Mycobacteria:
Tuberculosis and Leprosy
Andrew Racette MS IV
Tuberculosis
Epidemiology
Estimated 1.7 billion infected persons
1/3 of world’s population
10 million people in US
12 million new cases per year w/ 3 million deaths
4 million co-infected with HIV
¾ live in sub-Saharan Africa
Incidence tied to poverty, unemployment,
homelessness, AIDS and drug resistance
Multi-drug resistant disease (MDRTB) major
problem
http://www.med.sc.edu:85/fox/tuber-map3.jpg
Tuberculosis
Etiology
Mycobacterium tuberculosis (Tubercle bacillus,
MTB), M. bovis, M. africanum and BCG
Immune response contains infection in majority
5-10% of immunocompetent develop clinical disease
Rarely eradicated due to resistance to
macrophage destruction, dormancy within
granulomas
Dormant bacilli resistant to antimycobacterials
Immunosuppression often leads to clinical sx
Tuberculosis
Etiology
MTB Surface Coat
Mycolic acid
Highly inflammatory
Stimulates Macrophages and T lymphs
Adequate control depends on chronic inflammation
and caseating granulomas
Granulomas depends on Interferon (IFN) gamma & IL 12
Genetic component
Tuberculosis
Symptoms
Pulmonary:
SOB
Sputum production
Systemic:
Fatigue
Malaise
Fever (in ddx for FUO)
Lethargy
Weight loss
Tuberculosis
Symptoms
Disseminated Disease:
Miliary pattern on CXR
Pancytopenia (BM)
Other Sites:
Bones (Potts), GI, brain, meninges
Almost any organ
Asymptomatic in large number of persons
90%
The Tuberculin Reaction
The Koch Phenomenon
Most likely due to a Delayed T-cell Hypersensitivy
(DTH) rxn
Mediated by sensitized T lymphs when injected into a
nonsensitized individual
In sensitized individual rxn varies depending on
test dose and route of administration
Local intradermal inject. leads to the local TB rxn
Reaches max intensity after 48 hrs
Consists of a sharply circumscribed area of
erythema and induration
The Tuberculin Reaction
Purified Protein Derivative
(PPD) is currently used
Read 48-72 hours after
intradermal injection
Becomes positive between
2 and 10 weeks and
remains positive for many
years
http://www.info.gov.hk/dh/diseases/CD/photoweb/Tuberculosis-2.jpg
PPD evaluation
0.1ml of PPD (5U) placed intradermally to form a wheal
Measure true induration (not erythema) 48-72 hrs
>5mm Induration is positive in following hosts:
patients with recent close contact with a person with active TB
patients with fibrotic lesions on chest radiograph
patients with known or suspected HIV infection
>10mm Induration is positive in:
Patients with high risk comorbid conditions
Persons from endemic areas
IVDA
Residents of long-term (chronic) care facilities
>15mm required for positivity in normal hosts
Previous BCG vaccination does not alter PPD
TB Histopathology
Tubercle is the hallmark
Accumulation of epithelioid histiocytes with
Langerhans giant cells
Caseation necrosis in the center
Rim of lymphs & monos
The tuberculioid granuloma is characteristic
but NOT pathognomonic
This is a higher magnification of the tuberculous process illustrating
specifically the multinuclear giant cells (g) or Langerhans cells with numerous
adjacent histiocytes (h) or epithelioid cells. The epithelioid cells are the fat
histiocytes which bear some resemblance to epithelial cells. The Langerhans
giant cells possibly result from a coalescing of multiple histiocytes or perhaps
even by incomplete mitotic division of reproducing histiocytes.
This frame shows caseation necrosis (c). There is none of the
residual framework of the pre-existing tissue and the blue dots
represent the nuclear debris from necrotic cells. The peripheral
cells in the field are histiocytes (h).
BCG Vaccination
Bacillus Calmette-Guerin (BCG) is a living
attenuated bovine tubercle bacillus to
enhance immunity to tuberculosis
Only given to TB (-) persons
Reduces childhood TB up to 75%
Normal course of BCG vaccination
2 wks: infiltrated papule develops
6-12 wks: size of 10mm, ulcerates, and then
slowly heals leaving a scar
Rare BCG
Reaction
Tuberculosis
Four categories of cutaneous tuberculosis
Inoculation from an exogenous sourse
2. Endogenous cutaneous spread
3. Hematogenous spread to the skin
4. Tuberculids
1.
