Millions Still Suffer From Leishmaniasis

April 22, 2009

by Beryl Lieff Benderly

 

(c) 2005 Shiraz J Khan, Syed Muneeb, Courtesy of Dermatology Online Journal http://dermatology.cdlib.org/111/reviews/leishmaniasis3/khan.htmlCountless times between dusk and dawn in countries around the world, a tiny insect bites a person’s skin. If that bite happens to a young woman in Afghanistan, it can destroy her chances for a desirable marriage. In Nepal, it can cause a family’s economic ruin. In the refugee camps of Sudan, it often means certain death. 

The insects, female sand flies of the Phlebotominae subfamily, are only a third the size of a mosquito, but they carry huge consequences for people because in nearly 90 countries they can also carry Leishmania protozoa. These one-celled parasites can highjack crucial cells in the immune systems of human beings and other mammals and then invade a range of organs. The diseases they cause, known as leishmaniasis, result in disfigurement, debility, disability, and death.  

Efforts to treat and control leishmania infections have long centered on pentavalent antimonials, an antiquated drug according to the Disease Control Priorities in Developing Countries, 2nd ed., one of three publications of the Disease Control Priorities Project. Pentavalent antimonials have lost much of its former curative power in some of the world’s hardest-hit regions.i Fortunately, newer approaches offer hope of more effective diagnosis and treatment. “The tools exist to achieve much better control of leishmania,” public health experts believe. ii

The infections from leishmania are little known outside the developing countries that account for the vast majority of sufferers. Designated a neglected tropical disease, leishmaniasis overwhelmingly afflicts deprived and isolated people lacking adequate health care (see Box 1). In 2005, three of the most heavily affected nations, Bangladesh, India, and Nepal, joined forces to eliminate the most lethal form from their territories by 2015—an ambitious goal that experts nonetheless believe is both “technically feasible and operationally achievable.”iii But, they also warn that controlling leishmaniasis will require serious and ongoing commitments from the governments of endemic countries and the world community.

Box 1: Neglected Tropical Diseases
Neglected tropical diseases bring suffering and death to many millions around the world, but receive very little attention in developed countries. Rather than threatening the prosperous and well-informed citizens of nations with good medical services, they attack some of world’s poorest people, who live in isolated rural villages, crowded refugee camps, and urban slums that lack health care, sanitation, and safe water. And not only do these diseases thrive among the poor, they actually promote poverty by weakening, maiming, stigmatizing, and isolating their victims and destroying their ability to work, learn, and contribute to their families and communities.

Even more shocking, however, some of these diseases have well-known, inexpensive, and effective treatments. Others still require better treatments but get much less attention from researchers and pharmaceutical companies because victims lack the resources to pay for new medications. In either case, the world’s neglect and inattention permit these diseases to exact their terrible toll. In addition to leishmaniasis, DCP2 is spotlighting two other neglected tropical diseases and the steps that can end the suffering they cause. Previous features stories have covered trachoma, the major infectious cause of blindness, and schistosomiasis, a widespread cause of debilitating disease and death.

Varieties of Suffering
Though often called by a single name, infections by leishmania parasites form a constellation of distinct diseases. More than 30 species of sandfly spread more than 20 species of infectious protozoa. Varying by region, different parasite species do different kinds of damage to the human body. The particular symptoms and disease burden of leishmaniasis in a given area and, to some extent, the specific risk factors that people face, depend on local conditions and on the particular species and ecological and social factors involved.    

Some parasite species infect only humans, while others also target mammals such as dogs or rodents, which serve as secondary reservoirs of infection and make eliminating the disease all the more difficult. In some areas, multiple species of flies carry disease, in others; only one species is to blame. Some medications work better in certain regions and against certain species of parasite.  

Credits: 1. Kenya 1991 Wendy Stone WHOTDRStone 2.Iran 1997 Andy Crump WHO/TDR/Crump 

The commonest form of leishmania infection is cutaneous leishmaniasis (CL), which causes painful, unsightly and long-lasting skin legions.iv They eventually heal on their own but leave permanent, disfiguring scars that often mar exposed places on the face or arms. Very rarely fatal, CL nonetheless can stigmatize its victims, especially women. In the Pakistani province of Balochistan, for example, a woman whose first sores appeared when she was 12 was excluded from school and now remains single at 28, although early, arranged marriage is the overwhelming norm.v In parts of South America, CL is considered justification for a man abandoning his wife. In parts of Africa, mothers with scars may be kept from nursing or even caring for their children.

Sometimes fatal disfigurement can occur months or years after the initial CL sores heal, in the relatively rare cases when leishmania infections attack the tissues of the nose, mouth, and throat. This form, mucosal leishmaniasis (ML), can mutilate or destroy the nasal septum, soft palate and linings of the mouth and throat and occasionally kill by damaging a person’s ability to breathe.

