receive a full course

of antiTB drugs. Timely and proper administration of such
drugs is the best way to prevent TB transmission to the
baby.
  First-line antiTB drugs are safe in breast feeding.

 Mother and baby should stay together for continuation of

breastfeeding.

o Surgical mask should be used if the mother is

deemed infectious.
o Separation of the infant from the mother should be
considered if the mother has MDR-TB or is non-
compliant to treatment

 Once active TB in the baby is ruled out, the baby should be

given six months isoniazid prophylaxis, followed by BCG
vaccination

 Pyridoxine supplementation is recommended for all

pregnant or breastfeeding wom¬en taking isoniazid

OCP  Rifamycin drugs such as rifampicin and rifabutin reduce the

contraceptive efficacy of both combined oral contraceptives
and progesterone-only pills.

 Alternative contraceptive methods should be used during

rifamycin therapy and for one month after stopping the
therapy even if it has been administered for less than a
week.

HIV  Active tuberculosis should be ruled out in all HIV-positive

patients.

 TB-HIV co-infected patients require the diagnostic tests as in

HIV-negative individuals BUT work up remains a diagnostic
challenge .

 In all HIV-positive patients suspected of pulmonary

tuberculosis, sputum tuberculosis (TB) culture should be
done regardless of smear acid fast bacilli status.

o Many patients have no cough (45%) and negative

sputum AFB smears (49%)
o HIV infection is associated with lower AFB
concentration in sputum among patients with active
PTB.
o AFB density in sputum decreases with decreasing
CD4 count
 o Sensitivity of microscopic examination of two
sputum AFB is only 38%.
o The rate of normal CXR among patients with culture-
confirmed PTB is high

 Recommendations for the treatment of TB in HIV-infected

adults are identical to those for HIVuninfected adults

IPT IN HIV  HIV infection significantly increases the risk of progression

from latent to active TB.

 active TB causes higher HIV viral loads and more rapid

progression of HIV disease.

 MoH circular recommends daily IPT to be given for at least

six months.