Leprosy (Hansen's Disease)
Leprosy (Hansen's Disease)
Disease History, Characteristics, and Transmission
Introduction
Leprosy, also known as Hansen's disease, is a chronic (long-term) disease caused by infection with the bacillus Mycobacterium leprae (M. leprae). The disease was greatly feared for many centuries because of the extreme disfigurement it can cause; it is widely known today from references to Tzaraath in the Hebrew Bible, translated as “leprosy,” although the translation probably included a wide range of skin diseases. Leprosy is treatable by combination drug therapy, and eradication campaigns are under way in Africa, India, Brazil, and other places where the disease remains common.
Leprosy does not, as commonly assumed, cause fingers, toes, and noses to drop off: this is a side effect of the disease's attack on the peripheral nerves. Loss of sensation makes patients unable to respond to minor injuries and infections in their fingers, toes, and elsewhere, and it is these secondary causes that lead to the characteristic loss of body parts. However, leprosy can also cause puffy, deforming lesions on the face and elsewhere, as well as a number of other symptoms.
Disease History, Characteristics, and Transmission
History
Leprosy has been recognized for thousands of years in Asia, Egypt, and India. According to genetic data collected in recent years, M. leprae first probably infected human populations in East Africa over 100,000 years ago. From there, the disease spread to other parts of the world by hitchhiking on repeated waves of human migration. Leprosy is thought to have been brought to Europe by Greek soldiers returning from the conquest of India by Alexander the Great (356–323 BC); it is first mentioned explicitly in Roman records dating to 62 BC, coinciding with the return of troops from western Asia.
Particularly in the Middle Ages, when Arab invasions and the Crusades brought renewed rates of leprosy to Europe from Africa and the Middle East, the disease was intensely feared throughout Europe. People afflicted by leprosy were termed “lepers,” a term now disfavored as it implies social stigma. By the 1100s approximately 19,000 asylums or leper-houses had been established by monks and nuns to isolate and care for the victims of the disease. Persons with leprosy not confined to the leperhouses were required to give warning of their approach by sounding a wooden clapper, and were forbidden to enter churches, inns, mills, or bakeries, to touch or dine with persons without leprosy, or to walk on narrow pathways (where people coming the other way might have to touch them). Thanks to these stringent isolation measures—or possibly because of reduced frequency of the genes causing vulnerability to leprosy, leprosy slowly decreased in Europe and had become rare there by the 1600s.
Leprosy was probably spread to West Africa by European traders or colonialists, since the variety found there closely resembles that found in Europe. From West Africa it was brought to Caribbean and South America by the slave trade in the eighteenth century. The European variety is that found in North America and was introduced by colonialism and emigration. In the 1700s and 1800s, for example, immigrants from Scandinavia, where a leprosy epidemic was occurring at the time, brought the disease with them to the Midwestern United States.
In 1873, Norwegian physician The Gerhard Henrik Armauer Hansen (1841–1912) showed that leprosy is caused by a bacillus, later named M. leprae. Hansen did not actually identify the objects he saw in his microscope as bacteria, but noted that he found them in the tissues of all persons suffering from the disease. Initially, his discovery was given little attention. In 1879, he shared tissue samples with German physician Albert Neisser (1855–1916), who identified the bacteria and attempted to claim credit for their discovery.
Despite the identification of M. leprae as the cause of leprosy, progress on creating a treatment for the disease was slow. Until about 1940, treatment was by injection of oil derived from the chaulmoogra nut, a traditional remedy. Numerous injections forced the oil under the skin, a painful procedure, and today physicians do not assume that this treatment resulted in significant permanent benefit. In 1921, the U.S. Public Health Service built a research and live-in treatment center for leprosy in Carville, Louisiana. Carville researchers announced the discovery of an effective anti-leprosy drug, Promin, in 1941. Promin—a sulfone drug—still required numerous painful injections.
In the 1950s, another drug, dapsone, became available in pill form. Dapsone was highly effective but M. leprae began to evolve resistance to the drug over the next decade. Given alone, it would not have remained effective for more than a few decades. In the 1970s, the first multi-drug therapy (MDT) for leprosy was developed, blending dapsone with other drugs to prevent the development of resistance. In 1981, the World Health Organization (WHO) endorsed an MDT regimen consisting of dapsone, rifampin, and clofazimine. This mixture continues to be used today. Like the drug cocktails used to fight human immunodeficiency virus, MDT for leprosy exploits the fact that it is more difficult for a microorganism to evolve resistance to a several agents at once than to evolve resistance to each agent separately or in series.