The second most common form of leishmania infection, and by far the most dangerous, is a severe systemic illness known as visceral leishmaniasis (VL) and in South Asia as kala azar, the “black disease.” It causes fever, weight loss, pallor, enlarged spleen and liver, immunosuppression, anemia, and, eventually, marked wasting. Untreated, it is nearly always fatal. Affected pregnant women can pass it to their fetuses. In a substantial percentage of cases—up to 60 percent in Sudan—patients cured of VL develop dermal leishmaniasis, a severe and chronic rash.vi Increasingly in developing countries, VL patients also have HIV—up to 30 percent in Ethiopia, for example, and a growing percentage in India.vii In immuno-suppressed individuals, leishmaniasis symptoms can be more severe and involve organs not usually affected, such as the gastrointestinal system.viii

Leishmaniasis 1.Iran 2002 Andy Crump WHO/TDR/Crump 2.(c) 2005 Shiraz J Khan, Syed Muneeb, Courtesy of Dermatology Online Journal 3.Ethiopia 2003 Andy Crump WHO/TDR/Crump

Burden of Disease
Though the types of suffering caused by leishmania infections are well known, the worldwide toll is far less clear. The World Health Organization (WHO) estimates that 12 million people are currently infected; of these, 1.5 million to 2 million have the active disease, and 51,000 will die each year.ix But, notes R.K. Singh and co-authors, “gross underreporting of cases” prevent an accurate picture of the disease’s true scope. Leishmaniasis is known to be endemic in 88 countries and VL in 62, but only 33 endemic nations report case numbers, according to Disease Control Priorities in Developing Countries.xi

Bangladesh, Brazil, India, Nepal, and Sudan account for 90 percent of VL cases; Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria for 90 percent of CL cases; and Bolivia, Brazil and Peru for 90 percent of ML cases, according to WHO.xii But because the leishmaniases generally strike the poor and uneducated in isolated or severely underserved areas, reported cases are “likely to be at least a five-fold underestimate,” writes Caryn Bern and Rajib Chouwdhury.xiii

Judged in terms of disability-adjusted life years (DALYs), a measure of the loss of well-being that a disorder causes, the leishmaniases together rank as the world’s “third most important vector-borne disease” and annually account for 2.4 million DALYs, according to Richard Reithinger(see Box 2). Recent trends--migration due to war and famine, huge camps of destitute refugees, deforestation, and the growth of squatter slums around large cities--fuel spread into new territories.

Pre-Incan Bolivian pottery showing faces disfigured in ways typical of ML and local nicknames like “Aleppo boil,” for the CL found in Aleppo, Syria, indicate the infection’s long history in certain countries. But its history of invading new lands and populations goes back centuries. The rail and shipping routes that the British established during their 19th century rule of India, for example, also brought the parasite, which was severe enough to wipe out the population of at least one town. Noting the contagion’s ties to the activities of their colonial rulers, residents of India’s Garo Hills region called VL the “British government disease.”xiv

Box 2: Calculating DALYs
A year lived in complete health counts as 1.0 DALY. A year following death, on the other hand, is worth 0.0 DALYs. A year spent in less than total health counts as some portion of a DALY, the exact amount determined by the severity of the incapacity or disability that affected individuals typically suffer, a judgment based on expert estimate. The total DALY loss from an episode of disease or injury depends on the length of time the condition generally lasts, ranging from a stretch of acute illness lasting only days or weeks to a lifetime of disability. The value of a year of life does not depend on a person’s age when death or disability occurs; but, because the future is generally considered to be worth less than the present, and given the unreliability of predicting people’s future survival, years of life remaining from the time of occurrence are discounted at a rate of 3 percent per year. The DALY values of various disease and conditions used in the DCPP come from calculations based on worldwide research results.

Making the Attack
Phlebotomus-papatasi-sandfly_CDC_FrankCollins_2006_James_GathanyThis alarming spread through the British Raj in India, and especially to members of the British military, fostered research into the disease’s origins. In 1903, William Leishman, an army doctor in London, and Charles Donovan, a colonial medical service doctor in Madras, independently isolated the protozoa from patients’ spleens. That species, the first of many subsequently identified and associated with forms of the disease, was named Leishmania donovani in their honor.

Regardless of their species, all leishmania protozoans invade humans or animals when the sandfly feeds on a victim’s blood; some 2 million people become infected each year.xv Once in the victim’s bloodstream, the parasite almost immediately encounters cells from the victim’s immune system that arrive at the wound site. The parasite, as a recently published study shows, deploys a highly evolved ability “to both evade and exploit the [immune] response in order to establish and promote disease.”xvi The parasite’s success at this stage appears to vary among individuals and may depend in part on the individual’s genetics and general state of health and nutrition. If successful, however, parasites invade large immune cells known as macrophages.

