Mycobacteria: Tuberculosis and Leprosy

Andrew Racette MS IV

TuberculosisEpidemiology

Estimated 1.7 billion infected persons1/3 of world’s population10 million people in US

12 million new cases per year w/ 3 million deaths4 million co-infected with HIV

¾ live in sub-Saharan Africa

Incidence tied to poverty, unemployment, homelessness, AIDS and drug resistanceMulti-drug resistant disease (MDRTB) major problem

http://www.med.sc.edu:85/fox/tuber-map3.jpg

TuberculosisEtiology

Mycobacterium tuberculosis (Tubercle bacillus, MTB), M. bovis, M. africanum and BCGImmune response contains infection in majority

5-10% of immunocompetent develop clinical disease

Rarely eradicated due to resistance to macrophage destruction, dormancy within granulomasDormant bacilli resistant to antimycobacterialsImmunosuppression often leads to clinical sx

TuberculosisEtiology

MTB Surface CoatMycolic 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

TuberculosisSymptoms

Pulmonary: SOB

Sputum production

Systemic: Fatigue

Malaise

Fever (in ddx for FUO)

Lethargy

Weight loss

TuberculosisSymptoms

Disseminated Disease: Miliary pattern on CXR

Pancytopenia (BM)

Other Sites: Bones (Potts), GI, brain, meninges

Almost any organ

Asymptomatic in large number of persons90%

The Tuberculin ReactionThe Koch PhenomenonMost 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 administrationLocal intradermal inject. leads to the local TB rxnReaches max intensity after 48 hrsConsists of a sharply circumscribed area of erythema and induration

The Tuberculin ReactionPurified Protein Derivative (PPD) is currently usedRead 48-72 hours after intradermal injectionBecomes 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 evaluation0.1ml 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 conditionsPersons from endemic areasIVDAResidents of long-term (chronic) care facilities

>15mm required for positivity in normal hosts

Previous BCG vaccination does not alter PPD

TB HistopathologyTubercle 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 VaccinationBacillus Calmette-Guerin (BCG) is a living attenuated bovine tubercle bacillus to enhance immunity to tuberculosisOnly given to TB (-) personsReduces 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

1. Inoculation from an exogenous sourse2. Endogenous cutaneous spread3. Hematogenous spread to the skin4. Tuberculids

Primary Inoculation TB2-4 wks after inoculation painless brown-red ulcer with hemorrhagic base3-8 wks regional lymphadenopathy - painlessFace, hands, and legsHistopathology

Typical tubercles Langerhan’s cells w/ epithelioid cells surrounded by monocytes

Primary Inoculation TBCourse:

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

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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 entrymany 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

ScrofulodermaTB involvement of the skin by direct extensionUsually 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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ScrofulodermaHistopathology:

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 OrificialisTB of mucous membranes and skin surrounding orifices

Usually by autoinoculation

Seen in pts with TB of internal organsGI Tract or Lungs

Mouth most commonly affected siteTongue and palate

Prognosis poor – advanced internal diseasePresents 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 VulgarisCutaneous TB from hematogenous spread

Chronic and progressive50% have TB elsewhere

Single plaque of grouped red-brown papules that blanch with diascopic pressure

“Apple-jelly” nodules = pale brown/yellowSpreads peripherallyRisk of BCC/SCC with mets

90% occur head/neck

http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=-901045419

Lupus VulgarisHistopath

Hallmark: Classic Tubercles

Metastatic Tuberculous Abscess

Tuberculous GummaHematogenous dissemination from primary focus during a period of lowered resistance leading to distant abscess/ulcer

SubQ abcessesNontenderFluctuantSingly or as multiples on the trunk, ext, or headUsually 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

Multinucleated Giant Cell

Miliary TB of the Liver

TuberculidsCutaneous immunologic rxn to TB elsewhereBy definition cx and stains negativeMost 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 txStrongly positive PPDMost exhibit tuberculois features histologically

TuberculidsLichen 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

TuberculidsLichen ScrofulosorumHistopath:

Superficial noncaseating tuberculoid granulomas develop around hair follicles

Mycobacterium are not seen and can't be cultured

TuberculidsPapulonecrotic Tuberculid

Symmetric, necrotic papules that occur in crops over the extremities and heal by scarringDusky red, symptomless, pea-sized papulesUsually seen in children or young adultsMTB DNA has been detected in about 50% of pts