Primary Inoculation TB
2-4 wks after inoculation painless brown-red
ulcer with hemorrhagic base
3-8 wks regional lymphadenopathy - painless
Face, hands, and legs
Histopathology
Typical tubercles
Langerhan’s cells w/
epithelioid cells
surrounded by
monocytes
Primary Inoculation TB
Course:
W/o tx may last up to 12 mo
Lesions heal by scaring
Primary TB complex usually yields immunity
but reactivation my occur
Primary Cutaneous TB
http://www.embbs.com/img/i0000005.jpg
http://plaza.umin.ac.jp/~otaderma/pattern/nd/nd13.jpg
Tuberculosis Verrucosa Cutis
Exogenous reinfection of MTB in a person
previously sensitized
Minor wound often site of entry
many cases in pathologists/ postmortem
attendants - hence the expression “prosector’s
warts”
PPD highly (+)
http://dermis.net/doia/image.asp?zugr=d&lang=e&cd=21&nr=99&diagnr=17020
Tuberculosis Verrucosa Cutis
Usually a single slow-growing plaque or
nodule m/c on hands
Small papule that becomes hyperkeratotic
Peripheral expansion w/ wo central clearing
Clefts and fissures discharging pus extend
into the underlying base which is brownish-red
to purplish
Scrofuloderma
TB involvement of the skin by direct extension
Usually underlying TB lymphadenitis
Cervial Lymph nodes MC
Develops as firm subcutaneous bluish-red
nodules
Break down and perforate
leaving undermined ulcers
and discharging sinuses
Bilateral
http://www.indianpediatrics.net/jan2002/images/7.jpg
Scrofuloderma
Histopathology:
Massive necrosis and abscess formation in
the center
The periphery of the abscess or the
margins of the sinuses contain tuberculoid
granulomas and true tubercles
Acid-fast bacilli
MTB can be found
Tuberculosis Orificialis
TB of mucous membranes and skin
surrounding orifices
Usually by autoinoculation
Seen in pts with TB of internal organs
GI Tract or Lungs
Mouth most commonly affected site
Tongue and palate
Prognosis poor – advanced internal disease
Presents as painful yellow or red nodule that
ulcerates to form punched-out ulcer
Tuberculosis Orificialis
Histopath:
Massive nonspecific inflammatory infiltrate
and necrosis
Tubercles with caseation may be found
deep in the dermis
Numerous bacilli
Lupus Vulgaris
Cutaneous TB from hematogenous spread
Chronic and progressive
50% have TB elsewhere
Single plaque of grouped red-brown papules
that blanch with diascopic pressure
“Apple-jelly” nodules = pale brown/yellow
Spreads peripherally
Risk of BCC/SCC with mets
90% occur head/neck
http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=-901045419
Lupus Vulgaris
Histopath
Hallmark: Classic Tubercles
Metastatic Tuberculous Abscess
Tuberculous Gumma
Hematogenous dissemination from primary
focus during a period of lowered resistance
leading to distant abscess/ulcer
SubQ abcesses
Nontender
Fluctuant
Singly or as multiples on the trunk, ext, or head
Usually occurs in undernourished children or the
immunodeficient or immuosuppressed
Metastatic Tuberculous Abscess
Metastatic Tuberculous Abscess
Histo:
Similar to scrofuloderma
Massive necrosis and abcess formation
Acid fast stains = copious amounts of
myocbacteria
Miliary TB (Miliaris Disseminata)
Hematogenous dissemination of MTB
Infants / young children
Focus of infection typically meningeal/pulmonary
May follow infections such as measles and HIV
Presentation:
Minute erythematous macules or papules and purpuric
lesions
Sometimes umbilicated vesicles or a central necrosis
and crust develop in severely ill patients
Miliary TB (Miliaris Disseminata)
Histopath:
Initially:
Necrosis and nonspecific inflam infiltrates and