Once inside the macrophage, the parasite multiplies and moves on to infect other tissues. Whenever a female sandfly bites the infected individual, she will ingest some of the parasites. These parasites soon become promastigotes that move to the biting apparatus in her nose, ready to continue the cycle by being deposited into a new victim the next time the fly feeds.

Victims of leishmaniasis are generally “the poorest of the poor,” write Jan Kolaczinski and co-authors, whose research among the Pokot people of Kenya and Uganda identified low socioeconomic status as a major risk factor for VL.xvii A similar conclusion emerged from research in Bangladesh, India, and Nepal.xviii Leishmaniasis, however, “is not only the disease of the poor but a source of poverty itself”.xix It not only prevents the sufferer from working or studying, but VL also requires lengthy treatment far beyond poor families’ means.

Fighting Back
That potentially crippling cost encourages many people in the developing world to seek care first from traditional healers rather than modern health practitioners—a decision than often delays the start of effective therapy, if the patient gets any at all, by weeks or months while symptoms worsen. Correct diagnosis is especially crucial for proper treatment of leishmaniasis because the symptoms can be confused with other diseases endemic in poor countries: CL with leprosy, tuberculosis, and skin cancer; and VL with malaria. For many years, the “gold standard” of diagnosis was microscopic identification of the parasite from tissue smears of the patient’s spleen in the case of VL, and in the case of CL from the lesion itself. This process, however, is expensive, may be hazardous, and is rarely feasible in endemic regions lacking adequate medical care, laboratory facilities and trained personnel. Serological tests are therefore used in some countries, although they are less exact and also costly. Recently, a rapid strip test for antibodies has provided a cheaper alternative, despite the risk of inaccurate test results from individuals with weak immune systems and from healthy persons with antibodies to the parasite.xx

Since at least the 1940s, the “therapeutic cornerstone” of leishmaniasis treatment has been months of injections with toxic antimony-based drugs.xxi VL always requires treatment to save the patient’s life, while treating CL hastens healing and reduces disfigurement. Antimony-based medication generally requires hospitalization to deal with cardiac emergencies and other serious side effects, but for decades it provided reliable cures. In the highly endemic Bihar province of India, however, resistant protozoan strains have now destroyed its usefulness. In its place, the antibiotics amphotericin B and paromomycin have proven curative; in 2002, miltefosine, originally an anticancer drug, was licensed as the first oral treatment effective against VL. The newer drugs are themselves costly, however, and each also has its own set of side effects, so other pharmaceutical approaches are under study. Because at present “the primary control strategy…is based on case finding and treatment,” says Disease Control Priorities, “the priority for control is developing and implementing improved diagnostic methods and better treatments that are more amenable to field use.”xxii

But in India during the 1950s and 1960s, extensive insecticide spraying against malaria also wiped out the sandfly, and with it, leishmaniasis. When those efforts ended, however, malaria and leishmaniasis resurged.

An Eradication Campaign
The sandfly generally bites at night and indoors, spreading disease within households or among nearby houses, leading many to the erroneous belief that leishmaniasis is contagious through interpersonal contact—a misapprehension that worsens the stigma and isolation of countless sick people. But infected persons and domestic animals, even those showing no symptoms; passively help spread the disease by forming reservoirs of infection.

Studies in several countries clearly show that interrupting the sandfly’s flight among people and animals can sharply cut infection rates. Interior spraying of homes, regular use of treated bednets, and insecticide-treated collars for dogs are effective. A vaccine would also drastically slow leishmaniasis’s spread, but none exists at present although research is underway.

Despite the potential offered by new techniques, “current leishmaniasis programmes have largely failed, primarily because of inadequate regional health delivery systems and resources,” observe Henry Murray and co-authors.xxiii Because of the disease’s complexity, any successful elimination campaign must overcome many barriers, and will require “a massive effort in terms of up-scaling human resources, supplies, logistics and monitoring activities” writes Dinesh Mondal and co-authors.xxiv

Beryl Lieff Benderly is a prize-winning Washington journalist and author specializing in health, behavior, and science policy. Her articles appear in major magazines and on the Internet, and she is a regular contributor to the Science magazine website. Her eight books include In Her Own Right: The IOM Guide to Women’s Health Issues.
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i Cattand, P., P. Desjeux, M. G. Guzman, J. Jannin, A. Kroeger, A. Medici, and others. 2006. In Disease Control Priorities in Developing Countries, 2nd ed., ed. D.T. Jamison, J.G. Breman, A.R. Measham, G. Alleyne, M. Claeson, D.B. Evans, P. Jha, A. Mills, and P. Musgrove, 451. New York: Oxford University Press. 

