WEEK 4

22-2
4

Tuberculosis
Earl Louis Sempio, MD
earl.sempio@oum.edu.ws
 CASE

• A 63 year-old man seeks medical attention because of unintentional weight loss

of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following the
death of his wife a year ago, at which time he moved from Hong Kong (a region of
high prevalence for tuberculosis) to the U.S. to live with his daughter. He has never
smoked. He has had a 3 month history of productive cough with greenish sputum.
He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is 16
breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and green
sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection years
ago.
Outline

Tuberculosis
Pathogenesis of TB
Diagnosis
Mycoses
Treatment
Hemoptysis
Bronchiectasis
 CASE
• A 63 year-old man seeks medical attention because of unintentional weight loss
of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following the
death of his wife a year ago, at which time he moved from Hong Kong (a region of
high prevalence for tuberculosis) to the U.S. to live with his daughter. He has never
smoked. He has had a 3 month history of productive cough with greenish sputum.
He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is 16
breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and green
sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection years
ago.
 HISTORY OF TB

• TB has affected humans

for millennia

• Historically known by a
variety of names,
including:
• Consumption
• Wasting disease
• White plague

• TB was a death sentence

for many Vintage image circa 1919
Image credit: National Library of Medicine
 HISTORY OF TB
SCIENTIFIC DISCOVERIES IN 1800S
• Until mid-1800s, many
believed TB was hereditary

• 1865 Jean Antoine-Villemin

proved TB was contagious

• 1882 Robert Koch

discovered M. tuberculosis,
the bacterium that causes Mycobacterium tuberculosis

TB Image credit: Janice Haney Carr

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of

Tuberculosis
 TB HISTORY TIMELINE

1993: TB cases decline due to

increased funding and enhanced TB
control efforts

1865: 1884:
Jean-Antoine First TB 1943:
Villemin sanatorium Streptomycin (SM) Mid-1970s: Most TB
proved TB is established a drug used to treat sanatoriums in U.S.
contagious in U.S. TB is discovered closed

1840 1860 1880 1900 1920 1940 1960 1980 2000

1882: 1943-1952: Mid-1980s:
Robert Koch discovers Two more drugs are Unexpected rise in TB
M. tuberculosis discovered to treat TB: cases
INH and PAS

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of

Tuberculosis
 TB TRANSMISSION

Transmission is defined as the spread of an organism,

such as M. tuberculosis, from one person to another.

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of Tuberculosis

 TB TRANSMISSION
TYPES OF MYCOBACTERIA
• M. tuberculosis causes most TB cases in U.S.

• Mycobacteria that cause TB:

• M. tuberculosis
• M. bovis
• M. africanum
• M. microti
• M. canetti

• Mycobacteria that do not cause TB

• e.g., M. avium complex M. tuberculosis

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of Tuberculosis

 TB TRANSMISSION

• TB is spread person to person through

the air via droplet nuclei

• M. tuberculosis may be expelled when an

infectious person:
• Coughs
• Sneezes
• Speaks
• Sings
• Transmission occurs when another
person inhales droplet nuclei
 TB TRANSMISSION

The probability that TB will be transmitted depends

on what four factors?

• Infectiousness of person with TB disease

• Environment in which exposure occurred

• Length of exposure

• Virulence (strength) of tubercle bacilli

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of

Tuberculosis
 TB TRANSMISSION

• The best way to stop transmission is to:

• Isolate infectious persons
• Provide effective treatment to infectious persons as soon as
possible

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of Tuberculosis

 CASE
• A 63 year-old man seeks medical attention because of unintentional weight
loss of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following
the death of his wife a year ago, at which time he moved from Hong Kong (a
region of high prevalence for tuberculosis) to the U.S. to live with his daughter.
He has never smoked. He has had a 3 month history of productive cough with
greenish sputum. He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is
16 breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and
green sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection
years ago.
 TB Pathogenesis

Pathogenesis is defined as how an infection or

disease develops in the body.

Module 1 – Transmission and Pathogenesis of Tuberculosis

 TB Pathogenesis
Latent TB Infection (LTBI)
• Occurs when tubercle bacilli are in the body,
but the immune system is keeping them under
control
• Detected by the Mantoux tuberculin skin test
(TST) or by blood tests such as
interferon-gamma release assays (IGRAs) which
include:

– QuantiFERON®-TB Gold test (QFT-G)

– QuantiFERON®-TB Gold In-Tube (QFT-GIT)
– T-Spot®.TB test (T-SPOT)

• People with LTBI are NOT infectious

Module 1 – Transmission and Pathogenesis of Tuberculosis
 TB Pathogenesis
TB Disease
• Develops when immune system cannot keep
tubercle bacilli under control

– May develop very soon after infection or

many years after infection

• About 10% of all people with normal immune

systems who have LTBI will develop TB
disease at some point in their lives

• People with TB disease are often infectious

Module 1 – Transmission and Pathogenesis of Tuberculosis
 TB Pathogenesis

Droplet nuclei containing tubercle bacilli are

inhaled, enter the lungs, and travel to small
air sacs (alveoli)
Module 1 – Transmission and Pathogenesis of Tuberculosis
 TB Pathogenesis