TuberculidsPapulonecrotic 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 thatare symmetric and become necrotic

TuberculidsErythema Induratum (Bazin’s

Disease)Dusky-red 1-2 cm tender nodules usually occurring on the lower legs in middle-aged womenResolve spontaneously w or wo ulcerationThe 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

Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation

www.emedicine.com

Nodules after resolving withulceration

Atypical MycobacteriaMycobacterium marinum

“Swimming pool/fish tank” granulomaUlcerating lesions in skin at site of abrasions incurred in swimming pools about 2-3 wks. after inoculationSingle nodules, typically on hands, may ulcerate and suppurate with sporotricoid ascending spreadFresh and salt waterTx with Minocycline 100 mg bidHeals spont. w.in 1-2 yrs. w/residual scarring

Acid fast bacilli stain of tissue infected with M. marinum

Localized Necrosis

Intracellular bacilli

Mycobacterium marinum

Atypical MycobacteriaMycobacterium ulcerans infection

Buruli ulcer, Bairnsdale ulcer, Searl ulcerSubequatorial regions of Africa, wet, marshy, swampy areasNever found outside the human bodyIncubation period of ~3 moPainless subq swelling which enlarges to a nodule that ulceratesUlcer is deeply undermined and necrotic fat is exposed exposing muscle and tendon

Atypical MycobacteriaMycobacterium 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

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

http://www.cdc.gov/ncidod/eid/vol5no3/dobos.htm

Atypical MycobacteriaMycobacterium kansasaii

Unusual skin pathogen more commonly associated with pulmonary disease in middle-aged men

Infections localized to Midwestern states and Texas

Acquired from the environmentVariable skin presentations:

NodulesPlaquesCrusted ulcers m/c in immuno-suppressed

Responsive to anti-TB tx: Streptomycin, Rif, Emb

Atypical mycobacterium most closely related to MTB

Atypical MycobacteriaMycobacterium avium complex (MAI/MAC)M. avium and M. intracellulare infects lungs and lymph nodes but occasionally causes cutaneous lesions with disseminationSingle or multiple painless, scaling, yellowish plaques w/ a tendency to ulcerateCommon in AIDSHighly resistant to anti-TB drugs requiring several in combination:

Azithromycin, Rifampin, Ethambutol

Where feasible surgical tx is advisableRifampin used for prophylaxis

Mycobacterium avium

Mycobacterium intracellulare

http://meds.queensu.ca/~medpalm/PDA_Portal/case11.html

Atypical Mycobacteria

Mycobacterium szulgaiAssociated with:

Cervical lymphadenitisCellulitis Draining nodules and plaques

Can also cause bursitis and pneumoniaMore susceptible to antiTB drugs than most other atypical mycobacterium

Atypical Mycobacteria

Mycobacterium haemophilumSubQ 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 dzSimilar to M. avium intracellulare in HIV infected pts

Atypical MycobacteriaMycobacterium fortuitum complex

Three similar species:1. M. fortuitum2. M. chelonei3. M. abscessus

Saprophytes, found chiefly in soil and waterRarely cause human disease

Immunocompromised Prosthetic heart valves and joints

Usually follows puncture wound or surgery

Atypical MycobacteriaMycobacterium fortuitum complex

Surgical excision is useful for the treatment of isolated lesionsof lupus vulgaris, TB verrucosa cutis, or scrofuloderma

Initial Treatment of TB

LeprosyEtiology

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

LeprosyEtiology

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

LeprosyLepromin skin test

Analogous to the tuberculin testPositive at 48 hours = Fernandez reactionPositive again at 3-4 weeks = Mitusda reaction

Late reaction indicative of immune status of patientStrongly (+) in TTIntermediate in BBAbsent in LL

Clinical presentation complexLittle is known about why different people respond differently to leprosy bacillus

This reflects the underlying host immunity as measured by the T-lymphocyte 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.

LeprosyEpidemiology

5 million persons worldwide7 thousand active cases in USA250 new cases /year620,000 new cases worldwide/year.80% in 6 countries: Bangladesh, Brazil, India, Indonesia, Myanmar, NigeriaEndemic in SE Asia, Far East, Africa, South/Central AmericaCases in Puerto Rico, Cuba, USA

LeprosyBiological behavior and transmission

Cell-mediated immune responseLow 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

LeprosyBiological 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

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.

