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Lecture 6

Prepared and presented by
Marc Imhotep Cray, M.D.

Scanning electron micrograph of Staphylococcus aureus bound to the surface of a human neutrophil. “Granulocytic Phagocytes,” by Frank R. DeLeo and William M. Nauseef.
Learning Objectives
To provide the basic description, pathogenesis, types, morphology (gross and
microscopic), clinical presentation(signs & symptoms) and complications of
Mycobacterium tuberculosis.
Including:
1. Describing the main pathologic characteristics of secondary (reactivation)
pulmonary tuberculosis.
2. Defining miliary tuberculosis and tuberculous bronchopneumonia.
3. Discussing the histologic and laboratory methods useful in diagnosis of
tuberculosis.
4. Understanding the epidemiology, etiology, pathophysiology, risk factors,
diagnosis and management of Mycobacterium Leprae
5. Understanding the epidemiology, pathogenesis, clinical presentation,
diagnosis and management of HIV-TB coinfected

Marc Imhotep Cray, M.D. 2
Case Trigger
HPI: RJ, a 58-year-old man, immigrated to the United States from India 20 years
ago. He never experienced health problems until 2 months ago when he began
feeling ill. He has had chronic intermittent fevers, mostly at night and associated
with drenching sweats. He has had a nagging cough with small amounts of blood-
streaked sputum, a decreased appetite, and a 20-pound weight loss over the past
2 months. RJ has not recently traveled out of the country and has had no contacts
with persons who were ill. He does not recall if he has ever had a skin test for
tuberculosis or if he was ever immunized against tuberculosis in India.
Thought Questions:
• Which organism is responsible for tuberculosis (TB) and what distinguishes it from other
bacteria?
• What is the mode of transmission and the host’s immunologic reaction to the bacterium?
• What is the difference between primary and secondary TB?
• What is the role of purified protein derivative (PPD) in the diagnosis of TB?
• How is TB treated?
Marc Imhotep Cray, M.D. From: Mycobacterium tuberculosis Case-based Tutorial 3
Case Trigger Workup and Management
 RJ is admitted to the hospital to an isolation room.
 His chest x-ray shows a right upper lobe infiltrate that is concerning for
secondary TB.
 He is started on isoniazid, rifampin, ethambutol, and pyrazinamide.
 A PPD was placed on admission, and by 48 hours a discoid lesion about 20 mm
in diameter had formed at the injection site.
 On the second day, RJ was able to produce sputum that showed several
slender, curved organisms in clumps that were acid-fast.
 Several days after treatment he began to feel better and his cough decreased.
 After 14 days of isolation, antibiotic therapy, and several sputum samples that
showed no organisms, he was discharged from the hospital with a 6-month
course of oral isoniazid and rifampin.
 The culture results came back subsequently showing M. tuberculosis sensitive
to both isoniazid and rifampin.
Marc Imhotep Cray, M.D.
Introduction
 TB is leading infectious cause of death worldwide, and over 2 billion people
already have been infected* (roughly 10 million are in U.S.)
 Mycobacterial infections classically result in formation of slow growing,
granulomatous lesions that cause tissue destruction anywhere in body
 M tuberculosis (MTb) can cause latent tuberculosis infection (LTBI) and the
disease known as tuberculosis (TB)
 In LTBI, patient is infected with M. tuberculosis but does not have any signs or symptoms
of active TB disease
 Increasing in frequency are diseases caused by nontuberculosis mycobacteria
(NTM) These species include:
 M. avium-intracellulare *Note:
 M. chelonae  A third of world’s population has been infected with MTb, but just a
 M. abscessus subset of those persons have active disease
 M. Kansasii  Persons able to mount a more rapid and robust TH1 immunologic
response, with interferon-γ stimulated expression of inducible nitric
 M. fortuitum oxide synthase (i-NOS, also known as NOS2) in macrophages, are
 M. leprae more likely to have a subclinical infection with minimal lung disease
Marc Imhotep Cray, M.D.
Mode of Infection of Pulmonary TB

Jones CH. Mind Maps for Medical Students, 2015

Marc Imhotep Cray, M.D.
Primary tuberculosis: pathologic characteristics
Lungs are usual location of primary infection with M. tuberculosis

Most frequently, disease is a result of inhaling infected aerosols produced by
coughing on part of a person with cavitary (active) tuberculosis
 Signs and symptoms: cough, hemoptysis, weight loss, night sweats, fever

Initial focus of primary infection, called Ghon complex, consists of:
 A parenchymal subpleural lesion, usually just above or just below interlobar fissure,
 and enlarged lymph nodes (often caseous) draining parenchymal focus

