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 Hansen’s 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 27°–30°C, 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 bacteria’s 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 they’re 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 4°C; 28 days at -70°C. 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).

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

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

wet soil; 60 days in saline at room temperature; 7 days after 3-day exposure to sunlight; 60 days on refrigeration at 4°C; 28 days at -70°C. 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.

Discernible Early Disease Signs and Symptoms

See infection cycleInteraction of Host and Stimuli

Affect peripheral nervesIncubation period of 5 years

Early Pathogenesis

Skin lesions,sensory losst, hickened nerves, ositive skin smearsDiscernible Early Disease

Nerve involvement leading to eventual blindness and/or amputation of fingers and toesAdvanced Disease

Recovery with early diagnosis and treatmentDisability from advanced disease

Convalescence

Residual disabilities needing rehabilitationChronic State

Rarely fatalDeath

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.

Diagnosiso 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 smearso 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.

Treatmento 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 WHO’s mutltidrug therapy, leprosy is rarely fatal nowadays.

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