Leprosy

 

Leprosy today afflicts millions worldwide.  Recorded in an Egyptian papyrus dated 1550 BC, and visible on an African tribal mask with facial deformities are findings of lepromatous leprosy.  Biblical references include Miriam, sister of Moses who was stricken with the disease, her face covered with snow-white scales.  She was banned from the camp until she was healed. Numbers 12:1, 9-15 

 

Scholars have proposed that Biblical references to "leprosy" may be polygenic, plausible, if not obvious, but not exclusive of the disease known today as Hansen's disease.

 

Lepers were shunned, made to wear certain colors and bells warning people passing by on the streets to stay clear.  Later, states required their exile to remote colonies.  They were the original "untouchables."  Lew Wallace wrote, first published in 1880, about the incarceration of Miriam and Tirzah, mother and sister of Judah Ben-Hur, respectively:

 

They were thrown into a dungeon cell where prisoners were known to contract leprosy. Miriam had found a slowly enlarging lump on her palm, and, suspicious, took her daughter into the cell's only sliver of daylight and saw, to her horror, white plaques of leprosy in Tirzah's eyebrows." ^[1]                 

 

"Her skin was white as leprosy,

            The Nightmare's Life-in-Death was she,

            Who thicks a man's blood with cold."

                                                 -Coleridge           

 

 In 1873, Gerhard Henrick Armauer Hansen, a Norwegian physician, found the bacterium of leprosy, a disease now often referred to as, perhaps euphemistically, Hansen's disease.  The discovery of Mycobacterium lepræ was monumental, proving that leprosy was caused by a germ, and thus not simply by heredity, nor from a curse, or sin.

 

Physicians of that era were unable to grow the microorganism of leprosy in culture, even Dr. Koch; it fulfilled only the first his four postulates. ^[2] Today the microorganism has yet to be grown in culture, but it is known to be genetically weak, deprived of the machinery necessary to live outside the human body.

 

Vaccines cannot be made from it, due to its inability to grow it in culture flasks.  In 1960 it was found to grow slowly in mouse footpads, and showed inhibition of its activity by sunlight.  Genetic and epidemiological studies solidify M. lepræ's role in the disease leprosy.  Armadillos are the only natural host besides H. sapiens sapiens, and they are unable to transmit it to man.

 

Staining the microorganism shows it to be acid-fast, i.e. dye applied to it on a microscopic slide does not wash off with an acid-rinse, and hence the microorganism is called "acid-fast."  Another agent of pestilence is acid-fast: Mycobacterium tuberculosis. 

 

Vast amounts of knowledge about Mycobacterium lepræ come chiefly from epidemiological studies, where the "culture medium" is humanity.   It is currently growing in 12 million people on several continents. (See Map 1 at: http://www.cvmbs.colostate.edu/mip/leprosy/largemap.html )

 

High leprosy rates are found in crowded countries near the equator, with high rates of poverty.  The World Health Organization (WHO) lists poverty as the most important factor in initiating and maintaining the disease. ^[3]

 

Over the last 150 years the prevalence of leprosy has dropped in all northern and temperate areas of Europe, Asia, and North America, indicating a "nurture" effect rather than "nature" in establishment and maintenance of the disease.

 

However, where the disease is extant, genetic factors are readily apparent, as seen in the clustering of cases in and around families, and phenotypes observed along the lines of heredity.  Yet leprosy is a contagion, spread by close personal contact with infected individuals, evident in families and prisons.

 

In 1921, the United States Public Health Service established the nation's first leprosarium, which became known as "Carville" after the town, in Louisiana.  It served as an institution for persons with leprosy, a hospital for scientific experimentation and treatments for leprosy, and a laboratory to study the microorganism.

 

In 1941, Promin was discovered at Carville, which cured leprosy.  Unfortunately, it required injections, which were painful.  Promin became known as the "miracle of Carville."  Dr. R.G. Cochrane pioneered the use of dapsone pills in the 1950s at Carville, which became the treatment of choice for leprosy-the pills were inexpensive, well tolerated and highly effective-one drawback (other than sulfa allergy) was the development of resistance to dapsone by M. lepræ. ^[4]

 

In the 1970s, research on the island of Malta created the first successful MDT (multi-drug therapy) for leprosy, and 1981, the WHO recommended MDT for leprosy, a combination of dapsone, rifampicin, and clofazimine.  Treatment required 6 to 12 months to cure the infection, depending on the clinical manifestations.

 

     In 1986 the Carville facility became known as Gillis W. Long Hansen's Disease Center, named after the distinguished United States Congressman, close friend and associate of people working and living with leprosy.  During its century of service, Carville was home to several hundreds of patients, who spent a majority of their lives on the picturesque campus, some married there. ^[4]      

 

Here is a brief review of different phenotypic expressions of leprosy:

 

Phenotype LL-Lepromatous Leprosy: see Image 1 at:

 

As can be clearly seen, the bacterium has invaded and grown to extremely high levels in facial skin, causing protuberances and prominent creases.  Invisible is the fact that many of the areas are anesthetic-numb, to the microorganism growing along nerve sheaths in its quest for Schwann cells (nerve cells).  Tissues involved in LL may have bacterial counts of 10⁴ to 10⁷ microorganisms-LL is also known as "multibacillary" leprosy for this reason.