Most frequently, patients with this initial infection are asymptomatic, and
lesions undergo fibrosis and calcification=Latent TB (tubercle bacilli residing in
macrophages)
 In some instances, self-limited extension to pleura with secondary pleural effusion occurs
 Less commonly, progressive spread with cavitation tuberculous bronchopneumonia, or
miliary tuberculosis may follow primary infection
Marc Imhotep Cray, M.D. 7
Primary tuberculosis (2)
 Primary infection with TB occurs by inhaling bacilli into lungs phagocytized
by alveolar macrophages and carried to regional lymph nodes
 During first few weeks after primary infection, bacilli replicate locally and
T-cell mediated cellular immunity develops
 Lymphocytes and monocytes migrate to area of infection and form
histiocytic cells that organize into a granuloma
o granulomas most often contain infection and eventually become
calcified
o TB bacilli remain viable within macrophages in granuloma for years
and often never reactivate
 Once infected patients develop lifelong immunity to re-infection as is
manifested by a positive response to PPD antigen
 Patient with primary infection is not contagious as long as infection is
contained within a granuloma
Marc Imhotep Cray, M.D.
Secondary (reactivation) tuberculosis:
pathologic characteristics
 Patient with secondary pulmonary tuberculosis (active disease) is contagious

 Secondary pulmonary tuberculosis in most cases represents reactivation of an
old, possibly subclinical infection
 produce more damage to lungs than does primary tuberculosis

 Lesion is located in sites with high oxygen tension, particularly in lung apices

 A diffuse, fibrotic, poorly defined lesion develops, with focal areas of caseous
necrosis

 Most commonly, foci heal and calcify but some erode into a bronchus
drainage of infectious material creates a tuberculous cavity
Marc Imhotep Cray, M.D. 9
Secondary (Recrudescent* )TB (2)
 Secondary (recrudescent )TB, or reactivation TB, usually occurs many
years after the primary infection
 Reactivation is more prevalent in elderly, debilitated, and
immunocompromised
 TB recrudescence occurs when contained bacilli begin to multiply and
proliferate as pulmonary lesions progress, they necrotize and become
caseating granulomas these can necrotize into adjacent bronchi and
become cavitary lesions
 Secondary TB can also manifest as lobar infiltrates
 It is during this phase that patients are contagious
 PPD typically remains positive during secondary TB
 Anergy, or a false-negative PPD test, often occurs in end-stage AIDS and
in miliary TB (widespread hematogenous spread of bacilli)
*Recrudescence= reappearance of a disease after a
Marc Imhotep Cray, M.D. period without signs or symptoms of its presence.
Secondary (reactivation) tuberculosis:
pathologic characteristics (3)
 A yellow-grayish caseous material fills cavity, which is more or
less surrounded by fibrous tissue

Most important complications of secondary tuberculosis are:
 Miliary tuberculosis in lungs due to hematogenous
dissemination
 Hematogenous miliary spread to other internal organs
 Spread of infection through expectorated sputum (laryngitis);
sputum may be swallowed, resulting in gastrointestinal (GI)
infection
Marc Imhotep Cray, M.D. 11
Pulmonary tuberculosis: primary vs secondary
Ghon complex is typical of
primary tuberculosis and consists
of a subpleural granuloma,
usually involving lower part of
upper lobe or upper part of lower
lobe, and ipsilaterally enlarged
hilar lymph nodes, which also
contain tuberculous granulomas

Secondary tuberculosis (Sec) Damjanov I, Pathology Secrets 3rd ed. , 2009

typically presents in form of
apical lesions
Marc Imhotep Cray, M.D. 12
Pathogenesis and clinical course
of tuberculosis (TB) caused by
Mycobacterium tuberculosis

Marc Imhotep Cray, M.D. Rosenthal K, Tan J: Rapid Review Microbiology and Immunology, 2nd ed. Philadelphia, Mosby, 2007 13
Pathogenesis and clinical course of
tuberculosis (TB) caused by
Mycobacterium tuberculosis
“ANOTHER LOOK”

Marc Imhotep Cray, M.D. Le T and Bhushan V. Microbiology. In: First Aid for the USMLE Step 1 2015
Caseating granuloma, microscopic
Caseating granuloma. Central necrosis
(pinkish region in upper left) with
multinucleated Langhans giant cell (arrow). Important Note: Virulent strains of tubercle bacilli
form microscopic “serpentine cords” in which
acid-fast bacilli are arranged in parallel chains
 Cord formation is correlated with virulence
 A “cord factor” (trehalose-6,6′-dimycolate) has
been extracted from virulent bacilli with
petroleum ether
o It inhibits migration of leukocytes, causes
chronic granulomas, and can serve as an
immunologic “adjuvant”
 Cord factor is known to be most important
in triggering granulomatous reaction to
wall off and contain the infection
Le T and Bhushan V. Microbiology. In: First Aid for the USMLE Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th
Step 1 2015
Ed, 2016, Pg.312

