Transcript M leprae

Leprosy
Hansen’s disease
Introduction

Leprosy is a chronic granulomatous infection of
the skin and the peripheral nerves, with an
intracellular bacterium Mycobacterium Lepra.

Leprosy was recognized in the ancient
civilization of China, Egypt, and India. The first
known written mention of leprosy is dated
600BC.
Introduction
 Leprosy
shows a wide range of clinical
presentation from:

Tuberculoid leprosy (TT)

Borderline leprosy: borderline tuberculoid (BT),
midborderline (BB), borderline lepromatous (BL).

Lepromatous leprosy (LL).
(Classified by Ridley & Jopling 1966)

A simpler field classifications depending on the
number of skin lesions:
•
Single skin lesion (one patch).
•
Paucibacillary ( 2-5 patchs).
•
Multibacillary more than 5 patchs)
Etiologic agent

Mycobacterium Leprae,
discovered in 1873 by
G.A. Hansen.

Intracellular parasite with
tropism for macrophages
and Schwann cells.

Viable bacilli stained with
carbol-fuchsin appear as
solid rods with rounded
ends, while those is
irregular stain are dead.
Etiologic agent

M. leprae is an acid &
alcohol fast (Ziehl-Neelsen),
gram positive bacilli.

Prefer to grow in cooler
regions of the body <
37ºc.

It has never been
cultivated extracellularly,
but organism can
replicate in mouse
footpad & 9-banded
armadillo
Etiologic agent

Genome include 1605 genes encoding proteins
& 50 genes for stable RNA molecule.

More than half of the functional genes are
replaced by inactive or pseudogenes, retaining
the genes essential for Mycobacterial cell wall
formation.

Thus M. leprae depend on host metabolic
products, and this explain it’s slow rate of
replication and inability to grow in culture.
(Shin Y,et al. 2000)
Etiologic agent
 Mycobacterial
cell wall contain several
targets for host immune response:

Phenolic glycolipid I (PGL-I).

Lipoarabinomannan.

Other cell wall proteins purified from
glycolipid component of cell wall.
 Phenolic glycolipid I (PGL-I).

Prominent surface lipid specific for M. leprae.

Best characterized virulent factor:
 Binds to C3,»»» phagocytosis of the bacterium by

mononuclear phagocytes.
Protect against oxidative killing by hydroxyl radicals and
superoxide anions.
Phenolic glycolipid I (PGL-I).
•
Specific tropism for Schwann cells:

Trisaccharide terminal of PGL-I »»» G domain of α 2
chain of laminin 2, a basal component of lamina of
Schwann cells restricted to peripheral nerves.
•
Stimulates host immune response:

Potent IgM antibody response, that is proportional to
bacterial load and fall with therapy.
(Sridharan, et al. 2005)

Lipoarabinomannan:

Modulates macrophages phagocytic activity, & proteins
involved in cell wall synthesis.

Other cell wall proteins purified from glycolipid
component of cell wall:

Act as potent T-cell antigens, stimulate protective
immunity in murine M. leprae infection.
(Britton & Lockwood, 2004)
Epidemiology
Prevalence:

In the past 20 years more than 14 million
patients have been cured.

In 1985 »»» 12/10 000, dropped in 2000 »» >
1/10 000, with a 20% annual decrease in new
cases detected globally since 2001.

Leprosy is eliminated from 113 countries of 122
where leprosy was considered a public health
problem in 1985.
Epidemiology

In 9 countries in Africa, Asia & Latin America »»» more
than 1/10 000
 Eighty three % of cases are present in 6 countries: India,
Brazil, Burma, Indonesia, Madagascar & Nepal.
 India account for 64% of cases world wide.
(WHO, 2005)
WHO African region leprosy elimination program
meeting in 2003
Epidemiology

Primary host is human. Naturally occurring
infection is also reported armadillos in America &
African chimpanzee.

Sex: Male more affected than females (M/F ratio
1.5-2 to 1) except in some areas of Africa.

Age: All ages, about 20% of cases occur in
children below 10 years, but it is extremely rare
in infants.
Transmission

Aerosol spread of nasal secretion, & uptake
through nasal or respiratory mucosa.

M. Leprae in nasal secretion can survive up to
36 hours, or as much as nine days in tropical
areas.

Proximity is an important determinant of
transmission, & incidence among houses hold
contacts:
8-10 for lepromatous leprosy.
2-4 for tuberculoid leprosy
(Sridharan, et al. 2005)
Incubation Period

Varies widely from months to 30 years

With a mean of 4 years for TT and 10 years for LL.

Subclinical infection is reported in areas of high
prevalence, as M. leprae DNA was detected in 5% of
nasal swabs from normal individuals.
(Britton & Lockwood, 2004)
Host susceptibility

Genetic factors can affect both the development
and the pattern of the disease:
 susceptibility loci on chromosomes 10 & 6 »» Indian



patients.
Polymorphism TNF- promoter genes »» multibacillary
leprosy in Brazilian patients.
HLA DR2 & DR3 »» »» tuberculoid diseases, while HLA
DQ1with lepromatous form
Mutation in toll-like receptor-2 gene »» »» lepromatous
leprosy in Koreans.
(Britton & Lockwood, 2004)
Pathogenesis



Clinical forms of the diseases depend on the ability to
mount a cell mediated immune response.
One pole (TT) »»vigorous CMI »» lesions infiltrated with
Th1-like Tcell » » IFN  , TNF α, IL-2 and IL-15 »»well
demarcated granulomas with few mycobacteria found in
the lesions.
Diseases is limited to few well defined skin patchs or
nerve trunks.
Other pole (LL):



