LEPROSY:

Pre-pathogenesis & Pathogenesis

INTRODUCTION

Leprosy is a curable chronic mildly communicable disease caused by Mycobacterium leprae
that mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract and
also the eyes (World Health Organization, 2014). It is also called Hansens Disease, named
after Dr. Gerhard Henrik Armauer Hansen, a Norwegian physician who discovered the bacteria
in 1873 (Bennett, Parker & Robson, 2008). It has been associated throughout its history with
extreme prejudice, fear, and revulsion. Through the passage of time, the disease has spread
globally to affect nearly all regions of the earth.

According to the Global Health
Observatory (2014), at the beginning of
2013, a total of 115 countries or
territories reported on leprosy to WHO:
25 from the African Region, 28 from the
Region of the Americas, 11 from the
South-East Asia Region, 20 from the
Eastern Mediterranean Region and 31
from the Western Pacific Region. Most
countries in the European Region have
not reported cases in recent years,
although several detect a few cases
annually. At the beginning of 2012, 232
876 new cases of leprosy were
detected, and the registered
prevalence was 189 018 cases. The
table below shows the global, regional
and national data on the burden of
leprosy in 2010:

The next sections explain and illustrate
the pre-pathogenesis of the leprosy
through the epidemiologic triangle and
the infection cycle. Thereafter, pathogenesis of leprosy is discussed in detail. Finally, a health
belief model of leprosy is shown.









PRE-PATHOGENESIS


Human Host

Mycobacterium leprae Environmental Factors


Disease Agent
Leprosy is a caused by Mycobacterium leprae, an acid-fast, rod-
shaped bacillus closely related to Mycobacterium tuberculosis,
the pathogen of tuberculosis (WHO, 2014; &, Tortora, Funke &
Case, 2011). M. leprae is the first bacteria to be identified as a
human pathogen (Tortora, Funke & Case, 2011).
Pathogenicity, Invasiveness, Virulence & Infectivity: M.
leprae is slow-growing, with a doubling time of 11 to 13 days. It
is an obligate, intracellular parasite that grows best at 2730C, which is consistent with
the characteristic major target organs of the disease in humans as the skin, peripheral
nerves, nasal mucosa, upper respiratory tract, and eyes (Bennett, Parker & Robson,
2008). M. leprae possesses mycolic acids in the outermost layer of the bacterias cell
wall, contributing much to its virulence. This characteristic allows the bacterium to resist
penetration by antimicrobial drugs and prevents drying. The bacterium also has the
ability to survive within macrophages and the Schwann cells of peripheral nerves that
allows it to remain inside cells protected from immune forces, provided antigens do not
form on the host cell surface, and enables bacterial multiplication. Additionally, the
immune system responses to M. leprae through the lysis of infected cells thereby
damaging infected nerves and tissues. M. leprae does not produce toxins.

Human Host
Exposure: People who live in a country where the disease is widespread and who have
been in prolonged close contact with people who have untreated leprosy are susceptible
to contracting the disease (Centers for Disease Control and Prevention, 2013).
Age: Leprosy is known to occur at all ages ranging from early infancy to very old age
(WHO, 2014) but it has a bimodal age distribution, with peaks at ages 10-14 years and
35-44 years (Lewis, Conologue & Harrop, 2014). Children appear to be most susceptible
to leprosy than adults (Lewis, Conologue & Harrop, 2014; Vorvick & Vyas, 2011).
According to the United States Centers for Disease Control and Prevention (2013), most
adults around the world might face no risk at all of contracting leprosy adding that
evidence shows that 95% of all adults are naturally unable to get the disease, even if
theyre exposed to the bacteria that causes it (CDC, 2013). Leprosy is rare in infants
(Lewis, Conologue & Harrop, 2014).
Sex: Although leprosy affects both sexes, in most parts of the world males are affected
more frequently than females often in the ratio of 2:1. It should be pointed out that the
male preponderance in leprosy is not universal (WHO, 2014; &, Lewis, Conologue &
Harrop, 2014). Women tend to have a delayed presentation, which increases rates of
deformity (Lewis, Conologue & Harrop, 2014).
Genetic make-up: Variants of genes in the NOD2-mediated signaling pathway (which
regulates the innate immune response) are associated with susceptibility to infection
with M. leprae (Ferri, 2013).
Race: Leprosy was once endemic worldwide, and no racial predilection is known. Dark-
skinned africans have a high incidence of the paucibacillary type of leprosy, whereas
people with light skin and Chinese individuals tend to have multibacillary type (Costa, et.
al, 2003).
Defense mechanism: As mentioned earlier, certain genetic variations can alter the
innate immune response. However, the majority of people exposed to patients with
leprosy do not develop the disease because of their natural immunity (Ferri, 2013).
State of nutririon: In a study conducted by Kerr-Pontes, (2006) in Brazil, it was found
that leprosy can be related to food shortage since individuals who suffered from hunger
at least once during the last ten years are likely to have experienced nutritional
deficiencies in previous periods of their life; hence, it is conceivable that inadequate
nutrition weakens the immune competence against infection and, thereby, the infection
with M. leprae.

