Mycobacterium Leprae

Dr.T.V.Rao MD

Dr.T.V.Rao MD

Leprosy
Vedas Bible Fear and Social outcasts Hansen 1868 - Identifies First microorganism Least understood and not cultured in artificial medium
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What is Leprosy?
It is a disease of Historical importamce World's oldest recorded disease Stigmatized disease Gerhard Henrick Armauer Hansen
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LEPROSY
It is a chronic infectious disease caused by M.leprae, an acid fast, rod shaped bacillus. It mainly affects the skin, peripheral nerves, and mucosa of the respiratory tract etc., It has left behind a terrifying image in history and human memory of mutilation, rejection and exclusion from society.
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Transmission
Scientist are not quite sure how the disease is trasmitted but they believe that: 1. It can be trassmitted from one person to another through the air.

Carrier
Armadillo

What causes it?

Mycobacterium leprare Rod Shaped First bacterium disease in humans
Humans and Armadillos are only known natural hosts
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http://www.aaas.org/news/releases/2005/images/0512 http://www.worldproutassembly.org/leprosy%20patien leprosy.jpg t%20holding%20flower.jpg

http://genomenewsnetwork.org/articles/02_01/Leprosy.shtml

Mycobacterium leprae
Appear as straight or curved rods Size is 1 8 microns x 0.5 microns. Polar bodies present as clubbed forms. Lateral buds Branching is observed. Acid fast but less resistant only 5 % H2So4 Live bacilli, solid uniform structure. Dead appear as fragmented with granules.
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Mycobacterium leprae
Acid fast bacilli Strict human pathogens Cannot be cultivated in-vitro Armadillos used for obtaining M leprae Transmission - ? Air borne Low infectivity - prolonged contact required Spectrum of clinical presentations
dependent on host parasite interactions
Tuberculoid Borderline Tuberculoid Borderline Dr.T.V.Raolepromatous MD Lepromatous 9

Lepers are outcasts ?

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Bell to ring by Leper.

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Leprosy in India

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Bacterial Morphology
Bacilli may present in singles, can be intracellular. Agglomerates. Bacilli bound by lipid like substance ( Glia) Masses are Globi Appear cigar bundles.
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Cultivation
Not possible Can be propagated in Foot pads of Mice Granulomas develop at the site of inoculation. Nine banded armadillo highly susceptible. Chimpanzees Generation time 12 -13 days. Average may be 8- 42 days.
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Important Experimental Animal

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Most Important experimental Animal

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Resistance
Viable for 9 -16 days, and in moist soil for 46 days Direct sunlight for two hours. Ultraviolet light for 30 minutes..
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Leprosy
A chronic granulomatous disease Involves Skin, Peripheral nerves, Nasal mucosa, Affecting tissues and organs.
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Classification ( Madrid )
1 2 3 4 Lepromatous Tuberculoid Dimorphic Intermediate. Refers to immune status Chemotherapy Host Immune Status
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Symptoms
There is two ways leprosy is presented:
Tuberculoid Leprosy Symptoms

Lepromatous Leprosy Symptom

Eye problems Blindeness Enlarged nerves

Severe pain Muscle weakness Skin stiffness and dryness Loss of fingers and toes

Thickened skin on face Nasal stuffiness Bloody nose Laryngitis Collapsing of the nose Swelling of the lymph nodes in the groin and armpits Scarring of the testes that leads to infertility Enlargement of male breasts

Types of Leprosy
Depending on clinical features, leprosy is classified as:
1. 2. 3. 4. 5. 6. Indeterminate Leprosy (IL) Paucibacillary Leprosy (PB) Borderline Tuberculoid Leprosy (BT) Borderline borderline Leprosy (BB) Borderline lepromatous Leprosy (BL) Multibacillary Leprosy (MB)
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Ridley and Jopling Classification

Divided in to 5 types 1 Tuberculoid 2 Borderline Tuberculoid. 3 Borderline. 4.Boderline lepromatous 5 lepromatous
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WHO classification
Two Groups 1 Paucibacillary 2 Multibacillary Paucibacillary (PB): the number of M. leprae in the body is small (less than 1 million) and a skin smear test is negative. The patient presents five or fewer skin lesions. Most cases of leprosy are PB.
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WHO classification
2 Multibacillary M. leprae can multiple in the body almost without any check and is thus present in high numbers. The bacillus has likely spread to almost all areas of skin and peripheral nerves. A skin smear test is positive and the patient presents more than five skin lesions.
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Immunity
Innate Immunity Humoral x Cellular immune response. CMI destroys the bacilli. CMI determines the recovery. Good CMI can manifest with Tuberculoid leprosy. Good response with DH Tuberculoid leprosy. Lepromatous leprosy patient have large number of CD 8 lymphocytes.
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Immunity
HLA DR2 Tuberculoid HLA MTI HLA DQ Lepra reaction