Marc Imhotep Cray, M.D.
Miliary tuberculosis and tuberculous
bronchopneumonia
 Miliary tuberculosis refers to presence of multiple, small tuberculous
granulomas in many organs result from hematogenous dissemination of
bacteria
 Favored targets for miliary seeding are bone marrow, liver, spleen,
kidney, and retina

 Highly susceptible, highly sensitized individuals may exhibit spread of
tuberculous infection that rapidly involves large areas of lung parenchyma
 produces diffuse bronchopneumonia or lobar exudative consolidation
(galloping consumption)

Marc Imhotep Cray, M.D. 16
Miliary
(Disseminated) TB
 An acute, hematogenous
dissemination involving any
organ
 Often in pts with immune
deficiency
 Pts appear acutely ill and toxic
on top of chronic illness
 CXR shows a fine, millet seedlike
appearance (i.e., micronodular
infiltrates) throughout all the
lung fields
Crapo JD, Glassroth, Karlinsky JB, et al. Baum's textbook of pulmonary diseases,
7th Ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2004
Marc Imhotep Cray, M.D.
Classic Chronic Extrapulmonary Reactivation
Syndromes
 Pott's dz = TB of spine; presents with multiple compression fractures

 Scrofula= TB causing massive cervical lymphadenopathy

 Terminal ileal inflammation and colitis; mimicking Crohn's Disease

 Serous dz =chronic lymphocyte-predominant effusions of pleural space,
pericardia! space (associated with chronic constrictive pericarditis), or
peritoneum (lymphocyte-predominant ascites)

 Meningitis = chronic, lymphocyte predominant pleocytosis in cerebrospinal
fluid (CSF)
Marc Imhotep Cray, M.D.
Tuberculosis histologic and laboratory
diagnostic methods
 If tuberculosis is suspected in certain tissue
changes, diagnosis is confirmed by histologic
staining, smears, and cultures of acid-fast
organisms
 Acid-fast bacteria are visualized with Ziehl-Neelsen
stain, and
 M. tuberculosis is grown on Lowenstein-Jensen agar
 use of PCR amplification of mycobacterial DNA is a
more sensitive diagnostic technique
 Mycobacterium tuberculosis can be Mycobacterium tuberculosis Ziehl-Neelsen stain

demonstrated in early exudative and caseous
phases, but it is usually not possible to find
bacteria in late fibrocalcific stages
Marc Imhotep Cray, M.D. 19
Tuberculosis histologic and laboratory
diagnostic methods (2)
 Lesions with sparse organisms can be highly infective, and their absence in
histologic sections cannot be assumed as a sign of total microbial destruction

 Histologically, granulomas are composed of epithelioid cells surrounded by a
zone of fibroblasts, lymphocytes, and Langhans giant cells
 Some necrosis (caseation) is usually present in centers of these tubercles

Marc Imhotep Cray, M.D. 20
Interpretation of PPD Results
Result Negative/Positive Interpretation
<5 mm Negative, except in HIV patients
5–10 mm Positive in those likely infected (e.g., household contacts,
known exposure, healthcare worker)
10–15 mm Positive in those at elevated risk (e.g., homeless, endemic
area)
>15 mm Positive for general population
Redrawn from: Caughey AB et al. CASE 2-6: Tuberculosis. In: Cases and Concepts Step 1: Pathophysiology Review, 1st Ed., 2010

Marc Imhotep Cray, M.D.
Interpretation of PPD Results (2)
 PPD ⊕ if current infection or past exposure
 False positives with BCG vaccination (further workup required)
 PPD ⊝ if no infection or anergic (steroids, malnutrition,
immunocompromise) and in sarcoidosis
 Interferon-γ release assay (IGRA) has fewer false positives from BCG
vaccination
 Positive PPD (purified protein derivative) suggests prior infection with M.
tuberculosis, but does not necessarily imply active TB
 CXR, Hx and PE for active disease should be preformed Only
persons with active disease are infectious
o Pts with primary infection are not contagious as long as infection is contained
within a granuloma
 If pt. gives a Hx of Positive PPD, DO NOT REPEAT, rather go straight to
CXR, Hx and PE to r/o active disease
Marc Imhotep Cray, M.D.
Pulmonary Tuberculosis
Gross and Microscopic
Pathology Plates, Radiographs
and CT Scans

Marc Imhotep Cray, M.D. 23
Primary tuberculosis, gross
 There is a small, tan-yellow
subpleural granuloma in mid
lung field
 In hilum is a small yellow-tan
granuloma in a hilar lymph
node next to a large bronchus
 This is Ghon complex,
which is characteristic gross
appearance with primary
tuberculosis
 Over time, granulomas
decrease in size and can
calcify leaving a focal bright
spot on a chest radiograph that
suggests remote
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015
granulomatous disease
Marc Imhotep Cray, M.D. 24
Primary tuberculosis, gross
 A healed Ghon complex is represented
by a subpleural nodule (arrowhead) and
involved hilar lymph nodes (arrow)