Tubercle bacilli multiply in alveoli, where

infection begins
Module 1 – Transmission and Pathogenesis of Tuberculosis
 TB Pathogenesis

A small number of tubercle bacilli enter

bloodstream and spread throughout body

Module 1 – Transmission and Pathogenesis of Tuberculosis

 TB Pathogenesis
LTBI

• Within 2 to 8 weeks the immune system produces

macrophages that surround the tubercle bacilli
• These cells form a barrier shell that keeps the
bacilli contained and under control (LTBI)

Module 1 – Transmission and Pathogenesis of Tuberculosis

 TB Pathogenesis
TB Disease

• If the immune system CANNOT keep tubercle bacilli

under control, bacilli begin to multiply rapidly and
cause TB disease
• This process can occur in different places in the body
Module 1 – Transmission and Pathogenesis of Tuberculosis
https://www.clinicalkey.com/#!/content/3-s2.0-B9780323532662003088
 CASE

• A 63 year-old man seeks medical attention because of unintentional weight

loss of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following
the death of his wife a year ago, at which time he moved from Hong Kong (a
region of high prevalence for tuberculosis) to the U.S. to live with his daughter.
He has never smoked. He has had a 3 month history of productive cough with
greenish sputum. He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is
16 breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows
induration >10mm and 3 early morning sputum samples are collected for
culture and sensitivity. Because of the positive PPD, chest film findings, weight
loss, and green sputum he is presumed to have reactivation tuberculosis, with
the lesion becoming active after a period of dormancy, following up an initial
infection years ago.
 LTBI vs. TB Disease

Latent TB Infection (LTBI) TB Disease (in the lungs)

Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli in
in the body the body
TST or blood test results usually TST or blood test results usually
positive positive
Chest x-ray usually normal Chest x-ray usually abnormal
Sputum smears and cultures Sputum smears and cultures may be
negative positive
No symptoms Symptoms such as cough, fever,
weight loss
Not infectious Often infectious before treatment
Not a case of TB A case of TB

Module 1 – Transmission and Pathogenesis of Tuberculosis

 Progression to TB Disease

• Risk of developing TB disease is highest the

first 2 years after infection

• People with LTBI can be given treatment to

prevent them from developing TB disease

• Detecting TB infection early and providing

treatment helps prevent new cases of TB
disease

Module 1 – Transmission and Pathogenesis of Tuberculosis

 Progression to TB Disease
Some conditions increase probability of LTBI
progressing to TB disease
• Infection with HIV • Organ transplant

• Chest x-ray findings • Silicosis

suggestive of previous TB
• Diabetes mellitus
• Substance abuse
• Severe kidney disease
• Recent TB infection
• Certain types of cancer
• Prolonged therapy with
corticosteroids and other • Certain intestinal conditions
immunosuppressive
therapy, such as prednisone
and tumor necrosis • Low body weight
factor-alpha [TNF-α]
antagonists
Module 1 – Transmission and Pathogenesis of Tuberculosis
 Progression to TB Disease
People Exposed to TB

Not Latent TB
TB Infected Infection (LTBI)

Not Not
Infectious Infectious

Negative TST or Positive TST or

QFT-G test result QFT-G test result

May go on to
No Latent TB develop TB
TB Infection Infection disease
Figure 1.5
Module 1 – Transmission and Pathogenesis of Tuberculosis
 Progression to TB Disease
TB and HIV
In an HIV-infected person,
TB can develop in one of
two ways:
• Person with LTBI becomes
infected with HIV and then
develops TB disease as the
immune system is weakened

• Person with HIV infection

becomes infected with M. Image credit: Mississippi State Department of Health
tuberculosis and then
rapidly develops TB disease

Module 1 – Transmission and Pathogenesis of Tuberculosis

 Progression to TB Disease
TB and HIV
People who are infected with both M. tuberculosis and HIV
are much more likely to develop TB disease
TB infection TB infection
and NO risk factors and HIV infection
(pre-Highly Active Antiretroviral
Treatment [HAART])

Risk is about 5% in the Risk is about 7% to 10%

first 2 years after infection PER YEAR, a very high
and about 10% over a risk over a lifetime
lifetime
Module 1 – Transmission and Pathogenesis of Tuberculosis
 Sites of TB Disease
Bacilli may reach any part of the body, but
common sites include:

Module 1 – Transmission and Pathogenesis of Tuberculosis

 Sites of TB Disease (2)
Location Frequency
Pulmonary TB Lungs Most TB cases are
pulmonary
Extrapulmonary TB Places other than Found more often in:
lungs such as:
• Larynx • HIV-infected or
• Lymph nodes other
• Pleura immunosuppressed
• Brain persons
• Kidneys
• Bones and joints • Young children