ii Bern , C., J. H. Maguire, and J. Alvar. 2008. “Complexites of Assessing the Disease Burden Attributable to Leishmaniasis.”  PLoS Neglected Diseases

iii Bhattacharya, S. K., Dipika Sur, P.K. Sinha, and Juntra Karbwang. 2006. “Elimination of Leishmaniasis (kala-azar) from the Indian Subcontinent is Technically Feasible & Operationally Achievable.”  Indian Journal of Medical Research 123.

iv Kassi, M., M. Kassi, A. K. Afghan, R. Rehman, and P.M. Kasi. 2008. “Marring Leishmaniasis: The Stigmatization and the Impact of Cutaneous Leishmaniasis in and .” PLoS Neglected Tropical Diseases 2(10). 

v Kassi, M., and others. 2008. 

vi Bern , C., and others. 2008. 

vii Alvar, J., P. Aparicio, A. Aseffa, M. Den Boer, C. Canavante, J-P. Dedet, and others. 2008. “The Relationship between Leishmaniasis and AIDS: The Second 10 Years.”  Clinical Microbiology Reviews. 

viii Bern , C., and others. 2008. 

ix (a) World Health Organization (WHO). 2009. “Leishmaniasis: The Global Trend.” http://www.who.int/neglected_diseases/integrated_media_leishmaniasis/en/index.html

(b) Reithinger, R. 2008. “Leishmaniases’ Burden of Disease: Ways Forward for Getting from Speculation to Reality.”  PloS Neglected Tropical Diseases 2(10): e285. 

x Singh, RK; H.P. Pandey, and S. Sundar. 2006. “Visceral Leishmaniasis (Kala-azar): Challenges Ahead.”  Indian Journal of Medical Research. 

xi Cattand, P., P. Desjeux, M. G. Guzman, J. Jannin, A. Kroeger, A. Medici, and others. 2006. In Disease Control Priorities in Developing Countries, 2nd ed., ed. D.T. Jamison, J.G. Breman, A.R. Measham, G. Alleyne, M. Claeson, D.B. Evans, P. Jha, A. Mills, and P. Musgrove, 452. New York: Oxford University Press. 

xii Leishmaniasis: Burden of Disease. 2009. http://www.who.int/leishmaniasis/burden/en/

xiii Bern , C., and R. Chowdhury. 2006. “The Epidemiology of Visceral Leishmaniasis in : Prospects for Improved Control.” Indian Journal of Medical Research

xiv Sen Gupta, P.C. 1947. “History of Kala Azar in .”  The Indian Medical Gazette

xv World Health Organization (WHO). 2009. 

xvi Peters, N., J. Egen, N. Secundino, A. Debrabant, N. Kimblin, S. Kamhawi,  and others. 2008. “In Vivo Imaging Reveals an Essential Role for Neutrophils in Leishmaniasis Transmitted by Sand Flies.” Science 321: 589115. 

xvii Kolaczinski, J.; R. Reithinger, D. Worku, A. Ocheng, J. Kasimiro, N. Kabatereine, and others. 2009. “Risk Factors of Visceral Leishmaniasis in East Africa: A Case-Control Study in Pokot Territory of and .” International Journal of Epidemiology. 

xviii Mondal, D., S.P. Singh, N. Kumar, A. Joshi, S. Sundar, P. Das, and others. 2009. “Visceral Leishmaniasis Elimination Programme in , , and : Reshaping the Case Finding/Case Management Strategy.” PLoS Neglected Tropical Diseases  3(1). 

xix Adhikari, S., N. Maskay, and B. Sharma. 2009 "Paying for Hospital-Based Care of Kala-Azar in : Assessing Catastrophic Impoverishness and Economic Consequences."  Health Policy and Planning 24(2). 

xx Davis, C., P. Kaye, S. Croft, and S. Sundar. 2003. “Leishmaniasis: New Approaches to Disease Control.” British Medical Journal 326. 

xxi Murray, H., J. Berman, C. Davies, and N. Saravia.  2005. “Advances in Leishmaniasis.”  Lancet 366. 

xxii Cattand, P., P. Desjeux, M. G. Guzman, J. Jannin, A. Kroeger, A. Medici, and others. 2006. In Disease Control Priorities in Developing Countries, 2nd ed., ed. D.T. Jamison, J.G. Breman, A.R. Measham, G. Alleyne, M. Claeson, D.B. Evans, P. Jha, A. Mills, and P. Musgrove, 461. New York: Oxford University Press. 

xxiii Murray, H., J. Berman, C. Davies, and N. Saravia.  2005. 

xxiv Mondal, D., S.P. Singh, N. Kumar, A. Joshi, S. Sundar, P. Das, and others. 2009.

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