For years, an obstacle to a fuller scientific understanding of M. leprae was the fact that it apparently impossible to grow the bacillus in pure culture (growing cells in a prepared medium) in the laboratory. Also, its population doubling time in tissue is the longest of any known bacterium, from 13 to 20 days (compared to about 20 minutes for Escherichia coli, the dominant bacterium in the human digestive tract). Until the early 1970s, M. leprae was not known to thrive in any laboratory animal; it grew only in humans and, in relatively small numbers, in the footpads of mice. In 1971, however, researchers discovered that the nine-banded armadillo (a mammal native to South America and now also found across the southern United States) can be infected with M. leprae. Having acquired the disease from human sources, many armadillos in the wild now have leprosy. About five percent of armadillos in Louisiana show symptoms of the disease and about 20% probably are infected with M. leprae.
WORDS TO KNOW
ALLELE: Any of two or more alternative forms of a gene that occupy the same location on a chromosome.
CULTURE: A culture is a single species of microorganism that is isolated and grown under controlled conditions. The German bacteriologist Robert Koch first developed culturing techniques in the late 1870s. Following Koch's initial discovery, medical scientists quickly sought to identify other pathogens. Today bacteria cultures are used as basic tools in microbiology and medicine.
DROPLET TRANSMISSION: Droplet transmission is the spread of microorganisms from one space to another (including from person to person) via droplets that are larger than 5 microns in diameter. Droplets are typically expelled into the air by coughing and sneezing.
ENDEMIC: Present in a particular area or among a particular group of people.
ERADICATION: The process of destroying or eliminating a microorganism or disease.
LATENT: A condition that is potential or dormant, not yet manifest or active, is latent.
MULTI-DRUG THERAPY: Multi-drug therapy is the use of a combination of drugs against infection, each of which attacks the infective agent in a different way. This strategy can help overcome resistance to anti-infective drugs.
RESISTANCE: Immunity developed within a species (especially bacteria) via evolution to an antibiotic or other drug. For example, in bacteria, the acquisition of genetic mutations that render the bacteria invulnerable to the action of antibiotics.
Characteristics
Mycobacterium leprae is a rod-shaped bacterium about 1—8 μm long and .2–.5 μm wide. Bacteria of the genus Mycobacterium are characterized by an unusually thick, multi-layered cell wall, which helps make them resistant to antibiotics (drugs that kill bacteria). Both the bacterium that causes tuberculosis (Mycobacterium tuberculosis) and Mycobacterium leprae are in this genus.
M. leprae infects the mucus membranes, nerves, and skin. It tends not to invade deeper tissues because it thrives at temperatures slightly lower than that of the body core; the armadillo's low body temperature is thought to be one reason M. leprae can infect that species as well as humans. M. leprae has a particular affinity for nerve cells, which is why loss of feeling can be a symptom of leprosy.
Leprosy causes a spectrum of disease, from mild to severe. Progression of the disease is slow, with incubation times of a few years to 30 years. About 90% of persons with leprosy experience loss of temperature sensation of some part of the body (e.g., fingers) as their first symptom: that is, the patient cannot sense hot and cold with parts of their body. This often happens before any lesions or spots appear. Ability to sense pain is lost next, and then the ability to sense deep pressure. The inability to sense pain allows otherwise trivial injuries or irritations to go unchecked, often leading to infections, injuries, and loss of tissue. The progress of leprosy is divided into four stages:
- Intermediate leprosy. In this early, mildest form, some spots (lesions) may appear on the skin. Patients with low susceptibility may defeat the infection without assistance at this stage.
- Tuberculoid leprosy. Large pale spots called macules may appear on the skin. These lesions lack sensation. Nerves are infected, and may thicken and cease to function.
- Borderline leprosy. In this stage, skin lesions are present and numerous. They may now take the form protruding nodules or sunken lesions that are sometimes described as appearing punched-out.