Miliary TB Carried to all parts of Rare

body, through
bloodstream

Module 1 – Transmission and Pathogenesis of Tuberculosis

 GENERAL APPROACH

●Clinical manifestations, physical findings (cough generally >2 to 3 weeks

duration, lymphadenopathy, fevers, night sweats, weight loss). In general,
specific symptoms localize to site(s) of disease.
●History of prior TB infection or disease. Tuberculin skin testing and
interferon-gamma release assays are useful for identifying M.
tuberculosis infection, and one of these tests should be performed in a
suspected case.
●Epidemiologic factors (including known or possible exposures, and past or
present residence in or travel to an endemic area).
●Radiographic features and/or laboratory findings consistent with TB
Adapted from: Controlling tuberculosis in the United States. Recommendations from the American Thoracic
Society, CDC, the Infectious Diseases Society of America. MMWR Recomm Rep 2005; 54(RR-12):1. Daley CL,
Gotway MB, Jasmer RM. Radiographic manifestations of tuberculosis: a primer for clinicians. San Francisco,
CA: Francis J Curry National Tuberculosis Center; 2003: 1-30, and Updated guidelines for the use of nucleic
acid amplification tests in the diagnosis of tuberculosis. MMWR Morb Mortal Wkly Rep 2009; 58:7.
Natural History of TB
Diagnosis of Pulmonary Tuberculosis

• The diagnosis is based in part on the history and on physical and

radiographic findings of consolidation or cavitation in the apices of the
lungs.
• Tubercle bacilli must be identified.
• Acid-fast smears and cultures of the sputum of patients suspected of
having tuberculosis should be performed.
• Culture on solid agar media show growth at 3 to 6 weeks, but culture in
liquid media can provide an answer within 2 weeks.
• PCR amplification of M. tuberculosis DNA allows for even more rapid
diagnosis. A PCR test has recently come into use that both identifies the
presence of M. tuberculosis and, if the organism is detected, whether it is
resistant to rifampin. This PCR assay is as sensitive as culture in acid-fast
smear-positive samples, but it is slightly less sensitive in smear-negative
tuberculosis, and substantially less sensitive in children. Thus, culture
remains the gold standard because it also allows testing of drug
susceptibility.
Chest Xray
WEEK 4
2104

Tuberculosis
Earl Louis Sempio, MD
earl.sempio@oum.edu.ws
 CASE

• A 63 year-old man seeks medical attention because of unintentional weight loss

of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following the
death of his wife a year ago, at which time he moved from Hong Kong (a region of
high prevalence for tuberculosis) to the U.S. to live with his daughter. He has never
smoked. He has had a 3 month history of productive cough with greenish sputum.
He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is 16
breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and green
sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection years
ago.
STANDARDS vs GUIDELINES

STANDARDS GUIDELINES
• “what” should be done • “how” the action is to be
accomplished
• foundation on which care can be
based • framing for the whole structure of
care
• present principles that can be
applied in nearly all situations • must be tailored to local
conditions

-Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care (ISTC)
The Hague: Tuberculosis Coalition for Technical Assistance, 2006.
Standards for early TB detection
 1) For persons with signs or symptoms consistent with TB, performing prompt
clinical evaluation is essential to ensure early and rapid diagnosis

 2) All persons who have been in close contact with patients who have pulmonary
TB should be evaluated. The highest priority contacts for evaluation are those :
    with signs or symptoms suggestive of TB;
    aged <5 years;
    with known or suspected immunocompromising conditions, particularly
HIV infection;
    who have been in contact with patients with MDR-TB or XDR-TB.
 3) All persons living with HIV and workers who are exposed to silica should
always be screened for active TB in all settings. Other high-risk groups should be
prioritised for screening based on the local TB epidemiology, health system
capacity, resource availability and feasibility of reaching the risk groups
 4) CXR is an important tool for triaging and screening for pulmonary TB, and it is
also useful to aid diagnosis when pulmonary TB cannot be confirmed
bacteriologically. CXR can be used to select individuals for referral for
bacteriological confirmation and the role of radiology remains important when
bacteriological tests cannot provide a clear answer
 3 SMEARS VS 2 SMEARS

