Mycobacteria: Tuberculosis and Leprosy

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Mycobacteria Tuberculosis and Leprosy

• Ben Adams DO
• 3-21-06

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Tuberculosis

• Epidemiology
• Estimated 1.7 billion infected persons
• 1/3 of worlds 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

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http//www.med.sc.edu85/fox/tuber-map3.jpg
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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

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Tuberculosis

• Etiology
• MTB Surface Coat
• Mycolic acid
• Highly inflammatory
• Stimulates Macrophages and T lymphs

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Tuberculosis

• Symptoms
• Pulmonary
• SOB
• Sputum production
• Systemic
• Fatigue
• Malaise
• Fever (in ddx for FUO)
• Lethargy
• Weight loss

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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

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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

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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/Tub
erculosis-2.jpg
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PPD evaluation

• 0.1ml of PPD (5U) placed intradermally to form a
  wheal
• Measure true induration (not erythema) 48-72 hrs
• gt5mm 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
• gt10mm Induration is positive in
• Patients with high risk comorbid conditions
• Persons from endemic areas
• Residents of long-term (chronic) care facilities
• gt15mm required for positivity in normal hosts

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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

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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

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Rare BCG Reaction
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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
• Langerhans cells w/
  epithelioid cells
  surrounded by
  monocytes

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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

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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 prosectors warts
• PPD highly ()

http//dermis.net/doia/image.asp?zugrdlangecd
21nr99diagnr17020
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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

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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

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pg
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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

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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

• Orificial tuberculosis. A non-healing ulcer at
  the tip of the tongue

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Tuberculosis Orificialis

• Histopath
• Massive nonspecific inflammatory infiltrate and
  necrosis
• Tubercles with caseation may be found deep in the
  dermis
• Numerous bacilli

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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?Diag
nosis-901045419
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Lupus Vulgaris

• Histopath
• Hallmark Classic Tubercles

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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

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Metastatic Tuberculous Abscess
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Metastatic Tuberculous Abscess

• Histo
• Similar to scrofuloderma
• Massive necrosis and abcess formation
• Acid fast stains copious amounts of myocbacteria

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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

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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

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Miliary TB of the Liver
Multinucleated Giant Cell
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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

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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

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Tuberculids

• Lichen Scrofulosorum
• Histopath
• Superficial noncaseating tuberculoid granulomas
  develop around hair follicles
• Mycobacterium are not seen and can't be cultured

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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

• Papulonecrotic tuberculid. Erythematous papules
  and papulopustules on the heel.

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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

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Papulonecrotic Tuberculid
Dusky red, pea sized papules that are symmetric
and become necrotic
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Tuberculids

• Erythema Induratum (Bazins 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

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Erythema Induratum
www.emedicine.com
Evidence of panniculitis exhibiting lobular,
granulomatous, and lymphohistiocytic inflammation
Nodules after resolving with ulceration
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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

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Mycobacterium marinum
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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

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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.

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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
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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

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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

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http//meds.queensu.ca/medpalm/PDA_Portal/case11.
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Mycobacterium avium
Mycobacterium intracellulare
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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

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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

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Atypical Mycobacteria

• Mycobacterium genavese
• Little is known about this organism
• Causes disseminated dz
• Similar to M. avium intracellulare in HIV
  infected pts

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Atypical Mycobacteria

• Mycobacterium fortuitum complex
• Three similar species
• 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

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Atypical Mycobacteria

• Lymphangitic spread by Mycobacterium fortuitum.
  The inoculation chancre was on the foot.

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Leprosy (Hansens 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

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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

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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

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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

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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

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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

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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.
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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 gt 20 yrs

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Leprosy

• Diagnosis
• 2 of 3 clinical criteria
• 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 (multibacillary vs.
  paucibacillary)
• Punch bx of skin lesion (USA)
• Fite stain reveals intracellular bacilli
• PCR

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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.

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Leprosy

• Identification and Quantification of Bacilli
• AFB in tissue are best shown by carbolfuschin
  staining using modifications of the Ziehl-Neelson
  method collectively called Fite-Farraco 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

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Clasification of Leprosy
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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

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Tuberculoid Leprosy
Central Hypo- Pigmentation
Elevated Border
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Tuberculoid Leprosy Histology
Linear granuloma following the course of a nerve
Higher power view of granuloma surrounding the
nerve
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Borderline Tuberculoid Leprosy

• Lesions similar to TT
• Borders less distinct
• Multiple (gt5)
• Satellite lesions sometimes seen around larger
  lesions
• Peripheral nerves involved earlier
• Lepromin Rxn Mild
• Bacillary Density Scant

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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

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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

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Borderline Lepromatous Leprosy
Multiple Erythematous Plaques with Vague border
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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

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Lepromatous Leprosy
Note the diffuse infiltration of the face with
leonine facies and madarosis
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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

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Lepromatous Leprosy
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Indeterminate Leprosy

• Vaguely defined hypopigmented or red macules
• With or without sensory deficit
• Lepromin Rxn Weak
• Bacillary Density Rare

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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

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Sequelae of Leprosy

1. Madarosis
2. Saddle nose
3. Blindness in the left eye

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Reactional States

• 50 of patients after initiation of therapy
• Causes considerable morbidity
• Immune response-destructive, inflammatory process

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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 4060 mg/daily
• Note downgrading reactions occur before the
  initiation of tx and represent shift to LL

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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 Sxs 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
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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

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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

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Treatment of Leprosy

• Type of Leprosy Monthly Daily Duration
• Paucibacillary
• (I, TT, BT) Rifampin 600mg Dapsone 100mg
  6 months
•  
• Multibacillary
• (LL,BL,BB) Rifampin 600mg Clofazimine
  50mg 24 months
• Clofazimine 300mg Dapsone 100mg

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Treatment of Leprosy

• Effective 2nd-line drugs
• Ofloxacin
• Minocycline
• Clarithromycin

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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

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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

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Low Resistance Lepromatous Leprosy

• Characterized by
• Wide dissemination
• Abundant orgs
• Foamy macrophages
• Untreated relentless progression