Marc Imhotep Cray, M.D. Rubin R and Strayer DS Eds. Rubin’s Pathology:
Clinicopathologic Foundations of Medicine, 7th Ed. , 2015
Secondary tuberculosis, gross
 These scattered tan granulomas
are present mostly in upper lung
fields
 Granulomatous lung disease
grossly appears as irregularly
sized, rounded nodules
 Larger nodules may have central
caseous necrosis that includes
elements of liquefactive and
coagulative necrosis
 This upper lobe pattern of
involvement is most
characteristic of secondary
(reactivation) tuberculosis,
typically seen in adults
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015

Marc Imhotep Cray, M.D. 26
Cavitary tuberculosis, gross

 Apex of left upper lobe shows
tuberculous cavities
surrounded by consolidated and
fibrotic pulmonary parenchyma
that contains small tubercles

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
of Medicine, 7th Ed. , 2015
Marc Imhotep Cray, M.D.
Miliary tuberculosis, gross
 When immune response is poor
or is overwhelmed by an extensive
infection, it is possible to see gross
pattern of granulomatous disease
known as a miliary pattern
because there are a multitude of
small, pale tan granulomas,
averaging 2 to 4 mm in size,
scattered throughout lung
parenchyma
 This pattern gets its name from
resemblance of granulomas to
millet seeds
 Dissemination of causative
infectious agent (Mycobacterium
tuberculosis or fungi) may
produce a similar miliary pattern Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015
in other organs
Marc Imhotep Cray, M.D. 28
Miliary tuberculosis, gross
 Multiple millimeter-sized
nodules (arrows) are
scattered throughout lung
parenchyma

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations
Marc Imhotep Cray, M.D. of Medicine, 7th Ed. , 2015
Ziehl-Neelsen stain shows numerous
acid-fast organisms

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic
Foundations of Medicine, 7th Ed. , 2015

Marc Imhotep Cray, M.D.
Acid-fast bacilli, microscopic
 To identify mycobacteria in a
tissue section, a stain for
acid-fast bacilli (AFB) is
performed
o Mycobacteria stain as
red rods (arrow), seen
here at high
magnification
 Large amount of lipid in
form of mycolic acid imparts
this acid-fast property to
mycobacteria and accounts
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015
for their resistance to
immune cell destruction
Marc Imhotep Cray, M.D. 31
Tuberculosis, microscopic
 A granulomatous inflammatory
response to Tb includes mainly
epithelioid cells, lymphocytes,
and fibroblasts
 This granuloma shows that
epithelioid macrophages are
elongated with long, pale nuclei
and pink cytoplasm
 Macrophages organize into
committees called giant cells
 Typical giant cell for infectious
granulomas is called a Langhans
giant cell and has nuclei lined up
along one edge of cell
 Process of granulomatous
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015
inflammation occurs over months
to years
Marc Imhotep Cray, M.D. 32
Necrotizing granuloma
due to MTb
 A small tuberculous granuloma with
conspicuous central caseation is present in
pulmonary parenchyma
 Necrotic center is surrounded by
histiocytes, giant cells and fibrous tissue

Rubin R and Strayer DS Eds. Rubin’s Pathology:
Marc Imhotep Cray, M.D. Clinicopathologic Foundations of Medicine, 7th Ed. , 2015
Tuberculosis, microscopic, well-defined
granulomas
 Well-defined granulomas have rounded
outlines with discrete borders
 Granulomas are composed of
transformed macrophages
called epithelioid cells, along with
lymphocytes, occasional polymorphonuclear
leukocytes, plasma cells, and fibroblasts
 Macrophages stimulated by cytokines,
such as interferon-γ secreted from nearby
T lymphocytes, may group together to
form Langhans giant cells
 Localized, small appearance of these
granulomas suggests that immune
response is good, and infection is
being contained Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015
 This would produce a reticulonodular
radiographic pattern in the lungs.
Marc Imhotep Cray, M.D. 34
Primary and miliary tuberculosis, radiographs

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015

PA chest radiograph on left is characteristic of primary tuberculosis with a subpleural granuloma (up arrow ) and marked hilar
lymphadenopathy (down arrow ). These two findings together constitute Ghon complex.
PA chest
Marc radiograph
Imhotep Cray, M.D.on the right reveals a miliary pattern in all lung fields. Note the stippled appearance throughout 35
Secondary tuberculosis, CT image
Axial view of upper chest
shows cavitary lesions (arrow)
typical of reactivation-
reinfection pattern of
secondary tuberculosis most
common in adults