Environmental Factors
Leprosy is common in many countries worldwide, and in temperate, tropical, and
subtropical climates (Vorvick & Vyas , 2011).
A study by Desikan and Sreevatsa (1995) in India, where there disease is endemic,
revealed that M. leprae was viable up to 5 months after drying in the shade; 46 days on
wet soil; 60 days in saline at room temperature; 7 days after 3-day exposure to sunlight;
60 days on refrigeration at 4C; 28 days at -70C. This suggests that the bacteria is
viable outside the human body for varying periods of time in different environmental
conditions and may be contracted via indirect contact.











CHAIN OF INFECTION



Infectious Agent
See disease agent in the previous section.

Reservoir
The natural reservoir of the disease is thought to be humans (Bennett, Parker & Robson,
2008).
The disease has been discovered in wild armadillos in the southern United States
(Bennett, Parker & Robson, 2008). According to Tortora, Funke and Case (2004),
several Texans have actually contracted leprosy from contact with armadillos in that
state, where they are common.
Additionally, it has been reported in three species of nonhuman primates, i.e.,
chimpanzees, cynomolgus macaques, and sooty mangabey monkeys, but these are not
thought to be significant sources for human disease (Bennett, Parker & Robson, 2008).
Furthermore, organisms have been found to survive for up to nine days outside of the
human host under tropical conditions, raising the possibility of contact spread through
broken skin. The possibility of the disease being spread through insect vectors also
cannot be definitively excluded (Bennett, Parker & Robson, 2008).
Infectious Agent:
Mycobacterium leprae
Reservoir: (Generally)
Humans
Portal of Exit: Upper
respiratory tract of
untreated patients with
severe disease
Mode of Transmission:
Droplet
Portal of Entry: Exposed
nasal and oral mucosa
of the host
Susceptible Host:
People with prolonged
close contact with
people who have
untreated leprosy
A study by Desikan and Sreevatsa (1995) in India, where there disease is endemic,
revealed that M. leprae was viable up to 5 months after drying in the shade; 46 days on
wet soil; 60 days in saline at room temperature; 7 days after 3-day exposure to sunlight;
60 days on refrigeration at 4C; 28 days at -70C. This suggests that the bacteria is
viable outside the human body for varying periods of time in different environmental
conditions and may be contracted via indirect contact.

Portal of Exit
M. leprae exits the reservoir through the upper respiratory tract, i.e., the nose and
mouth, of untreated patients with severe disease during coughing or sneezing (WHO,
2014; International Federation of Anti-Leprosy Associations, 2014; &, CDC, 2013).
The ulcerated nasal mucosa of multibacillary patients can yield more than 10 million
viable bacilli per day (Bennett, Parker & Robson, 2008).

Mode of Transmission
It is transmitted via droplets released into the
air from the nose and mouth of untreated
patients with severe disease through
coughing or sneezing (WHO, 2014; ILEP,
2014; &, CDC, 2013).
Additionally, organisms have been found to
survive for up to nine days outside of the
human host under tropical conditions, raising the possibility of contact spread through
broken skin. The possibility of the disease being spread through insect vectors also
cannot be definitively excluded (Bennett, Parker & Robson, 2008).

Portal of Entry
The pathogen enters through the exposed nasal and oral mucosa of the host after
constant exposure to droplets from the upper respiratory tract, particularly the nose and
mouth, of untreated patients with severe disease (WHO, 2014; ILEP, 2014; &, CDC,
2013).

Susceptible Host
See human host in the previous section.










PATHOGENESIS



Interaction of Host and Stimuli
M. leprae (infectious agent) exits the upper respiratory tract, i.e., nose and mouth, (portal
exit) of untreated patients with severe disease (reservoir) during coughing or sneezing
and transmitted via droplets released into the air (mode of transmission) and enters
through the exposed nasal and oral mucosa (portal of entry) of another person who has
prolonged close contact with people who have untreated (susceptible host). See
infection cycle for more details.

Early Pathogenesis
M. leprae multiplies slowly and has a long incubation period of about 5 years (WHO,
2014). The ILEP (2014), explains further that the incubation period is usually between 2
and 8 years, but can extend up to 20 years in some cases.
M leprae is an obligate intracellular bacillus with an affinity for macrophages and
Schwann cells. For Schwann cells in particular, the mycobacteria bind to the G domain
of the alpha-chain of laminin 2 (found only in peripheral nerves) in the basal lamina,
causing demyelination. Their slow replication within the Schwann cells eventually
stimulates a cell-mediated immune response, which creates a chronic inflammatory
reaction. As a result, swelling occurs in the perineurium, leading to ischemia, fibrosis,
and axonal death.