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Pathology and Pathogenesis

Bacilli seen as Globi inside lepra cells. Can be seen extracellularly, Multibacilllary disease. Nodular lesions. Granuloma. Different pathways Nodular lesions ulcerate Invade mucosa of Nose, Mouth, URT Involve RES, Eyes, Testis, Kidney. Bones
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Pathogenesis
Leprosy target cell Schwanncell Causes Anesthesia Muscle paralysis. Repeated injuries to Anesthetic areas leads to gradual destruction. Infiltration of skin, subcutaneous lesions leads to formation of visible lesions. First lesions Non specific indeterminate skin lesions
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Hyper reactive -Tuberculoid Leprosy

Tuberculoid leprosy with small number of localized skin lesions, contain so few bacilli. Granulomatous response that often damages major nerve trunks.
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Anergic Lepromatous leprosy Skin lesions are numerous or confluent Contain high number of bacilli Cluster of globi within monocytes
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Other Intermediate Form

Classified as 1 Borderline Tuberculoid 2 Mid borderline 3 Borderline lepromatous

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Who is at risk?
It can affect all ages and both sexes 95% of people who are exposed do not develop

Mainly affects:
Skin Eyes The peripheral nerves Mucosa of the upper respiratory tract
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Who is at risk?

bp2.blogger.com/.../s320/lepromatous_lep rosy.jpg

http://www.leprosymission.o rg/web/pages/leprosy/image s/girlwithleprosypatch.jpg

http://microbes.historique.net/images/lep3.jpg

http://www.leprosymission.org/web/pages/le prosy/leprosy.html

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Other consequences
Destruction of Nasal bones. Collapse of Nose Eye is damaged lead to blindness.

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Pathology and Pathogenesis Tuberculoid Leprosy

, Tuberculoid High degree of Immunity. Tuberculoid -Few skin lesions, Sharply demarcated Maculo anesthetic patches Neural Involvement. Involves Hands and Feet. Bacilli few bacilli are seen A paucibacillary diseases CMI Adequate.Lepromin test positve Good Prognosis
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Borderline Leprosy
Contains characters of both Tuberculoid and Lepromatous leprosy

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How to diagnose leprosy

Examine Check Test

skin

for patches

for sensation the number of patches

Count Look

for damage to nerves

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Diagnosis of Leprosy
Diagnosis must therefore be made by doing a biopsy, in which a small piece of skin is taken to analyse for the leprosy bacterium. Early diagnosis is very important because it can prevent permanent deformities and disability.
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Laboratory Diagnosis
Lepromatous easy to diagnose. Tuberculoid difficult Histological examination 0n skin Biopsy Detection for Acid Fast Bacilli. Nasal discharges, Slit skin smears. Ear lobes Take specimens from unaffected areas too Stain with Z N method with 5% H2So4
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Z N Staining and description of bacilli

Stain weakly, irregularly dead Count the bacilli in high power field called as Bacterial index Clinically active disease With No bacilli Pauci bacillary disease With bacilli - Multibacillary diseases
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Smear Examination
1+ 1 -10 bacilli / 100 fields 2+ 1-10 bacilli / 10 fields. 3+ 1 10 bacilli / one field. 4+ 10 100 bacilli / one field 5+ 100 - 1000 bacilli /field 6 + > 1000 bacilli /field Number of Bacilli seen in each field is recorded as Bacillary index
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The bacteriological index (BI)

This is an expression of the extent of bacterial loads. It is calculated by counting six to eight stained smears under the 100 x oil immersion lens. in a smear made by nicking the skin with a sharp scalpel and scraping it;
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Quantifying the bacillus as per

WHO
1+ At least 1 bacillus in every 100 fields. 2+ At least 1 bacillus in every 10 fields. 3+ At least 1 bacillus in every field. 4+ At least 10 bacilli in every field. 5+ At least 100 bacilli in every field. 6+ At least 1000 bacilli in every field. Number of Bacilli seen in each field is Dr.T.V.Rao MD 44 recorded as Bacillary index

Bacteriological Index
Indicates the Prognosis of the Disease Total score in all smears -----------------------------------Number of smears Eg 16/8 =2 So the index is 2 Dr.T.V.Rao MD 45

The Morphological index (MI)

This is calculated by counting the numbers of solid-staining acid-fast rods. Only the solid-staining bacilli are viable. It is not unusual for solid-staining M. leprae to reappear for short periods in patients being successfully treated with drugs. It is important to recognize that measurement of MI is liable for observer variations and therefore not always reliable.
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Morphological index (MI)