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015

Marc Imhotep Cray, M.D. 36
Secondary tuberculosis, radiographs

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. 2015

 PA chest radiograph on left reveals upper lobe granulomatous disease marked by irregular reticular and
nodular densities and upper lobe cavitation ( *) caused by central caseous necrosis
 PA chest radiograph on right reveals extensive granulomatous disease of both lungs. Focal brighter
Marc Imhotep Cray, M.D. 37
calcifications are typical of healed tuberculosis
 Pott disease from tuberculosis
infection of spine resulting in a severe
kyphoscoliosis
 Note to continue skin ulceration on
right and a severe deformity caused by
this disease

FIGURE 54-5
Marc Imhotep Cray, M.D. Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013
Scrofula of neck caused by M. tuberculosis in a child. Scrofula of the neck caused by M. tuberculosis in an
Chronic drainage and fistulous tract formation are adult who did not complete his tuberculosis treatment. The
commonly associated with this entity, and therapy is same long duration of therapy leads to challenges for adherence, and
as for pulmonary tuberculosis drug-resistant tuberculosis commonly results.

Figure 7-33 Figure 7-34
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013

 Tuberculous lymphadenitis and cutaneous TB (designated scrofula when it affects neck)
Scrofula in the inguinal area caused by M. tuberculosis. The
patient appears systemically ill with weight loss.
Figure 7-32

Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013

Marc Imhotep Cray, M.D.
Pulmonary Tuberculosis: Summary
Pathophysiology
 Primary Infection
 Mycobacterium has a cell wall that is rich in lipids and is acid-fast (AFB)
 Proteins in cell walls are highly antigenic
 Inhaled bacilli are phagocytized by macrophages and carried to regional
lymph nodes
 Macrophages initiate an inflammatory response by releasing chemotactic
factors
 Cell-mediated hypersensitivity results with influx of lymphocytes and
monocytes
 Primary granuloma is formed around initial site of infection that consists
of macrophages, histiocytes, and lymphocytes
 Cord factors is most important in triggering granulomatous reaction to
wall off and contain the infection
Marc Imhotep Cray, M.D. 41
Pulmonary Tuberculosis: Summary (2)
Pathophysiology
Latent Phase
 Majority of primary infections are asymptomatic
 Granuloma self-contained, heals, and forms calcified
granuloma that is evident on chest x-ray
 Calcified granuloma “dormant” but contains viable
Mycobacteria
 PPD test becomes positive several weeks after primary
infection and remains so during latent phase

Marc Imhotep Cray, M.D. 42
Pulmonary Tuberculosis: Summary (3)
Pathophysiology
 Secondary (Reactivation) TB
 Disease manifests years later as a result of age, comorbid disease, or
immunocompromised state
 Reactivation occurs typically in apices and upper poles of lower lobes
where the V/Q ratio is high
 Spread of Mycobacteria outside original granuloma results in formation
of caseating granulomas that can necrotize and become cavitary
granulomas
 Cavitary granulomas erode into bronchioles and generate sputum with
M. tuberculosis
 Cavitary granulomas can also erode into blood vessels, causing
hemoptysis
Marc Imhotep Cray, M.D. 43
Pulmonary Tuberculosis: Summary (4)
Risk Factors
Endemic regions of world: Southeast Asia, Africa, India,
Latin America
Overcrowded living conditions, homeless, inner-city urban
dwellers, jailed or institutionalized

Marc Imhotep Cray, M.D. 44
KEY POINTS
Presenting symptoms of reactivation TB include chronic cough,
hemoptysis, intermittent fevers, night sweats, and weight loss

Chest x-ray may show any variety of infiltrate although classically
shows granulomatous or cavitary lesions in upper lobes

Patients with pulmonary infiltrates suspicious for TB must be kept
in isolation until three sputum samples are negative for acid-fast
organisms

Positive PPD suggests prior infection with M. tuberculosis, but
does not necessarily imply active TB
Marc Imhotep Cray, M.D. 45
KEY POINTS (2)
 Any reaction in immunocompromised persons is positive

 For individuals at high risk, 5 mm is positive

 For individuals with several risk factors, 10 mm is positive

 For individuals at low risk, 15 mm is positive

 Initial treatment of active TB consists of a three-drug regimen

 Duration of treatment is at least 6 months due to large number of inactive
organisms and poor drug penetration into caseating granulomas and
cavitary lesions

Marc Imhotep Cray, M.D. 46
TB Treatment
 M. tuberculosis is slow growing and requires treatment for months to years

 LTBI can be treated for 9 months with isoniazid (INH) monotherapy or with
12 once-weekly doses of INH (900 mg) and rifapentine (900 mg)