•The optimum number of sputum specimens to establish a

diagnosis has been examined in a number of studies that
have served to support recommendations to decrease the
minimum number of sputum specimens examined from 3 to
2, assuming they are examined in a quality-assured
laboratory.
•In a systematic review of 37 studies on the yield of sputum
smear microscopy
• initial specimen was positive in 85.8% of all patients ultimately
found to have acid-fast bacilli detected
• additional 11.9% with the second specimen
• further 2.3% on the third specimen.
• the mean incremental yield in sensitivity of the second
specimen was 11.1% and that of the third was 3.1%.6
• Sputum microscopy
▪ A positive test result requires the presence of
at least 104 bacilli per ml of specimen.
▪The concentration of viable M. tuberculosis
decrease by more than 90% (10-fold) during
the first 2 days of treatment and by more than
99% (100-fold) by Days 14–21.
▪ ISTC: Because FQs are active against M.
tuberculosis complex and, thus, may cause
transient improvement and smear-negativity,
they should be avoided.
Standards for TB diagnosis
 5) To safely and efficiently diagnose TB and drug-resistant TB requires a
functional network of quality-assured laboratories with appropriate biosafety
measures in place for performing different technical procedures. As such, TB
programmes require a tiered network of integrated laboratories in which different
levels use complementary tools to diagnose TB and HIV, and have mechanisms
for referring specimens between the different levels of the network.
 6) All patients with signs and symptoms of pulmonary TB who are capable of
producing sputum should have as their initial diagnostic test at least one
sputum specimen submitted for Xpert MTB/RIF Ultra assay. This includes
children who are able to provide a sputum sample and patients with EPTB. A
second Xpert MTB/RIF Ultra assay may be performed for all patients who
initially test negative by Xpert MTB/RIF Ultra but whose signs and symptoms of
TB persist.
 7) The Xpert MTB/RIF Ultra assay should be used in preference to
conventional microscopy and culture as the initial diagnostic test for
cerebrospinal fluid specimens from patients being evaluated for TB meningitis.
The Xpert MTB/RIF Ultra assay is recommended as a replacement test for usual
practice (including conventional microscopy, culture or histopathology) for testing
specific nonrespiratory specimens (lymph nodes and other tissues) from patients
suspected of having EPTB.
Standards for TB diagnosis
 8) For persons living with HIV, the Xpert MTB/RIF Ultra assay should be used
as an initial diagnostic test. LF-LAM can be used to assist in the diagnostic
process for HIV-positive patients who are seriously ill.
 9) DST using WHO-recommended rapid tests should be performed for all TB
patients prior to starting therapy, including new patients and patients who require
retreatment. If rifampicin resistance is detected, rapid molecular tests for
resistance to isoniazid, fluoroquinolones and second-line injectable agents
should be performed promptly to inform the treatment of MDR-TB and XDR-TB
 10) Culture-based DST for selected second-line anti-TB agents should be
performed for patients enrolled in individualised (longer) MDR-TB treatment.
LF LAM
BENEFITS OF THE LF-LAM

• Urine-based testing has advantages over sputumbased testing because urine

is easy to collect and store, and lacks the infection control risks associated
with sputum collection.
• Presence of LAM in urine is indirectly related to human immune response,
and its detection process is amenable to inexpensive point of care platforms.
• Owing to suboptimal sensitivity and specificity, current urinary LF-LAM assays
are deemed unsuitable as a general screening or diagnostic test for TB.
• Unlike traditional TB diagnostic methods, however, LF-LAM demonstrates
improved sensitivity in seriously ill* HIV infected individuals, especially in
those with low CD4 counts.
Childhood TB

Tuberculosis should be considered in any child with:

• Unexplained weight loss or failure to grow normally
• Unexplained fever, especially when it continues for
more than 2 weeks
• Chronic cough
• Exposure to an adult with probable or definite
pulmonary infectious tuberculosis.
Findings on examination that suggest tuberculosis

• Fluid on one side of the chest (reduced air entry, dullness to

percussion);
• Enlarged non-tender lymph nodes or a lymph node abscess,
especially in the neck;
• Signs of meningitis, especially when these develop over several days
and the spinal fluid contains mostly lymphocytes and elevated protein;
• Abdominal swelling, with or without palpable lumps;
• Progressive swelling or deformity in the bone or a joint, including the
spine.
 CASE
• A 63 year-old man seeks medical attention because of unintentional weight loss
of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following the
death of his wife a year ago, at which time he moved from Hong Kong (a region of
high prevalence for tuberculosis) to the U.S. to live with his daughter. He has never
smoked. He has had a 3 month history of productive cough with greenish sputum.
He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is 16
breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and green
sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection years
ago.
Standard for diagnosing LTBI

11) Either TST or IGRA can be used to test for LTBI.

TST is not required before initiating  isoniazid

preventative therapy (IPT) in persons living with HIV
Standards for treating drug-susceptible TB

 12) While awaiting DST results, patients with drug-susceptible TB and TB

patients who have not been treated previously with anti-TB agents and do not
have other risk factors for drug resistance should receive a
WHO-recommended first-line treatment regimen using quality assured anti-TB
agents. The initial phase should consist of 2 months of isoniazid, rifampicin,
pyrazinamide and ethambutol. The continuation phase should consist of
4 months of isoniazid and rifampicin. Daily dosing should be used throughout
treatment. The doses of anti-TB agents should conform to WHO's
recommendations. FDC anti-TB agents may provide a more convenient form
of administration

 13) In patients who require retreatment for TB, the category II regimen
should no longer be prescribed and DST should be conducted to inform the
choice of treatment regimen

 14) In patients with tuberculous meningitis or tuberculous pericarditis,

adjuvant corticosteroid therapy should be used in addition to an appropriate
TB treatment regimen.
Standards for treating drug-resistant TB

 15) In patients with rifampicin-susceptible, isoniazid-resistant TB,

6 months of combination treatment with rifampicin, ethambutol, pyrazinamide
and levofloxacin, with or without isoniazid, is recommended.

 16) Patients with MDR/RR-TB require second-line treatment regimens.

