Transcript Tuberculosis and Leprosy
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
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Tuberculosis
Etiology Mycobacterium
tuberculosis
MTB), M.
bovis
, M.
africanum
(Tubercle bacillus, 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
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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 >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
1.
2.
3.
4.
Four categories of cutaneous tuberculosis
Inoculation from an exogenous sourse Endogenous cutaneous spread Hematogenous spread to the skin Tuberculids
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
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Primary Cutaneous TB
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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 “ 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
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Erythema Induratum
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
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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
1.
2.
Three similar species: M. fortuitum 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
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 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.
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 1.
2.
2 of 3 clinical criteria Anesthesia of the skin Thickened peripheral nerves 3.
Typical skin lesions Slit-skin smear (Abroad) Tissue fluid exudate examined with
Fite
determine bacterial index stain to 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 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
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
Central Hypo Pigmentation
Tuberculoid Leprosy
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
Grenz Zone Seperates dermis from epidermis Lepra Cells Foamy histiocytes (macrophages) in the 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/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 2
nd
-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