 In contrast, active TB disease must be treated with several drugs

 Treatment for drug-susceptible TB lasts for at least 6 months, while
treatment of multidrug-resistant TB (MDR-TB) typically lasts for about 2
years
Note:
 TB treatment generally includes four first-line drugs
 Second-line drugs are typically less effective, more toxic, and
less extensively studied.  used for patients who cannot
tolerate first-line drugs or who are infected with resistant TB.
 No drugs are specifically developed for NTM infections.
Marc Imhotep Cray, M.D.
Mechanism of action for each of the following
first-line antituberculosis medications:
 Rifampin 1st line Anti-TB Drugs
Inhibition of DNA-dependent RNA polymerase Ethambutol
 Isoniazid Isoniazid (INH)
Inhibition of mycolic acid synthesis Pyrazinamide
Rifamycins
 Pyrazinamide
Rifabutin
Unknown; activated by susceptible bacterial strains Rifampin
which in turn lowers pH of surrounding environment Rifapentine
 Ethambutol
Inhibition of RNA synthesis

Marc Imhotep Cray, M.D.
Adverse Effects for 1st line antituberculosis
medications:
 Rifampin
Flu-like syndrome; hepatitis; elevated liver function tests (LFTs); drug-drug interactions
(cytochrome P-450 inducer); proteinuria; thrombocytopenia; red-orange discoloration of
tears, sweat, urine
 Isoniazid
Drug-induced systemic lupus erythematosus (SLE); hepatitis; peripheral neuropathy;
hemolytic anemia in G6PD deficiency; seizures
 Pyrazinamide
Phototoxicity; increased porphyrin synthesis; hepatitis; arthralgias; myalgias; hyperuricemia
 Ethambutol
Optic (retrobulbar) neuritis; decreased visual acuity; red-green color blindness;
hyperuricemia
 How can INH-induced peripheral neuropathy be prevented?
Supplementation of vitamin B6 (pyridoxine)

Marc Imhotep Cray, M.D.
Tuberculosis Map

Marc Imhotep Cray, M.D. Modified from: Jones CH. Mind Maps for Medical Students, 2015
Mycobacterium
(Leprosy and Tuberculosis-HIV Coinfection)
Lepromatous leprosy with leonine facies in a woman. Note loss
LEPROSY of eyebrows called madarosis and prominent ear involvement.
Patient Story
A women presents with significant
changes to her face. A slit-skin
examination is performed on the
ear lobe of the woman and many
acid-fast bacilli, characteristic of
Mycobacterium leprae, are found.
The woman is started on the WHO-
standard multidrug using rifampin,
clofazimine, and dapsone.
Figure 6-15
Usatine RP etal. (Eds.) The Color Atlas of Internal Medicine. 2015

Marc Imhotep Cray, M.D.
Introduction
 Leprosy (Hansen disease) is caused by M. leprae and is still endemic in
many parts of the developing world where there is poverty and poor
access to clean water

 At one time, persons with leprosy were called “lepers” and isolated to
leper colonies because disease was disfiguring and communities were
afraid that it was highly contagious

 Current science and epidemiology tell us that leprosy is transmitted via
droplets from nose and mouth during close and frequent contact over a
period of years, and not by casual contact thus, doctors working with
patients who have leprosy are at no real risk of becoming in effected

 Issues related to stigma and discrimination still exist
Marc Imhotep Cray, M.D.
Epidemiology
There were 219,075 new cases reported in the world by 105
countries in 2011

United States reported 173 new cases in 2011

Since 1990, more than 14 million leprosy patients have been
cured, about 4 million from 2000 to 2010
Refs.
Global leprosy situation. Wkly Epidemiol Rec. 2012;87(34):316-328.
World Health Organization. Leprosy; Fact Sheet No.101. http:// www. who.int/ mediacentre/ factsheets/ fs101/ en/
index.html

Marc Imhotep Cray, M.D.
Etiology and Pathophysiology
Clinical manifestations of leprosy depend on immunologic
reaction to infection
 2 opposite ends of spectrum consist of following:
o Lepromatous leprosy in which there is a strong antibody response
and a poor cell-mediated immunity resulting in larger amounts of
M. leprae in tissues
o
o Tuberculoid leprosy in which there is a strong cell-mediated
immunity and a poor antibody response resulting in less M. leprae
in tissues this tends to present with hypopigmented anesthetic
patches

Marc Imhotep Cray, M.D.
Lepromatous leprosy with leonine facies in a young boy.
A. Note the loss of eyebrows called madarosis. B. Also note the prominent ear involvement.
Figure 7-26 Figure 7-26

Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013
Tuberculoid leprosy
Multibacillary leprosy with hypopigmented patches. These
patches are commonly numb due to cutaneous nerve damage
from mycobacterial infection.