- Lepromatous leprosy. This is the most developed and severe form of the disease. Lesions are numerous and more severe (that is, more protruding or deeper-set) than in the earlier stages. The eyes may become involved, leading to pain, light-sensitivity, glaucoma, and blindness. The testicles may atrophy. Deepening nerve damage may lead to partial paralysis. Any of the three earlier stages of leprosy may regress to less severe stages, but not this stage.
For purposes of treatment, leprosy is separated into two types, paucibacillary and multibacillary. In paucibacillary leprosy, there are no more than five skin lesions on the patient and the number of M. leprae bacteria in the body is small, approximately less than a million. A skin smear shows no M. leprae. (A skin smear is a obtained by making a small cut in the most prominent lesion and scraping tissue from it. The sample is then placed on a microscope slide, stained with a substance that highlights the presence of M. leprae, and examined to see if any of the bacteria are present.) Most leprosy infections are of this type. In multibacillary leprosy, a skin smear is positive and there are more than five lesions. All more severe and advanced cases of leprosy are in the multibacillary category.
IN CONTEXT: TRENDS AND STATISTICS
As of early 2006, the World Health Organization stated that there were approximately 220,000 active cases of leprosy worldwide, with 296,500 new cases detected in 2005—a 27% decrease from the number of new cases detected in 2004. There can be more new cases than active cases because MDT treatment is widely available for new cases but is not able to prevent the emergence of new ones. In the early 2000s, however, the new-case rate was declining rapidly; 775,000 new cases ere counted in 2001, 296,500 in 2005.
Transmission
The mode of transmission of leprosy remains uncertain. Most experts state that the disease is probably transmitted by mucus and saliva droplets produced by sneezing and coughing. People who have close contact with people with active, untreated infection are at risk for contracting the disease and so, more generally, is anyone living in a country where the disease is endemic. Experts speculate that insect bites, some animals, and bacilli in soil may also spread the disease, but none of these routes has been proved.
Only about 10% of the human population is vulnerable to infection by M. leprae; and of those persons, only about half will develop detectable disease. Susceptibility to infection by M. leprae has been shown to be associated with a person's genetic makeup, namely the possession of certain alleles (alternative forms of a gene) for a specific area of human DNA also shared by the Parkinson's disease gene PARK2 and its co-regulated gene PACRG. The mechanism by which these alleles make persons more susceptible to leprosy is not yet known.
Scope and Distribution
Between one and two million people worldwide have been disabled by leprosy. In many countries, leprosy has been virtually eliminated. It still exists in over 100 countries, however, combining the cases in Angola, Brazil, India, Madagascar, Mozambique, Nepal, and Tanzania together account for over 95% of all cases. India accounts for 70% of cases and Brazil has the world's highest per-capita leprosy rate. In the United States, only a few dozen cases occur each year.
Treatment and Prevention
Prevention of leprosy was traditionally through isolation of victims from the uninfected. Conventional antibiotics such as penicillin have never been effective against M. leprae. However, the MDT combination of dapsone, rifampin, and clofazimine first developed in the late 1970s has proved highly effective. The primary drug in this combination is dapsone, which inhibits bacterial growth by preventing the formation of folic acid. Rifampin acts by inhibiting the bacterial enzyme RNA polymerase, which is needed for cell functioning. It is always used in combination with another drug. The third drug, clofazimine, inhibits bacterial growth by binding to DNA and so interfering with transcription and replication.
For paucibacillary leprosy, a two-drug MDT consisting of dapsone and rifampin is given for six months; for multibacillary leprosy, the full three-drug MDT is given for two years. MDT is given out in calendar marked blister packs to patients, who must take the pills at home on a regular schedule.
IN CONTEXT: SCIENTIFIC, POLITICAL, AND ETHICAL ISSUES
The stubbornness of the leprosy stigma was underlined in Japan in 2001, when a court ruled that the Japanese government owed millions of dollars in compensation to leprosy patients who had been confined and abused in leper colonies since the 1950s. The colonies or centers were established under the 1953 Leprosy Prevention law (repealed in 1996) that forced all persons with leprosy, including children, to move to those locations. According to a Japanese government commission that studied the leper colonies, patients were sterilized—surgically rendered unable to have children—forced to have abortions, and treated as research subjects. Infanticide was also practiced. All this continued for decades after outpatient treatment with anti-leprosy drugs became available in 1960. “For 60 years, I was not treated as a human,” one former patient, Mamoru Kunimoto, said. The fact that the government apologized rather than disputing the court's ruling, he said, “has given me back my humanity.”