Absent specific cellular immunity,»» uncontrolled
proliferation of bacilli with many lesions and extensive
infiltration of the skin and nerves.
There is no organized granuloma, foamy macrophages,
and high antibody titer to PGL-I.
Deviation of CD4+ve T cells, with Th2 like cytokines IL-4
and IL-10, deletion of T cells, or suppressor T cells
Pathogenesis


Most of the patients have the intermediate form (BT,BB,
and BL).
They are unstable and either progress:

Slowly toward lepromatous pole, or

Type 1 leprosy reaction (reversal reaction)
Spontaneous increased T cell reactivity & in cytokines IFN  , TNF α

Type 2 reaction (erythema nodosum leprosum)
Systemic inflammatory immune response»» extravascular immune
complexes »» neutrophil infiltration, complement activation and high
concentration of TNF α
Clinical features

Skin involvement:
Commonly macules or plaques rarely papules or nodules
are seen.
In tuberculoid and BT, lesions are few, hypopigmented with
raised edges, and with reduced sensation
Clinical features

Lepromatous form, many skin lesion,
symmetrical, confluent in some cases, and many
of them are not hypoaesthetic.
Clinical features
Clinical features

Nerve damage:

Peripheral nerve trunk
damage:
Posterior tibial, ulnar, median,
lateral popliteal and facial.
Involved nerves are enlarged, and
with regional sensory and
motor loss.

Small dermal sensory &
autonomic nerves:
Hypoaesthesia »» TT and BT.
Glove & stocking »» lepromatous
form.

Pure neuritic leprosy:
Clinical features

Eye involvement:

Blindness »»» nerve damage &
direct invasion

Lagophthalmus »»» orbicularis
oculi »»» zygomatic & temporal
branches of facial nerve.

Corneal ulceration »»»
anaesthesia »»» ophthalmic
branch of trigeminal nerve.
Clinical features

Systemic features:

Nasal mucosa »»»
cartilage »»» saddle
shape.

Bone destruction »»»
osteomylitis.

Testicular atrophy »»»
loss of testosterone .

Renal involvement and
amyloidosis
Diagnosis


Lepromin test:
Intradermal inoculation of killed M leprae.
 Early reactions (48 h, Fernandez)
 Late reactions (3-4 wk, Mitsuda)
 strongly positive responses (>5 mm) in TT or BT, while
patients with LL do not respond.
Diagnosis


Slit smear technique:
Skin incision in 6 sites ( ear lobes, elbow, knee and a
lesion)
 Slit is smeared on a slide and stained with ZiehlNeelsen.
 Microscopic score (1+ to 6+), reflect number of bacilli by
HPF
 Useful to quantitate bacterial load
 High specificity but low sensitivity 70%
Diagnosis

Serology:

ELISA: to detect antibodies against carbohydrate portion
of the PGL-I.
 Postive in lepromatous but not the tuberculoid form.
 Antibody titer decreases with effective therapy.

Polymarase chain reaction (PCR):

Amplify the DNA of M leprae
Low bacterial loads (<10 bacilli) can be detected.
60-75% of smear -ve patients with TT leprosy have
positive results on PCR.


Diagnosis

Histologic diagnosis:

In TT: Noncaseating
granuloma, bacilli are few
or absent, dermal nerve
involvement, with normal
skin organs.

In LL: Diffuse
granulomatous reaction,
foamy macrophages,
more common around
blood vessels and nerves
Treatment

Chemotherapy:
All patient should receive multi-drug therapy (MDT).
First line drugs: Rifampicin, Clofazimine, and Dapsone.
Treatment
Second line therapy: Minocycline, clarithromycin, and
ofloxacin, are highly effective against M. leprae.
Reversal reaction:
Peak time: during the first 2 month of therapy, even up 12
months, and after (MDT) is completed.
Corticosteroids 40-60mg daily, taper 5 mg every 2-4 weeks,
duration of therapy 3-4 months.
Recovery rate for nerve function 60-70%, less with preexisting nerve damage or recurrent reaction.
Treatment
Type 2 reaction (ENL):
Develop during 1st or 2nd year of MDT, and can relapse
over several years.
Anti- inflammatory: Clofazimine 300mg daily. Or
Drug that target overproduction of TNF-α,Thalidomide
400mg daily, or pentoxifylline. Or
Neutralization of TNF-α with monoclonal antibodies, or
soluble inhibitors.
Prophylaxis

Immunoprophylaxis:

BCG offer variable protection against leprosy (34-80%) in different
countries, adding heat –killed M. leprae increases the protective
effect to 64%.

Endemicity of leprosy, background saprophytic mycobacterial flora,
and the age at vaccine may affect the response to vaccination.

Vaccination may precipitate TT leprosy in apparently healthy
contacts, thus immunoprophylaxis is best carried out at an early
age.

Chemoprophylaxis:

Rifampicin, to close contact of a case, and can be give to children
under the age 12 years (15mg/kg monthly for 6 months)
Pregnancy & leprosy

Little evidence that pregnancy can cause new diseases
or relapse.

However, pregnant BL patients may experience type 1
reaction in the post partum period.

Also lepromatous leprosy patients can experience ENL
during pregnancy and lactation, with early loss of nerve
function than non-pregnant patients.

MDT (Rifampicin, Clofazimine, and Dapsone) is safe.
HIV infection & leprosy

Unlike tuberculosis, leprosy is not significantly
associated with HIV infection.

HIV-associated neuropathy might be confused with
leprosy neuritis, also neuropathy due to antiretroviral
chemotherapy might be confused with leprosy.

There is difference in treatment strategy for patients with
leprosy and HIV, icluding treatment of reactions.
Thank you