MDR/RR-TB patients may be treated using a 9–11-month MDR-TB treatment
regimen (the shorter regimen) unless they have resistance to second-line
anti-TB agents or meet other exclusion criteria. In these cases, a longer
(individualised) regimen with at least five effective anti-TB agents in the
intensive phase and four agents in the continuation phase is recommended for
≥20 months. Partial resection surgery has a role in treating MDR-TB

 17) A system to actively monitor and manage harms caused by anti-TB

agents is required whenever drug-resistant TB patients are treated with novel or
repurposed medicines and MDR-TB regimens
 MDR TB

•Multidrug-resistant TB (MDR-TB) is TB that does

not respond to at least isoniazid and rifampicin,
the 2 most powerful anti-TB drugs.
•The 2 reasons why multidrug resistance
continues to emerge and spread are
mismanagement of TB treatment and
person-to-person transmission.
MDR TB

• Solutions to control drug-resistant TB are to:

• cure the TB patient the first time around
• provide access to diagnosis
• ensure adequate infection control in facilities where patients are treated
• ensure the appropriate use of recommended second-line drugs.
(XDR) tuberculosis

•Extensively drug-resistant (XDR) tuberculosis

•Tuberculosis caused by M. tuberculosis resistant
to at least isoniazid and rifampicin, as well as
to any one of the fluoroquinolones and to at
least one of three injectable second-line drugs
[amikacin, capreomycin, or kanamycin])
The two strongest risk factors for XDR tuberculosis

1. Failure of a tuberculosis treatment which

contains second-line drugs including an
injectable agent and a fluoroquinolone.
2. Close contact with an individual with
documented XDR tuberculosis or with an
individual for whom treatment with a regimen
including second-line drugs is failing or has
failed.
TB Treatment in liver disease

•In patients with unstable or advanced liver disease,

liver function tests should be done at the start of
treatment, if possible.
•If the serum alanine aminotransferase level is more
than 3 times normal before the initiation of treatment
adjustment should be considered
• The more unstable or severe the liver disease is,
the fewer hepatotoxic drugs should be used.
TB Treatment in liver disease

•Two hepatotoxic drugs (rather than the three in the

standard regimen):
•9 months of isoniazid and rifampicin, plus ethambutol (until
or unless isoniazid susceptibility is documented)
•2 months of isoniazid, rifampicin, streptomycin and
ethambutol, followed by 6 months of isoniazid and
rifampicin
•6–9 months of rifampicin, pyrazinamide and ethambutol. •
•One hepatotoxic drug:
•2 months of isoniazid, ethambutol and streptomycin,
followed by 10 months of isoniazid and ethambutol.
•No hepatotoxic drugs:
•18–24 months of streptomycin, ethambutol and a
fluoroquinolone.
TB Treatment in renal disease

•Isoniazid and rifampicin are eliminated by biliary excretion, so

no change in dosing is necessary.
•There is significant renal excretion of ethambutol and
metabolites of pyrazinamide, and doses should therefore be
adjusted.
•Three times per week administration of these two drugs at
the following doses is recommended: pyrazinamide (25
mg/kg), and ethambutol (15 mg/kg)
Tb and malignancy

• A study conducted by the National Cancer Institute found that

pulmonary tuberculosis was associated with an increased risk of lung
cancer, after adjustment for active smoking and socioeconomic status
(odds ratio [OR] 2.1, 95% CI 1.4-3.1).
• The causal relationship is not clear but mycobacterial cell wall
components may induce production of nitric oxide and reactive oxygen
species, which have been implicated in DNA damage leading to
carcinogenesis.
• Chronic inflammation may also enhance mutagenesis. In addition,
immune suppression and radiation therapy for lung cancer may be
associated with an increased risk of tuberculosis. Clinical and
radiographic similarities between TB and malignancy may lead to a
delay in establishing the correct diagnosis.
Chemoprophylaxis

• Daily or twice weekly INH for 6 to 9 months, or daily rifampin for 4 months.
• Patients who have been exposed to drug-resistant M. tuberculosis should
receive prophylaxis with pyrazinamide and either ethambutol or levofloxacin for 6
to 12 months.
Immunodiagnosis

• The traditional test to assess the patient's response to exposure to M.

tuberculosis is the tuberculin skin test.
• Reactivity to an intradermal injection of mycobacterial antigens (purified protein
derivative [PPD]) can differentiate between infected and noninfected people, with
a positive reaction usually developing 3 to 4 weeks after exposure to M.
tuberculosis .
• The only evidence of infection with mycobacteria in most patients is a lifelong
positive skin test reaction and radiographic evidence of calcification of
granulomas in the lungs or other organs.
• In this test, a specific amount of the antigen (5 tuberculin units of PPD) is
inoculated into the intradermal layer of the patient's skin. Skin test reactivity
(defined by the diameter of the area of induration) is measured 48 hours later.
Immunoprophylaxis

• Vaccination with attenuated M. bovis (BCG) is commonly used in countries

where tuberculosis is endemic and is responsible for significant morbidity and
mortality.
• Unfortunately, BCG immunization cannot be used in immunocompromised
patients (e.g., those with HIV infection).
• Positive skin test reactivity develops in all patients and may persist for a
prolonged time. However, skin test reactivity is generally low, so a strongly
reactive skin test (e.g., >20 mm of induration) is generally significant for recent
exposure to M. tuberculosis .
• The second-generation IFN-γ release assays are not affected by BCG
immunization, so they can be used for screening this population.
Standard for treating LTBI