(Figure 6-16)
Usatine RP etal. (Eds.) The Color Atlas of Internal Medicine. 2015

Marc Imhotep Cray, M.D.
Etiology and Pathophysiology cont.
 There is also borderline leprosy in which there is a mixed cell mediated
immunity and antibody response showing features of both lepromatous
leprosy and tuberculoid leprosy

 Treatment regimens differ depending on whether patient has
paucibacillary (fewer organisms) or multibacillary leprosy

 Lepromatous leprosy and borderline lepromatous leprosy are most likely
to be multibacillary

Marc Imhotep Cray, M.D.
Risk factors
 Poverty and living in an endemic area
 Inadequate access to clean water and poor hygiene
 Living in the household of an infected person
 Eating or handling armadillos  natural hosts for M. leprae

Marc Imhotep Cray, M.D.
Diagnosis
 Clinical features
 Facial features include leonine facies, madarosis (loss of eyebrows),
elongated and dysmorphic earlobes, and saddle-nose deformities from
destruction of nasal cartilage and bone
 Visible skin changes include nodules in lepromatous leprosy,
hypopigmented patches in tuberculoid and borderline leprosy, and annular
saucer-like lesions in borderline leprosy
 Nerve involvement can cause a clawhand (flexion contractures of fingers )
wristdrop, footdrop, Bell palsy, hammertoes, and sensor and sensory
neuropathy leading to neurotropic ulcers and traumatic blisters
 Eye involvement can cause corneal anesthesia, keratitis, episcleritis,
lagophthalmos (inability to close eyelid completely) and blindness
 Advanced untreated leprosy can lead to shortening and/or loss of fingers
as a result of bone resorption in hands that have become anesthetic and
not protected from repeated trauma
Marc Imhotep Cray, M.D.
Clawhand caused by the neurological damage of leprosy. Leprosy has caused this older man to lose his
This condition may be amenable to surgical intervention fingers but he continues to lead a productive life
involving tendon transfer. weaving rugs for sale at a leprosy hospital.

Figure 7-28 Figure 7-29
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013

Marc Imhotep Cray, M.D.
Laboratory testing
 In obvious cases of leprosy, slit skin exam done on ear lobe for bacillary
index is most important test to determine if patient has multibacillary
or paucibacillary leprosy
 In cases that are suspicious for leprosy (especially outside of
endemic areas), a skin punch biopsy of a suspicious lesion is useful for
finding M. leprae in tissues

Differential diagnosis
 Superficial mycoses, vitiligo, and cutaneous filariasis all cause changes
in pigmentation similar to leprosy
 Infiltrated lesions that resemble leprosy include those of leishmaniasis,
psoriasis, and sarcoidosis
Marc Imhotep Cray, M.D.
Management
 Early diagnosis and multidrug therapy are essential to reducing disease
burden of leprosy worldwide

 WHO has supplied multidrug therapy free of cost to leprosy patients in all
endemic countries

 Leprosy is curable and treatment in an early stage can prevent disability

 Multidrug therapy is a combination of rifampin, dapsone, and
clofazimine for multibacillary leprosy

 Duration of multidrug therapy is 12 to 24 months for multibacillary
and 6 months for paucibacillary patients
World Health Organization. Leprosy Elimination. WHO Multidrug Therapy.
http:// www.who.int/ lep/mdt/ en/index.html
Marc Imhotep Cray, M.D.
HIV-Tuberculosis Coinfection
Epidemiology
 Compared with HIV-negative patients, HIV-infected patients with MTb
infection are markedly (21–34 times) more likely to develop active
tuberculosis disease
World Health Organization. Global Tuberculosis Control. 2011.
http://www.who.int/tb/publications/global_report/2011/en/index.html

 Tuberculosis (TB) is a very common HIV-associated infection, and
causes at least 13% of HIV-associated deaths worldwide
National Institutes of Health Clinical Guidelines Portal. Federally Approved HIV/AIDS Medical Practice
Guidelines. http://www.aidsinfo. nih.gov/contentfiles/lvguidelines/adult_oi_041009.pdf

 In 2010, WHO estimated there were 1.1 million HIV-associated
new cases of TB, majority of who live in sub-Saharan Africa
 Globally, about one-third of HIV-infected people are coinfected with TB (at
least 11 million people)
Marc Imhotep Cray, M.D.
Figure 7-30

 Young girl who acquired HIV at birth and
now has papular pruritic eruption
 One in 3 children born to HIV-infected
mothers may be infected; mother-to-child
transmission is preventable with antiviral
regimens

“Fortunately this girl had no signs or
symptoms of tuberculosis”
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013

Marc Imhotep Cray, M.D. Usatine RP etal. (Eds.) The Color Atlas of Family Medicine.
2013
 Young Ethiopian girl with HIV
since birth who has neck
swelling secondary to
tuberculosis
 She also has tinea capitis
 HIV is a highly stigmatizing
disease in most cultures, and
clinicians can play an
important role in mitigating
community stigma by
modeling compassionate care Figure 7-31
Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. 2013

Marc Imhotep Cray, M.D.
Pathogenesis
As already stated, TB is transmitted by aerosolized respiratory
droplet nuclei

Weakened cell-mediated immunity in HIV-infected individuals
allows more rapid disease progression and causes higher
mortality rates from TB
 At same time, untreated TB infection accelerates
immunologic decline in HIV infection

