Transcript Tuberculosis and Leprosy - Osteopathic Medical School

Mycobacteria:
Tuberculosis and
Leprosy
Ben Adams DO
3-21-06
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
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
– Other Sites:
• Bones, 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
• Residents of long-term (chronic) care facilities
– >15mm required for positivity in normal hosts
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
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
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
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
–
•
Seen in pts with TB of internal
organs
–
•
Orificial tuberculosis. A nonhealing ulcer at the tip of the
tongue
GI Tract or Lungs
Mouth most commonly affected site
–
•
Usually by autoinoculation
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
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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 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 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 tuberculosis 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, peasized papules
• Usually seen in children or
young adults
•
• MTB DNA has been detected
in about 50% of pts
Papulonecrotic tuberculid. Erythematous papules and
papulopustules on the heel.
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. within 1-2 yrs. w/residual scarring
Mycobacterium 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/Rifampicin 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, Rifampicin,
Ethambutol
• 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. M. fortuitum
2. M. chelonei
3. 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
• Lymphangitic spread by Mycobacterium
fortuitum. The inoculation chancre was on the
foot.
Leprosy (Hansen’s Disease)
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 (intradermal inj of 0.1ml of a crude
semi-standardized preparation of bacilli from a lepromatous nodule
or armadillo liver)
– Positive at 48 hours = Fernandez reaction
– Positive again at 3-4 weeks = Mitusda reaction
• Late reaction indicative of immune status of patient
• Little is known about why different people respond
differently to leprosy bacillus
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
– Nasal mucosa
– Typically requires extensive contact
• Incubation for Tuberculoid leprosy is up to 5
yrs and may be > 20 yrs
Leprosy
Diagnosis
• 2 of 3 clinical criteria
1. Anesthesia of the skin
2. Thickened peripheral nerves
3. Typical skin lesions
•
Slit-skin smear (Abroad)
– Tissue fluid exudate examined with Fite stain to
determine bacterial index (multibacillary vs.
paucibacillary)
•
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 Ziehl-Neelson
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:
•
•
•
•
•
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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
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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
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/Latin American
patients
• May give rise to obstructive vasculitis
– Aka Lucio phenomenon
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)
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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
Erythema nodosum leprosum (type 2 reaction) with the
appearance of multiple red papulonodules in a patient with
lepromatous leprosy
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