 18) Persons living with HIV and children younger than 5 years who are
household or close contacts of persons with TB and who, after an
appropriate clinical evaluation, are found not to have active TB but to
have LTBI should be treated
Positive sputum smear at the end of intensive phase

•the initial phase of therapy was poorly supervised and

patient adherence was poor;
•poor quality of anti-TB drugs
•doses of anti-TB drugs are below the recommended range
•resolution is slow because the patient had extensive
cavitation and a heavy initial bacillary load
•there are co-morbid conditions that interfere either with
adherence or with response
•the patient may have drug-resistant M. tuberculosis that is
not responding to first-line treatment
•non-viable bacteria remain visible by microscopy
 Group 1.

•Group 1 drugs are the most potent and best

tolerated. If there is good laboratory evidence
and clinical history that suggests that a drug from
this group is effective, it should be used.
•If a Group 1 drug was used in a previous
regimen that failed, its efficacy should be
questioned even if the DST result suggests
susceptibility. The newer rifamycins, such as
rifabutin, have very high rates of cross-resistance
to rifampicin.
 Group 2

• All patients should receive a Group 2 injectable agent if susceptibility

is documented or suspected.
• Among aminoglycosides, kanamycin or amikacin is the first choice of
an injectable agent, given the high rates of streptomycin resistance in
drug-resistant TB. In addition, both these agents are inexpensive,
cause less otoxicity than streptomycin, and have been used
extensively for the treatment of drugresistant TB.
• Amikacin and kanamycin are considered to be very similar and have
a high frequency of cross-resistance. If an isolate is resistant to both
streptomycin and kanamycin, or if DRS data show high rates of
resistance to amikacin and kanamycin, capreomycin (a polypeptide)
should be used.
 Group 3

• All patients should receive a Group 3 medication

if the M. tuberculosis strain is susceptible or if the
agent is thought to have efficacy.
•One of the higher generation fluoroquinolones,
such as levofloxacin or moxifloxacin, is the
fluoroquinolone of choice. Ciprofloxacin is no
longer recommended to treat drug-susceptible or
drug-resistant TB.
 Group 4

• Ethionamide (or protionamide) is often added to the treatment

regimen because of its low cost. If cost is not a constraint,
p-aminosalicylic acid (PAS) may be added first, given that the
enteric-coated formulas are relatively well tolerated and that there is
no cross-resistance to other agents. When two agents are needed,
cycloserine can be added. Since the combination of ethionamide (or
protionamide) and PAS often causes a high incidence of
gastrointestinal side-effects and hypothyroidism, these agents are
usually used together only when three Group 4 agents are needed:
ethionamide (or protionamide), cycloserine and PAS. Terizidone can
be used instead of cycloserine and is assumed to be equally
efficacious.
 Group 5

•Group 5 drugs are not recommended by WHO for routine

use in drugresistant TB treatment because their contribution
to the efficacy of multidrug regimens is unclear.
•They can be used in cases where it is impossible to design
adequate regimens with the medicines from Groups 1–4,
such as in patients with XDR-TB.
•They should be used in consultation with an expert in the
treatment of drug-resistant TB.
 Duration of treatment for MDR-TB

• In MDR-TB treatment, the intensive phase is defined by the duration of

treatment with the injectable agent.
• The injectable agent should be continued for a minimum of 6 months, and for at
least 4 months after the patient first becomes and remains smear- or
culture-negative. Review of the patient’s cultures, smears, X-rays and clinical
status may also aid in deciding whether or not to continue an injectable agent
longer than the above recommendation, particularly in the case of patients for
whom the susceptibility pattern is unknown, effectiveness of one or more
agents is questionable, or extensive or bilateral pulmonary disease is present.
• Culture conversion also determines the overall duration of MDR treatment.
These guidelines recommend continuing therapy for a minimum of 18 months
after culture conversion. Extension of therapy to 24 months may be indicated in
chronic cases with extensive pulmonary damage.
COMPLICATIONS

•BRONCHIECTASIS
•HEMOPTYSIS
Bronchiectasis
• Abnormal and permanent dilatation of
bronchi – either focal or diffuse
• Associated with destructive & inflammatory
changes in the walls of medium-sized airways
(segmental/sub-segmental bronchi)
• Neutrophil-mediated upregulation of elastase
and metalloproteinases
• Destruction of normal structural components,
replaced by fibrous tissue, impairs
muco-ciliary clearance
Bronchiectasis

Bronchiectasis is
primarily in the
lower lobe, which is
the most common
distribution.