Because these 2 diseases preferentially afflict populations with
reduced access to medications and supportive care, emergence
of multidrug resistant TB has become an increasing threat
Marc Imhotep Cray, M.D.
Clinical presentation
Clinical presentation of TB in an HIV-infected person with a
relatively preserved immune system (CD4+ T-cell count greater
than 350 cells/μL), is identical to that seen in HIV-negative
patients
 With increasing immunodeficiency, however, TB often
presents atypically
o Chest radiographs may not demonstrate classic findings of
upper lobe fibronodular or cavitary disease, and
extrapulmonary presentations (lymphadenitis, pleuritis,
pericarditis, meningitis) are seen

Marc Imhotep Cray, M.D.
Diagnosis
 HIV screening should be performed in all patients diagnosed with TB
and
 HIV-infected patients should be screened annually for M. tuberculosis
with purified protein derivative (PPD) skin testing, chest x-ray,
and/or blood test for interferon-γ release assay (IGRA) [depending on
availability]

 Patients with low CD4 cell counts (below 200 cells/μL) commonly have
poorly reactive skin tests for TB need a careful history of exposures,
review of symptoms, and monitoring of chest x-ray for evidence of active
disease, with repeat TB screening when CD4 cell count rises above 200
cells/μL

Marc Imhotep Cray, M.D.
HIV-TB coinfected Management
Latent TB infection
 HIV-positive patients with latent tuberculosis infection (LTBI) should
have a chest x-ray and 3 sputum smears for AFB to rule out active disease
 Once active TB is ruled out, isoniazid prophylaxis should be initiated
regardless of age for any HIV-positive person with following characteristics:
(a) A positive diagnostic test for LTBI, or
(b) A negative LTBI test but with evidence of old or poorly healed fibrotic lesions on chest
x-ray, or
(c) negative LTBI diagnostic test in a close contact of a person with infectious pulmonary
TB
 Duration of LTBI prophylaxis: Isoniazid 300 mg daily or twice
weekly for 9 months given with vitamin B6 (pyridoxine 25 mg daily)
 An alternative regimen of 12 doses of once weekly isoniazid-rifapentine
 Pyridoxine prevents isoniazid-associated peripheral neuropathy

Marc Imhotep Cray, M.D.
HIV-TB coinfected Management cont.
Active M. tuberculosis disease
 Any HIV-positive patient with cough and pulmonary infiltrates should
be placed in respiratory isolation until TB is ruled out by 3 separately
obtained sputum smears (Ziehl-Neelsen) with cultures sent for acid fast bacilli
 This rule applies even when chest radiograph does not demonstrate
cavitary or upper lobe infiltrates
o Smear-negative, culture positive M. tuberculosis is not uncommon

Marc Imhotep Cray, M.D.
HIV-TB coinfected Management cont.
 Treatment regimens for HIV-TB coinfected patients are largely identical to
those of TB mono-infected patients

 Important not to start antiretroviral therapy (ART) and TB therapy
simultaneously to avoid confusion about drug allergies and side effects
 In addition, there is a risk of immune reconstitution syndrome (IRIS
[immune reconstitution inflammatory reaction]: inflammatory
response that worsens manifestations of any opportunistic infection)
when ART is started too soon after initiating TB medication

Marc Imhotep Cray, M.D.
HIV-TB coinfected Management cont.
Guidelines for ART in TB coinfection are specific
 If CD4 cell count is less than 50, ART should start within 2 weeks of TB
therapy

 If CD4 count is greater than 50, ART should start within 8 to 12 weeks of TB
therapy

 If IRIS does occur, both ART and TB treatment should be continued while
managing the IRIS

 Directly observed therapy (DOT) for TB is strongly recommended for HIV-TB
coinfected patients

Marc Imhotep Cray, M.D.
Marc Imhotep Cray, M.D. 73
Sources and further study:
 Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee Eds. JS. Pathophysiology of
Disease : An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-Hill Education, 2014
 Caughey AB et al. Cases and Concepts Step 1: Pathophysiology Review, First Ed. Baltimore: Lippincott
Williams &Wilkins, 2010; Pgs. 50-52
 Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015
 Jones CH. Mind Maps for Medical Students. Boca Raton, FL: CRC Press, 2015
 Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 7th Ed.
Baltimore: Lippincott Williams & Wilkins, 2015
 Usatine RP etal. (Eds.) The Color Atlas of Family Medicine. New York: McGraw-Hill Education, 2013
 Usatine RP etal. (Eds.) The Color Atlas of Internal Medicine. New York: McGraw-Hill Education, 2015

eLearning (IVMS Cloud)
 Infectious Disease
 Microbial biology & Immune System
 Rural Medicine Global Health (Focus on Ethiopia)

Textbooks:
 Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010
 Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016
Marc Imhotep Cray, M.D. 74