abcesses
Occasionally signs of vasculitis
MTB are present in and around vessels
Later stages (if the pt. develops immunity):
Lymphocytic cuffing of vessels and even tubercles
Miliary TB of the Liver
Multinucleated Giant Cell
Tuberculids
Cutaneous immunologic rxn to TB elsewhere
By definition cx and stains negative
Most likely the result of hematogenous
dissemination in pts with high degree of
immunity
With PCR, mycobacterial DNA demonstrated in both
papulonecrotic tuberculid and erythema induratum of
Bazin
All demonstrate rapid response to antiTB tx
Strongly positive PPD
Most exhibit tuberculois features histologically
Tuberculids
Lichen Scrofulosorum
Rare eruption of asymptomatic, minute, flat-topped
yellow to pink follicular or parafollicular papules
May have a minute horny spine or fine scales
Occurs m/c on trunk of children and adolescents
with TB in lymph nodes/bone
PPD (+)
Persist for months but spontaneous involution
ensues
AntiTB tx results in resolution w/in weeks
Tuberculids
Lichen Scrofulosorum
Histopath:
Superficial noncaseating
tuberculoid granulomas
develop around hair
follicles
Mycobacterium are not
seen and can't be
cultured
Tuberculids
Papulonecrotic Tuberculid
Symmetric, necrotic papules that occur in
crops over the extremities and heal by
scarring
Dusky red, symptomless, pea-sized
papules
Usually seen in children or young adults
MTB DNA has been detected in about 50%
of pts
Tuberculids
Papulonecrotic Tuberculid
Histopath:
Wedge-shaped necrosis of the upper dermis
extending into the epidermis
Involvement of blood vessels is a cardinal
feature
Consists of an obliterative and sometimes
granulomatous vasculitis leading to thrombosis and
complete occlusion
Papulonecrotic Tuberculid
Dusky red, pea sized papules that
are symmetric and become necrotic
Tuberculids
Erythema Induratum (Bazin’s Disease)
Dusky-red 1-2 cm tender nodules usually
occurring on the lower legs in middle-aged
women
Resolve spontaneously w or wo ulceration
The vessels of these pts react abnormally to
changes in ambient temp
The eruptions assoc w/ exposure to cold
Active TB is found only rarely
Erythema Induratum
www.emedicine.com
Evidence of panniculitis exhibiting
lobular, granulomatous, and
lymphohistiocytic inflammation
Nodules after
resolving with
ulceration
Atypical Mycobacteria
Mycobacterium marinum
“Swimming pool/fish tank” granuloma
Ulcerating lesions in skin at site of abrasions
incurred in swimming pools about 2-3 wks. after
inoculation
Single nodules, typically on hands, may ulcerate
and suppurate with sporotricoid ascending spread
Fresh and salt water
Tx with Minocycline 100 mg bid
Heals spont. w.in 1-2 yrs. w/residual scarring
Mycobacterium marinum
Localized Necrosis
Intracellular bacilli
Acid fast bacilli stain of tissue
infected with M. marinum
Atypical Mycobacteria
Mycobacterium ulcerans infection
Buruli ulcer, Bairnsdale ulcer, Searl ulcer
Subequatorial regions of Africa, wet, marshy,
swampy areas
Never found outside the human body
Incubation period of ~3 mo
Painless subq swelling which enlarges to a nodule
that ulcerates
Ulcer is deeply undermined and necrotic fat is
exposed exposing muscle and tendon
Atypical Mycobacteria
Mycobacterium ulcerans infection
Histo- Central necrosis in the interlobular
septa of the subcut. fat, surrounded by
granulation tissue w/giant cells but no
typical caseation necrosis or tubercles. AF
orgs. can always be demonstrated.
TX- Excision of early lesion. Local heat,
hyperbaric oxygen and chemo w/RIF and
Bactrim.