The fluid and tissue obtained are spread fairly thickly on a slide and stained by the Ziehl-Neelsen method and decolorized (but not completely) which 1% acid alcohol. The results are expressed on a logarithmic scale.
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Lepromin Test
Mitsuda in 1919 skin test delayed hypersensitivity. Lepromin is boiled emulsified lepromatous tissue rich in lepra bacilli. Lepromins, made from boiled bacilli from lepromatous lesions. Leprosins ultisonicates of tissue free bacilli
Human source ,Leprosins H ,Armadillo Leprosins - A

Events in the reaction Biphasic reaction Fernandez Reaction .> 24 48 hours, remains for 3 5 days, like tuberculin reaction, little significant.
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Lepromin test
Mitsuda in 1919. Human source of bacilli Lepromin H Armadillos source of bacilli Lepromin A Bacillary Lepromin - Dharmendra antigen Inject 0.1 ml of Lepromin Read for two types of reactions 1 Early Farnedez reaction 2 Late Mitsuda reaction
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Lepromin Test
Mitsuda reaction occurs after 1 2 weeks. prominent after 4 weeks Infiltration with Lymphocytes ,Epitheloid cells,and giant cells, Indicates CMI Differentiates those mount immune response and those cannot Now antigens are derived from Armadillo derived lepra bacilli
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Lepromin Test (Cont)

Test is not employed for Diagnosis of leprosy, Effectiveness of CMI Helps to asses the prognosis Positive test good response /recovery Negative Bad prognosis
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Problems of over diagnosis

Wrong diagnosis in 0% to 28.6% (9.4%) Govt. of India, WHO, NIHFW 2004
Causes:

1. lack of

knowledge by HCP to exclude dermatological and neurological conditions mimicking leprosy, therefore many doubtful cases included

Causes of under diagnosis

Thicken peripheral nerve with sensory deficit highly subjective Tools used for sensation testing in the field is of low to moderate scientific validity Lesions on the face, difficult to elicit sensory impairment Difficult to diagnose clinically the early LL cases without slit smear examination and\or skin biopsy

Treatment of Leprosy
Multidrug regime Rifampicin 600 mg / once month Dapsone 100/day Clofazimine 50 mg/daily. Continue for 6 months Other Drugs for Leprosy 1.Ethionamide 2.Prothionamide.

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About Dapsone
It was discovered by German chemists Fromm and Wittmann in 1908 Was not utilized as a treatment until decades later Available in 25mg & 100 mg tablets Rated a pregnancy risk category C by the American Food and Drug Administration

About Rifampicin
In the U.S. Rifampicin is marketed as:
Rifadin (Aventis) Rifater ( in combination with isoniazid and pyrazinamide) (Aventis) Rimactane (Novartis)

Do not wear contact lenses while taking Rifampicin Rated a pregnancy risk category C by the American Food and Drug Administration

Pharmaceutical Treatment
Multiple Drug Treatment (MDT)
There are several effective chemotherapeutic agents: Dapsone (diaphenylsulfone, DDS), Rifampicin (RFP), Clofazimine (CLF), Ofloxacin (OFLX), and Minocycline (MINO) constitute the backbone of the multidrug therapy (MDT) regimen.
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Side Effects
Dapsone (DDS) Occasional cutaneous eruptions A slight reddish coloration of urine, sweat, and tears Brownish Black discoloration and dryness of skin

Rifampicin (RFP)

Clofazimine (CLF)

Dosage Contd......
Multidrug Therapy for Paucibacillary (PB) Leprosy
RFP
Adult 50-70kg Child 10-14 years 600mg/m* 450mg/m*

Dapsone
100mg/d 50mg/d

Less than 10 years

300mg/m*

25mg/d

PB patients treated with MDT are cured within six months

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Cost of MDT- Funding

Since 1995, WHO has supplied MDT FREE of cost to all leprosy patients in FREE the world. Initially drug funds were provided by Nippon Foundation Since 2000, donations are provided by Novartis and the Novartis Foundation for Sustainable Development

Prophylaxis
Long term chemotherapy BCG vaccine useful

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Epidemiology
Nasal secretions rich source of infection, Skin contact get infected. Incubation 2 5 years. May take 30 years to manifest. I/3 world Leprosy patients are Indians. Orissa and Bihar highest.
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Prevention Of Leprosy
Early Diagnosis and treatment. BCG vaccination ? Health awareness and active surveillance high endemic areas Field trails with different vaccines BCG + killed lepra bacilli ( ICRC ) bacillus have not given conclusive results.
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What is Leprosy Today

No at all a feared disease. Only 5 % spouse infective rate Leprosy is uncommon in most countries today, but it causes massive suffering in the areas where it is still found. These areas are largely confined to tropical and subtropical regions of Africa, Asia, and Central and South America. .
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