Nerve Examination Sites

LeprosyBiological behavior and transmission

Transmission similar to TBRespiratory “Globi”

Nasal mucosa

Typically requires extensive contact

Incubation for Tuberculoid leprosy is up to 5 yrs and may be > 20 yrs for LL

LeprosyDiagnosis

2 of 3 clinical criteria1. Anesthesia of the skin2. Thickened peripheral nerves3. 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 bacilliPCR

LeprosyDiagnosis

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.

LeprosyIdentification and Quantification of Bacilli

AFB in tissue are best shown by carbolfuschin staining using modifications of the Ziehl-Neelson method collectively called Fite-Farraco stainsM. leprae are weekly acid fastRod shaped bacilli

Found in macrophages and nervesQuantified 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 LeprosyTT = Polar Tuberculoid

Features:Single to few anesthetic macules or plaquesHypopigmentedBorders well definedPeripheral nerve involvement common Localized & asymmetrical May contact epidermis and do more damage to nerves than LL

Lepromin Rxn: very strongBacillary density: None

Elevated Border

Central Hypo- Pigmentation

Tuberculoid Leprosy

Linear granuloma following the course of a nerve

Higher power view of granuloma surrounding the nerve

Tuberculoid Leprosy Histology

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: MildBacillary Density: Scant

Borderline LeprosyStill more lesions that BTBorders more vagueAsymmetricBizarre punched-out lesionsHair loss Anhydrosis Most common type Lepromin Rxn: WeakBacillary Density: Moderate

Borderline Lepromatous Leprosy

Multiple macular/papular/plaquesSymmetric lesionsVague borders Neuritis late then neural lesionsSurface smooth and shiny with ill-defined borderMixed granulomasLeprae in neurons = enlargementLepromin Rxn: NoneBacillary Density: Heavy

MultipleErythematous Plaques withVague border

Borderline Lepromatous Leprosy

Lepromatous LeprosyMultiple, non-anesthetic, macular and papular lesionsNo neural lesions until very lateLate complications:

MadarosisLeonine faciesTesticular damage

Lepromin Rxn: NoneBacillary Density: Heavy

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

Lepromatous Leprosy

Lepromatous LeprosyPts 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

Lepra Cells

Grenz ZoneSeperates dermis from epidermis

Foamy histiocytes (macrophages) in the dermis

Lepromatous Leprosy

Indeterminate LeprosyVaguely defined hypopigmented or red macules

With or without sensory deficit

Lepromin Rxn: Weak

Bacillary Density: Rare

Lucio LeprosyScleroderma-like with hair loss and telangiectasias

Diffusely seen in Mexican/LA patients

May give rise to obstructive vasculitisAka Lucio phenomenon

Sequelae of Leprosy

1.Madarosis2.Saddle nose3.Blindness in the

left eye

Sequelae of Leprosy

Reactional States

50% of patients after initiation of therapy

Causes considerable morbidity

Immune response-destructive, inflammatory process

Reactional StatesType 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 StatesErythema Nodosum Leprosum (Type II lepra rxn)

Josling's type 2 reactionOccurs in 50% of patients with LL and BLImmune complex reaction (type III) between M. leprae antigens and host IgWidely distributed dermal nodules

Do not occur at previous skin lesions

IC precipitate in skin, endothelium, nerves, eyesSystemic Sx’s: Fever, malaise, ulceration, neuritis, uveitis, glaucoma, acute inflammationTx with Thalidomide 400 mg daily

Reactional StatesLucio Phenomenon (Type III Lepra Reaction)

Latin Americans - MexicansPts 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 deathTx:

Unresponsive to steroids or thalidomideAntimicrobial chemo for leprosy Wound care of ulcers

Treatment of LeprosyMedications of choice

Dapsone: 100mg/d in adults 1mg/kg/d in children

Clofazimine (Lamprene): 50-100mg/d in adultsunestablished in children

Rifampin: 600mg/mo in adults

Treatment of LeprosyType 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

Treatment of Leprosy

Effective 2nd-line drugsOfloxacin

Minocycline

Clarithromycin

Treatment of Leprosy

MonitoringDapsone:

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 lesionsRare organismsEpitheloid cell granulomas w/ tendency to self-curePlaques w/ sharp margins are the inscription of anti-M. leprae DTH on the skinNerve trunk palsies are its inscription on the peripheral nerves

Low Resistance Lepromatous Leprosy

Characterized by:Wide dissemination

Abundant orgs

Foamy macrophages

Untreated relentless progression