The saccular
dilatations and
grapelike clusters
with pools of mucus
are signs of severe
bronchiectasis.
Bronchiectasis

(A) shows dilated and thickened

airways (arrow); (B) shows airways
that do not taper (arrows) toward
the periphery in a patient with
Kartagener’s syndrome; (C) shows
varicose changes (dilated and
beaded airways [arrows]); (D) shows
clustered cysts or saccules (arrow) as
well as a peripheral infiltrate; (E)
shows middle-lobe bronchiectasis
(arrows) in a patient with M. avium
complex.
Bronchiectasis
Bronchiectasis
TB Bronchiectasis

• A major cause of hemoptysis in Asia

• By necrotizing effect on pulmonary
parenchyma and airways
• Indirectly as a consequence of airway
obstruction from bronchostenosis or
extrinsic compression by lymph nodes
• TB hemoptysis can recur even after effective
treatment because the TB sequelae are
permanent and cause continuous
pulmonary inflammation.
TB Bronchiectasis

•Fungus balls or pleural thickening are also

sequelae of TB and these lesions receive a
significant blood supply from non-bronchial
systemic arteries (NBSAs).
Bronchiectasis

• Impaired bacterial clearance, resulting in

colonization and recurrent infection

• Recurrent cough and purulent sputum

production; fatigue, weight loss, myalgias
Bronchiectasis

• Hemoptysis in 50-70% (only 25%

associated with TB) – friable, inflamed,
eroded airway mucosa and hypertrophied
bronchial arteries

• Dyspnea and wheezing (75%) suggest

widespread bronchiectasis or underlying
COPD
 Bronchiectasis

• No defined cause in 50% of cases

•Most frequently isolated potential pathogens:
▪H. influenzae (29-42%)
▪P. aeruginosa (13-31%)
▪Streptococcus pneumoniae (6-13%).

•P. aeruginosa is associated with increased

sputum production, more extensive
bronchiectasis visible on CT, more
hospitalizations, and reduced QOL.
Bronchiectasis
4 or more symptoms suggest exacerbation:
•Change in sputum production
•Increased dyspnea
•Increased cough
•Fever (temperature, >38.0°C)
•Increased wheezing
•Malaise, fatigue, lethargy, or decreased exercise
tolerance
•Reduced pulmonary function
•Radiographic changes consistent with a new
pulmonary process
•Changes in chest sounds
Bronchiectasis

• Exacerbations lead to increased sputum

production – more purulence, often more
bloody; fever

• PE: any combination of crackles (70%),

rhonchi (44%) and wheezes (34%); chronic
hypoxemia leads to clubbing (3%), cor
pulmonale and RV failure
Bronchiectasis
• CXR may be normal with mild disease;
saccular, cystic spaces + air-fluid level;
peribronchial inflammation – “tram tracks,”
“ring shadows”

• High Resolution CT as standard technique

for detection/confirmation

• Sputum exam: neutrophilia, colonizing

organisms
Bronchiectasis

• FOB: endobronchial obstruction with focal

involvement – upper lobes in TB

• PFT: airflow obstruction, bronchial

hyper-reactivity with some reversibility as
relatively common
Bronchiectasis

• Treatment goals:
▪ Treatment of infection
▪ Improved clearance of secretions
▪ Reduction of inflammation
▪ Treat identifiable underlying problem
▪ Control of hemorrhage
▪ Removal of extremely damaged segments or lobes
that may be nidus for infection or bleeding
Bronchiectasis

• Antibiotics for acute exacerbations: guided

by GS, C&S; no FQs if TB a consideration
• Control of cough
• Postural drainage, chest physiotherapy, and
thinning and loosening of secretions –
▪ Cochrane review found little justification for chest
percussion and postural drainage
▪ Adequate systemic hydration, enhanced by
nebulization with saline for viscous secretions
and mucous plugging
Hemoptysis

• If minimal, gas-exchange usually preserved;

prioritize establishing diagnosis.
• If massive, maintain adeq. gas exchange,
prevent from spilling to unaffected areas and
avoid asphyxiation.
▪ Endotracheal intubation + MV support
▪ Dependent position for affected side; selective
intubation of non-bleeding lung – double lumen
▪ Interventional Pulmo: balloon catheterization to
occlude bronchus and cause tamponade; laser
photocoagulation; electrocautery
 CAUSES OF HEMOPTYSIS

Inflammatory
Vascular
Airway Lesions

Neoplastic Traumatic/Iatrogenic

Infectious Miscellaneous
 Main Objectives of Treatment

To prevent asphyxiation

Site Localization

Stop the hemorrhage

Determine the etiology

Prevent recurrence
J. Hourgon et. al. Eur J Cardiothorac Surg 2002; 22:345-351
J. Wilson, Respi and Crit Care Med, 2003
Airway Protection and Patient Stabilization

•Maintenance of an adequate airway

•Administration of supplemental oxygen
•Correction of coagulopathy
•Fluid resuscitation
•Possibility of intubation using large caliber ETT

Flores et al. Massive Hepmoptysis, May 2006:

Localization of the Bleeding Source

• Localize the bleeding site

• Control the bleeding
• Pulmonary toilette
• Aid in intubation
• Identify the etiology
Bronchoscopy
MASSIVE HEMOPTYSIS UNSTABLE

Intubation
STABLE
Bronchoscopy
CHEST CT Localized?
N0 Yes
Mucosal/
Airway lesions?
Bronchial No Yes
Arteriogram
BAE
Balloon Tamponade APC, Laser, Elec’try
Selective intubation
Bleeding
Controlled?
N0 Yes

Specific Treatment
Surgery
Cahill BC, Ingbar DH. Massive hemoptysis. Assessment and management.
Clin Chest Med 1994;15:147-67.
Edward F. Haponik, Alan Fein and Robert Chin. Managing
Life-threatening Hemoptysis. Chest 2000;118;1431-1435
Bronchial Arterial Embolization

•Angiography should be performed initially.