M. ulcerans
http://www.cdc.gov/ncidod/eid/vol5no3/dobos.htm
In A, arrows indicate necrosis of adipose
tissue distant from the location of AFB,
and in B, the arrow indicates
predominance of extracellular bacilli and
microcolonies
Atypical Mycobacteria
Mycobacterium kansasaii
Unusual skin pathogen more commonly associated
with pulmonary disease in middle-aged men
Infections localized to Midwestern states and Texas
Acquired from the environment
Variable skin presentations:
Nodules
Plaques
Crusted ulcers m/c in immuno-suppressed
Responsive to anti-TB tx: Streptomycin, Rif, Emb
Atypical mycobacterium most closely related to MTB
Atypical Mycobacteria
Mycobacterium avium complex (MAI/MAC)
M. avium and M. intracellulare infects lungs and
lymph nodes but occasionally causes cutaneous
lesions with dissemination
Single or multiple painless, scaling, yellowish
plaques w/ a tendency to ulcerate
Common in AIDS
Highly resistant to anti-TB drugs requiring several
in combination:
Azithromycin, Rifampin, Ethambutol
Where feasible surgical tx is advisable
Rifampin used for prophylaxis
http://meds.queensu.ca/~medpalm/PDA_Portal/case11.html
Mycobacterium avium
Mycobacterium intracellulare
Atypical Mycobacteria
Mycobacterium szulgai
Associated with:
Cervical lymphadenitis
Cellulitis
Draining nodules and plaques
Can also cause bursitis and pneumonia
More susceptible to antiTB drugs than
most other atypical mycobacterium
Atypical Mycobacteria
Mycobacterium haemophilum
SubQ granulomatous eruptions
Immunosuppressed - HIV
Histo:
mixed polymorphonuclear and granulomatous inflam
“Dimorphic inflammatory response”
No caseation necrosis
May be sensitive to p-aminosaliclyic acid and
Rifampin
Atypical Mycobacteria
Mycobacterium genavese
Little is known about this organism
Causes disseminated dz
Similar to M. avium intracellulare in HIV
infected pts
Atypical Mycobacteria
Mycobacterium fortuitum complex
Three similar species:
1.
2.
3.
M. fortuitum
M. chelonei
M. abscessus
Saprophytes, found chiefly in soil and water
Rarely cause human disease
Immunocompromised
Prosthetic heart valves and joints
Usually follows puncture wound or surgery
Atypical Mycobacteria
Mycobacterium fortuitum complex
Surgical excision is useful for the treatment of isolated lesions
of lupus vulgaris, TB verrucosa cutis, or scrofuloderma
Leprosy
Etiology
Dreaded, chronic, poorly-transmissible
granulomatous disease of the skin and
nerves caused by acid-fast M. leprae
Probably least infectious of all diseases:
Strong cell-mediated immunity keeps
organism at bay in most people
Humans only natural host but reservoirs:
9-banded armadillo (Texas)
3 species of monkey
Leprosy
Etiology
Pregnancy is a precipitating factor in 10-25%
of female patients
Due to altered immunity
Approx 1/3 of newly dx'ed pts w/leprosy will
eventually have some chronic disability
Secondary to irreversible nerve injury
M/C hands or feet
Leprosy
Lepromin skin test
Analogous to the tuberculin test
Positive at 48 hours = Fernandez reaction
Positive again at 3-4 weeks = Mitusda reaction
Late reaction indicative of immune status of patient
Strongly (+) in TT
Intermediate in BB
Absent in LL
Clinical presentation complex
Little is known about why different people respond
differently to leprosy bacillus
This reflects the underlying
host immunity as
measured by the Tlymphocyte and antibody
responses to
Mycobacterium leprae .
Spontaneous fluctuations
in the immune response
are responsible for type 1
and type 2 reactions. TT,
tuberculoid leprosy; BT,
borderline–tuberculoid
leprosy; BB, mid-borderline
leprosy; BL, borderline–
lepromatous leprosy; LL,
lepromatous leprosy; IFN,
interferon; IL, interleukin.
Leprosy
Epidemiology
5 million persons worldwide
7 thousand active cases in USA
250 new cases /year
620,000 new cases worldwide/year.
80% in 6 countries: Bangladesh, Brazil,
India, Indonesia, Myanmar, Nigeria
Endemic in SE Asia, Far East, Africa,
South/Central America
Cases in Puerto Rico, Cuba, USA
Leprosy
Biological behavior and transmission
Cell-mediated immune response
Low antigenicity
Obligate intracellular parasite
Grows only in colder areas:
skin, cutaneous nerves, testes, hands, feet
Multiplies in neurons in macrophages and
keratinocytes causing nerve damage/disability
Leprosy
Biological behavior and transmission
Strips away myelin from
nerve fibers
Directly harms nerve cells
with involving the
inflammatory system
Does not have to enter
the schwann cells to cause
degeneration of myelin
Nerve Examination Sites
1) Ulnar Nerve
Muscle wasting in hand with contracture 4th and 5th fingers
with anaesthesia. Enlarged at or above Olecranon groove at
elbow - may be confused with an enlarged Trochlear lymph
gland adjacent to the nerve.