See infection cycle
Interaction of Host and Stimuli
Affect peripheral nerves
Incubation period of 5 years
Early Pathogenesis
Skin lesions,sensory losst, hickened nerves, ositive
skin smears
Discernible Early Disease
Nerve involvement leading to eventual blindness
and/or amputation of fingers and toes
Advanced Disease
Recovery with early diagnosis and treatment
Disability from advanced disease
Convalescence
Residual disabilities needing rehabilitation
Chronic State
Rarely fatal
Death
Discernible Early Disease
Signs and Symptoms
o The clinical signs and symptoms of leprosy include (WHO, 2014; &, Vorvic &
Vyas, 2011):
Skin lesions that can be single or multiple, usually less pigmented than
the surrounding normal skin; sometimes reddish or copper-colored;
may be seen as macules (flat), papules (raised), or nodules.

Sensory loss is a typical feature of leprosy manifested by skin lesions
that may show loss of sensation to pin prick and/or light touch.
Thickened nerves, mainly peripheral nerve trunks constitute another
feature of leprosy and are often accompanied by other signs as a
result of damage to the nerve. These may be loss of sensation in the
skin and weakness of muscles supplied by the affected nerve. In the
absence of these signs, nerve thickening by itself, without sensory
loss and/or muscle weakness is often not a reliable sign of leprosy.
Positive skin smears: In a small proportion of cases, rod-shaped, red-
stained leprosy bacilli, which are diagnostic of the disease, may be
seen in the smears taken from the affected skin when examined under
a microscope after appropriate staining.

Diagnosis
o Diagnosis of leprosy is most commonly based on the clinical signs and
symptoms. In an endemic country or area, an individual should be regarded
as having leprosy if he or she shows one of the following cardinal signs
(WHO, 2014):
Skin lesion consistent with leprosy and with definite sensory loss, with
or without thickened nerves
Positive skin smears
o A person presenting with skin lesions or with symptoms suggestive of nerve
damage, in whom the cardinal signs are absent or doubtful should be called a
`suspect case' in the absence of any immediately obvious alternate diagnosis.
Such individuals should be told the basic facts of leprosy and advised to
return to the centre if signs persist for more than six months or if at any time
worsening is noticed. Suspect cases may be also sent to referral clinics with
more facilities for diagnosis (WHO, 2014).
o Leprosy can be classified on the basis of clinical manifestations and skin
smear results.
In the classification based on skin smears (WHO, 2014):
Paucibacillary leprosy (PB), formerly known as tuberculoid
leprosy: negative smears at all sites
Multibacillary leprosy (PB), formerly known as lepromatous
leprosy: positive smears at any site
In the classification based on clinical manifestations (Ferri, 2013):
PB leprosy: <5 skin lesions with definite sensory loss, with or
without thickened nerves
MB leprosy: >5 skin lesions with definite sensory loss, with or
without thickened nerves
In practice, most programs use clinical criteria for classifying patients,
particularly in view of the non-availability or non-dependability of the
skin-smear services.
Treatment
o Leprosy is curable and treatment provided in the early stages averts disability
(WHO, 2014).
o Since 1995, WHO has supplied multidrug therapy (MDT) free of cost to
leprosy patients in all endemic countries. The drug combinations vary with the
type of leprosy (WHO, 2014):
PB leprosy: rifampicin and dapsone
MB leprosy: rifampicin, clofazimine and dapsone
o The most important antileprosy drug and therefore is included in the treatment
of both types of leprosy. Treatment of leprosy with only one antileprosy drug
will always result in development of drug resistance to that drug. Treatment
with dapsone or any other antileprosy drug used as monotherapy should be
considered as unethical practice (WHO, 2014).


Advanced Disease
Nerve involvement, especially if it is left untreated, commonly leads to weakness of
various muscles and loss of sensation in the hands and feet, so that the person no
longer feels hot or cold, or even pain that eventually lead to unintentional damage,
ulceration, infection and eventual destruction of fingers and toes, and the well-known
deformities of untreated leprosy. The muscles around the eye may also be affected and
blindness is another important complication of untreated disease (ILEP, 2014).

Convalescence
Recovery
o As previously mentioned, leprosy is curable and early diagnosis and
treatment averts disability, prevents disease transmission, and allows the
person to have a normal lifestyle. (WHO, 2014; &, Vorvic & Vyas, 2011).

Disability
o See advanced disease.


Chronic State
Some people who get leprosy are unfortunately left with some residual disabilities after
the infection itself has been cured. The eyes, hands and feet are the parts commonly
affected. In addition, many also face long-term problems within their family and
community, simply because they once had leprosy. Rehabilitation involves a whole
range of interventions, i.e., physical and socioeconomic rehabilitation, that attempt to
restore the person affected to as normal a life as possible (ILEP, 2014).
Leprosy reactions, i.e., inflammation of the skin patches, the nerves, the eyes and, in a
few cases, the internal organs, can still occur before diagnosis, at the time of diagnosis,
during treatment and even after treatment (ILEP, 2014).

Death
Due to the development of WHOs mutltidrug therapy, leprosy is rarely fatal nowadays.



























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