Impacts and Issues
International efforts to eliminate leprosy have been under way since 1991, when the 49th World Health Assembly (the body which governs the World Health Organization) resolved to eliminate leprosy as a public health problem by 2000, defined as reducing the worldwide prevalence rate to less than 1 in 10,000 persons. In 1999, WHO formed the Global Alliance for the Elimination of Leprosy, based in India, with a strategy of early detection, MDT treatment, and eliminating the stigma historically attached to persons with leprosy. The global elimination goal was met, but rates remain significantly higher in the countries listed above. At an annual new-case rate of less than 1 per 10,000, India alone could register as many as 100,000 new cases a year. The U.S.-based company that makes the three anti-leprosy drugs, Novartis, is in partnership with the Global Alliance for the Elimination of Leprosy and supplies them at no cost.
The genome of M. leprae was sequenced in 2000, aiding researchers who are attempting to develop new anti-leprosy drugs and vaccines.
The impact of leprosy on the infected symptomatic individual has historically been severe. Furthermore, isolation and shunning of persons with Hansen's disease (use of the alternate name Hansen's disease today is intended to reduce social stigma associated with the term leprosy, although both terms are correct) did not end with the Middle Ages. Loss of one's job, social standing, family position, and the like continue to be common consequences in many societies for persons with leprosy.
In 2006, a worrisome problem was discovered; the drugs being given for the AIDS virus, which already infects about 38 million people in the undeveloped world, can make silent or asymptomatic leprosy become symptomatic. Patients on AIDS drugs are reporting ulcers or are losing sensation in toes and fingers as their latent (dormant) leprosy becomes active. This is something of a medical paradox; AIDS itself, which weakens the immune system, has not caused latent leprosy to become active, but the treatment for AIDS has.
Finally, as with all drug treatments for infectious disease, the evolution of drug resistance by M. leprae is a concern. Resistance to all major anti-leprosy drugs has been reported worldwide, particularly for dapsone. However, reports of relapse after MDT have been rare, and resistance to leprosy drugs is not yet considered a major problem.
Primary Source Connection
In January 2006 in New Delhi, India, Yohei Sasakawa, chairman of The Nippon Foundation, published a Global Appeal to End Stigma and Discrimination against People Affected by Leprosy. The text of that appeal was issued in the names of 12 world leaders and Nobel Peace Prize laureates.
The Nippon Foundation, a non-governmental organization, founded in 1962, supports research and programs for the betterment of people's lives around the world. With a special focus on developing countries, the foundation is active in issues dealing with human resources development, hunger alleviation, public health, and help for the disabled.
BIBLIOGRAPHY
Books
Demaitre, Luke. Leprosy in Premodern Medicine: A Malady of the Whole Body. Baltimore, MD: Johns Hopkins University Press, 2007.
Gould, Tony. A Disease Apart: Leprosy in the Modern World. New York: St. Martin's Press, 2005.
Periodicals
McNeil Jr., Donald G. “Worrisome New Link: AIDS Drugs and Leprosy.” New York Times. October 24, 2006.
Mira, Marcelo, et al. “Susceptibility to Leprosy is Associated with PARK2 and PACRG.” Nature. 427(2004):636-40.
Monot, Marc, et al. “On the Origin of Leprosy.” Science. 308(2005):1040–1042.
Web Sites
British Broadcasting Corporation. “Koizumi Apologises for Leper Colonies.” May 25, 2001 <http://news.bbc.co.uk/2/hi/asia-pacific/1350630.stm> (accessed February 6, 2007).
Centers for Disease Control and Prevention. “Hansen's Disease (Leprosy).” October 12, 2005 <http://www.cdc.gov/ncidod/dbmd/diseaseinfo/hansens_t.htm> (accessed February 6, 2007).
International Leprosy Association. “Global Project on the History of Leprosy.” October 10, 2003 <http://www.leprosyhistory.org/english/englishhome.htm> (accessed February 6, 2007).
World Health Organization, United Nations. “Leprosy.” 2007 <http://www.who.int/topics/leprosy/en/> (accessed February 6, 2007).