•The success rate within 24hr was 98%
•Collateral arteries branching from the
phrenic, intercostal, mammary, and the
subclavian arteries are cause of failure of
BAE.
•Complication: embolization of the spinal
artery
 Schematic diagram of the standard coil deployment manoeuvre in bronchial artery embolisation.

Hideo Ishikawa et al. BMJ Open 2017;7:e014805

©2017 by British Medical Journal Publishing Group

Bronchial Arterial Embolization

•Introduced in 1977
•Angiographic technique
•Cannulation of the bronchial artery that supplies
the area of hemorrhage and embolization with
• Polyvinyl alcohol particles
• Absorbable gelatin powder (Gelfoam)
• Coils
•90% effective for short-term control of hemoptysis

Tanaka N, Yamakado K, Murashima S, et al. Superselective bronchial artery embolization

for hemoptysis with a coaxial microcatheter system. J Vasc Interv Radiol 1997;8(1 Pt 1):
65-70
Infection control

• There is no need to hospitalize on the basis of suspected infectiousness if the

patient poses no danger to public health.
• Outpatients can be instructed to remain at home, without visitors and away from
other family members. Individuals particularly susceptible to tuberculosis (such as
small children and immunocompromised individuals) should not visit or live with
patients who may be infectious.
• These types of decisions are usually made in conjunction with the local public
health authority, which should be notified at the time tuberculosis is suspected.
• Hospitalization with respiratory isolation is appropriate if social or clinical
circumstances preclude outpatient management or if there is public health risk for
transmission
• In these settings, assessments of the patient’s social circumstances (eg, living,
employment, school, access to healthcare resources) by public health personnel
can be used to determine whether isolation is warranted.
 Infection control

Hospitalized patients with suspected pulmonary/respiratory tract TB should be placed

in negative pressure respiratory isolation until infectious M. tuberculosis has been
ruled out on the basis of the following criteria
●An alternative diagnosis explaining the clinical syndrome has been established.
●Demonstration of three negative acid-fast bacilli (AFB) sputum smear results.
●Demonstration of two negative sputum Xpert MTB/RIF results. Serial sputum
specimen collection for mycobacterial culture remains necessary because
Xpert MTB/RIF does not detect all patients with pulmonary tuberculosis, and
recovery of organisms is needed for drug susceptibility testing.
●Antimycobacterial therapy initiated with clinical response to treatment (usually four
to seven days), with either three subsequent negative-sputum AFB smears or one
negative Xpert and two negative sputum smears (in patients with fewer than seven
days' treatment) Decisions regarding discontinuation of isolation for patients on
treatment for≥7 days should not be based on Xpert MTB/RIF testing.
 CASE
• A 63 year-old man seeks medical attention because of unintentional weight
loss of 12 lbs., over a 3 month period. His appetite is diminished, but he denies
vomiting or diarrhea. He acknowledges some depressive symptoms following
the death of his wife a year ago, at which time he moved from Hong Kong (a
region of high prevalence for tuberculosis) to the U.S. to live with his daughter.
He has never smoked. He has had a 3 month history of productive cough with
greenish sputum. He denies fever or night sweats.
• On physical examination, his temperature is 100.4o F, and his respiratory rate is
16 breaths per minute. His thyroid is not enlarged and there is no cervical or
supraclavicular lymphadenopathy. His chest reveals a few scattered rales in the
left mid-lung fields. His heart rhythm is regular without murmurs or gallops. His
abdominal examination shows no organomegaly.
• His chest radiograph reveals a large cavitary lesion in the left upper lung and
opacities of the left lung. His PPD (purified protein derivative) shows induration
>10mm and 3 early morning sputum samples are collected for culture and
sensitivity. Because of the positive PPD, chest film findings, weight loss, and
green sputum he is presumed to have reactivation tuberculosis, with the lesion
becoming active after a period of dormancy, following up an initial infection
years ago.
Updates
Updates
Natural History of TB
 TB TRANSMISSION

• The best way to stop transmission is to:

• Isolate infectious persons
• Provide effective treatment to infectious persons as soon as
possible

CDC Tuberculosis Learning Module 1 – Transmission and Pathogenesis of Tuberculosis

 MDR TB

•Multidrug-resistant TB (MDR-TB) is TB that does

not respond to at least isoniazid and rifampicin,
the 2 most powerful anti-TB drugs.
•The 2 reasons why multidrug resistance
continues to emerge and spread are
mismanagement of TB treatment and
person-to-person transmission.
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