2) Median Nerve
Muscle wasting and contractures of thumb and 2nd and 3rd
fingers. Enlarged at anterior wrist but difficult to distinguish
from adjacent tendons.
3) Radial Nerve
Wrist drop - not common. An enlarged radial cutaneous nerve
may be palpated at the lateral border of the radius proximal to
the wrist. This nerve passes to the dorsum of the hand.
4) Lateral or External Popliteal Nerve
Foot drop. May be palpated crossing the neck of the fibula.
Can often be palpated in a normal muscular person.
5) Posterior Tibial Nerve
Posterior and inferior to the medial malleolus.
6) Great Auricular Nerve
A sensory skin nerve which crosses the sternomastoid muscle
in the neck. It is usually not palpable in a normal person.
7) Skin Sensory Nerves near skin lesions may be enlarged.
8) 7th Cranial Nerve
It is not palpable but damage to the nerve leads to facial
paralysis and lagophthalmos.
9) 5th Cranial Nerve Sensory Fibers
If it is damaged, it leads to anaesthesia of cornea.
Leprosy
Biological behavior and transmission
Transmission similar to TB
Respiratory “Globi”
Nasal mucosa
Typically requires extensive contact
Incubation for Tuberculoid leprosy is up to 5
yrs and may be > 20 yrs for LL
Leprosy
Diagnosis
2 of 3 clinical criteria
1.
2.
3.
Anesthesia of the skin
Thickened peripheral nerves
Typical skin lesions
Slit-skin smear (Abroad)
Tissue fluid exudate examined with Fite stain to
determine bacterial index
Punch bx of skin lesion (USA)
Fite stain reveals intracellular bacilli
PCR
Leprosy
Diagnosis
Histologic changes helpful but are not
diagnostic
One exception to this rule:
Presence of epitheloid cell granulomas w/in
nerves = Tuberculoid leprosy or a severe
reversal reaction.
Leprosy
Identification and Quantification of Bacilli
AFB in tissue are best shown by carbolfuschin
staining using modifications of the ZiehlNeelson method collectively called FiteFarraco stains
M. leprae are weekly acid fast
Rod shaped bacilli
Found in macrophages and nerves
Quantified logarithmically by the bacillary index
(BI): the numbers of bacilli per oil-immersion field or
the numbers of OIFs sought to find 1 bacilli
Clasification of Leprosy
Tuberculoid Leprosy
TT = Polar Tuberculoid
Features:
Single to few anesthetic macules or plaques
Hypopigmented
Borders well defined
Peripheral nerve involvement common
Localized & asymmetrical
May contact epidermis and do more damage to
nerves than LL
Lepromin Rxn: very strong
Bacillary density: None
Tuberculoid Leprosy
Central
HypoPigmentation
Elevated
Border
Tuberculoid Leprosy Histology
Linear granuloma following the
course of a nerve
Higher power view of granuloma
surrounding the nerve
Borderline Tuberculoid Leprosy
Lesions similar to TT
Borders less distinct
Multiple (>5)
Satellite lesions sometimes
seen around larger lesions
Peripheral nerves involved
earlier
Lepromin Rxn: Mild
Bacillary Density: Scant
Borderline Leprosy
Still more lesions that BT
Borders more vague
Asymmetric
Bizarre punched-out lesions
Hair loss
Anhydrosis
Most common type
Lepromin Rxn: Weak
Bacillary Density: Moderate
Borderline Lepromatous Leprosy
Multiple macular/papular/plaques
Symmetric lesions
Vague borders
Neuritis late then neural lesions
Surface smooth and shiny with ill-defined border
Mixed granulomas
Leprae in neurons = enlargement
Lepromin Rxn: None
Bacillary Density: Heavy
Borderline Lepromatous Leprosy
Multiple
Erythematous
Plaques with
Vague border
Lepromatous Leprosy
Multiple, non-anesthetic, macular and
papular lesions
No neural lesions until very late
Late complications:
Madarosis
Leonine facies
Testicular damage
Lepromin Rxn: None
Bacillary Density: Heavy
Lepromatous Leprosy
Note the diffuse
infiltration of the
face with leonine
facies and
madarosis
Lepromatous Leprosy
Pts have masses of histiocytes
Do not form good granulomas
Lepra cells = foamy macrophages packed
with bacilli
Globi = masses of bacilli
Grenz Zone = seperates epidermis from
dermis
Lepromatous Leprosy
Grenz Zone
Seperates dermis
from epidermis
Lepra Cells
Foamy
histiocytes
(macrophages)
in the dermis
Indeterminate Leprosy
Vaguely defined hypopigmented or red
macules
With or without sensory deficit
Lepromin Rxn: Weak
Bacillary Density: Rare
Lucio Leprosy
Scleroderma-like with hair loss and
telangiectasias
Diffusely seen in Mexican/LA patients
May give rise to obstructive vasculitis
Aka Lucio phenomenon
Sequelae of Leprosy
Sequelae of Leprosy
1.Madarosis
2.Saddle nose
3.Blindness in the
left eye
Reactional States
50% of patients after initiation of therapy
Causes considerable morbidity
Immune response-destructive,
inflammatory process
Reactional States
Type 1 Lepra Reactions (upgrade)
Jopling's type 1 Reaction
Affects individuals with borderline disease
Type IV hypersensitivity – Cell-mediated change
Major Complication: Nerve swelling, pain and damage
Cutaneous lesions become tender, erythematous
Accelerated destruction of bacilli
Treat promptly with prednisone 40–60 mg/daily
Note downgrading reactions occur before the initiation of
tx and represent shift to LL
Reactional States
Erythema Nodosum Leprosum (Type II lepra rxn)
Josling's type 2 reaction
Occurs in 50% of patients with LL and BL
Immune complex reaction (type III) between M. leprae
antigens and host Ig
Widely distributed dermal nodules
Do not occur at previous skin lesions
IC precipitate in skin, endothelium, nerves, eyes
Systemic Sx’s: Fever, malaise, ulceration, neuritis, uveitis,
glaucoma, acute inflammation
Tx with Thalidomide 400 mg daily
Reactional States
Lucio Phenomenon (Type III Lepra Reaction)
Latin Americans - Mexicans
Pts have La bonita's form of leprosy
Diffuse Lepromatosis
Lucio reaction results in large bullous lesions that
ulcerate usually below knees
Due to deep cutaneous vasculitis (hemorrhagic infarcts)
Complications: sepsis and death
Tx:
Unresponsive to steroids or thalidomide
Antimicrobial chemo for leprosy
Wound care of ulcers
Treatment of Leprosy
Medications of choice
Dapsone:
100mg/d in adults
1mg/kg/d in children
Clofazimine (Lamprene):
50-100mg/d in adults
unestablished in children
Rifampin:
600mg/mo in adults
Treatment of Leprosy
Type of Leprosy
Monthly
Paucibacillary
(I, TT, BT)
Rifampin 600mg
Daily
Dapsone 100mg
Duration
6 months
Multibacillary
(LL,BL,BB) Rifampin 600mg
Clofazimine 50mg 24 months
Clofazimine 300mg Dapsone 100mg
Treatment of Leprosy
Effective 2nd-line drugs
Ofloxacin
Minocycline
Clarithromycin
Treatment of Leprosy
Monitoring
Dapsone:
Baseline G6PD and Hgb
Rifampin:
Baseline LFTs and platelets
Baseline and q 2 week PE of sensation and
motor nerve function first months of therapy
Opthalmology baseline and periodic exam
Repeat slit-skin, Bx, PCR for response to tx
High Resistance Tuberculoid Leprosy
Characterized by:
Few lesions
Rare organisms
Epitheloid cell granulomas w/ tendency to
self-cure
Plaques w/ sharp margins are the inscription
of anti-M. leprae DTH on the skin
Nerve trunk palsies are its inscription on the
peripheral nerves
Low Resistance Lepromatous Leprosy
Characterized by:
Wide dissemination
Abundant orgs
Foamy macrophages
Untreated relentless progression