 

In LL, florid growth of M. lepræ indicates a pattern of cellular immunity, specifically T-cells targeting plasmids (transferable fragments of genes) associated with the microorganism, failing to attack and kill the bug. 

 

M. lepræ heaps up in skin and nerves, enters lymph nodes, liver and spleen, and the nasal mucosa, causing congestion and crusting, with passing of the infectious nasal crusts, and discharges from cutaneous ulcers contributing to spread of the disease.  Blindness may occur. The process induces amyloid deposition, leading to renal failure, and death. ^[5]

 

Treatment with MDT is required for control and cure, often 12 months.

 

The other extreme of phenotypic immunological expression is TT-Tuberculoid Type leprosy.  The genetic pattern in this setting is characterized as hyper reactivity of T-cells.  A skin test, the Lepromin test, utilizing a solution of heat-killed M. lepræ injected superficially in the skin, causes people with TT to react, forming induration (hardness) at the injection site.  The lepromin test does not react in LL or noninfected individuals. This test is not useful for diagnosis of leprosy.  ELISA testing detects infection with M. lepræ. 

 

The microorganisms are sparse on microscopic examination of target tissues in TT leprosy, and so it is called paucibacillary .  Vigorous attacks on infected tissues kill the microorganism, but collateral damage results in depigmentation of the skin (vitiligo or white spots) and anesthesia of the face and extremities.  Numb digits are neglected and recurrently traumatized and slowly self absorb; ulcers form on the hands and feet, leading to osteomyelitis (bone infection).

 

TT leprosy rapidly responds to MDT, a course may require 6 months of oral therapy.

 

Much is known, but even more knowable, on the genetics of leprosy. ^[6]

 

Millions on our globe suffer, often shunning medical care and social help, stigmatized in their plight, fearing widespread prejudice, while billions-even a trillion surround them, not assisting, but eager to exile them.  The effort required to eliminate this scourge is many orders of magnitude greater than the campaign that eliminated in vivo smallpox.

 

WHO objectives for leprosy control:

 

(1) Interrupt transmission of the infection, thereby reducing the incidence of disease so that it no longer constitutes a public health problem.

 

(2) Treat patients in order to achieve their cure and where possible, complete rehabilitation.

 

(3) Prevent the development of associated deformities.

 

In recent years, leprosy control programs have faced the problem of emerging secondary and primary resistance of Mycobacterium lepræ to dapsone.  In 1981 the WHO Study Group on Chemotherapy of Leprosy for Control Programmes recommended multidrug regimens for both mulitbacillary (LL) and paucibacillary (TT) patients.  The Scientific Working Group on the Immunology of Leprosy (IMMLEP) has been making progress, but early detection and effective chemotherapy will remain in place for many years. ^[3]

 

 

 

 

Footnotes and references:

 

[1] Ben Hur: A Tale of the Christ Lew Wallace - 1922 - 522 pages        books.google.com

[2] Koch's postulates of disease causation are:

1) The microorganism must be found in abundance in all organisms suffering from the disease.

2) The microorganism must be isolated from a diseased organism and grown in pure culture.

3) The cultured microorganism should cause disease when introduced into a healthy organism.

   4) The microorganism must be reisolated from the inoculated, diseased       

            experimental host and identified as being identical to the original   

         causative agent.

[3] http://whqlibdoc.who.int/trs/WHO_TRS_716.pdf]   

[4] http://www3.niaid.nih.gov/topics/leprosy/Understanding/history.html

[5] References:  Cecil Textbook of Internal Medicine 1979 pp 501-505

[6] Susceptibility to leprosy in humans is related to the following genes, as published in Online Mendelian Inheritance of Man (OMIM):

 

OMIM# 609888, LPRSS1, at gene map locus 10p13, 10p13 is linked to paucibacillary disease in the South Asian Indian population.

 

OMIM# 607572, LPRS2, at gene map locus 6q25, Genes PARK2, PACRG are linked to leprosy susceptibility in the Vietnamese population.

 

OMIM# 246300, LPRS3, at gene map locus 4q32, 4p14, Gene TLR2 is inked to paucibacillary (TT) leprosy or to multibacillary LL (malignant) leprosy; the disease fails to manifest itself in most individuals exposed even to heavy exposures, except high rates seen in offspring of a consanguineous marriage.

 

OMIM# 610988, LPRS4, at gene map locus 6p21.3, Gene LTA is linked in Vietnamese familial samples, Indian case-control samples, and additional case-control samples from Brazil showing a significant increase in leprosy risk, with the effect much stronger in young individuals.

See also:

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609888

 

 

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Notes: [1] Ben Hur: A Tale of the Christ Lew Wallace - 1922 - 522 pages books.google.com [3] http://whqlibdoc.who.int/trs/WHO_TRS_716.pdf] [4] http://www3.niaid.nih.gov/topics/leprosy/Understanding/history.html [5] References: Cecil Textbook of Int

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