A DEVASTATING DISEASE; A DEVASTATING COST

If you’re sitting in a first-world country reading this, you probably don’t need to worry about getting leishmaniasis. Chances are good, in fact, that you haven’t even heard of it.

Leishmaniasis, or kala-azar, is classified as a neglected tropical disease (NTD), putting it in the company of guinea worm, African sleeping sickness, dengue fever, and trachoma. These are diseases you’re unlikely to find in most developed countries, but they persist in the poorest regions of the planet. According to the CDC, one billion people have at least one neglected tropical disease, and NTDs are estimated to cause well over 500,000 deaths each year. In addition to the associated social stigma, NTDs are responsible for significant and devastating loss of productivity, compounding the already high costs of treatment [1]. As there is no profit in developing affordable treatments for these diseases, they’re largely overlooked in favor of more profitable pursuits [2].

Leishmania and the phlebotomine

sandfly: a match made in hell [12, 7].

Leishmaniasis is an infection caused by the obligate intracellular protozoan Leishmania and is transmitted by the bite of the female phlebotomine sandfly. Leishmania causes four diseases: cutaneous, muco-cutaneous, visceral (VL), and post-kala-azar dermal leishmaniasis (PKDL). Though cutaneous and muco-cutaneous leishmaniasis boast the most striking presentations – skin lesions and bleeding ulcers that never resolve on their own – I’ll be focusing on visceral leishmaniasis, the deadliest, and PKDL [3].

Visceral leishmaniasis causes an estimated 50,000 deaths per year, placing it second only to malaria among deadly parasitic diseases. It’s a systemic infection caused by two species of Leishmania, L. infantum and L. donovani. The parasite invades macrophages, damaging the victim’s immune system and providing a playground for opportunistic infections like tuberculosis and pneumonia. Symptoms include enlarged organs, high fevers, fatigue, weakness, and loss of appetite and weight. Left untreated, VL is invariably fatal, and the victim dies of massive bleeding, anemia, or a bacterial co-infection. Those that survive are later at risk for PKDL, which presents as a nodular rash filled with Leishmania parasites, making it infectious to sandflies and capable of sparking an epidemic of VL [3].

Regions where visceral leishmaniasis is endemic [3]

Over 90 percent of visceral leishmaniasis cases occur in India, Bangladesh, Sudan, Brazil, Ethiopia, and Nepal. Because it predominantly affects the very poor, VL doesn’t have the benefit of national and international recognition. As a result, the health systems of affected countries lack sufficient resources to control VL and the people affected by the disease don’t have the political clout to make any difference [4]. The Carter Center, which works to eradicate neglected diseases, classifies VL as “not eradicable now,” citing, among other factors, insufficient surveillance and health care systems [5].

In Bihar, India, a region particularly hard hit by leishmaniasis, however, efforts at alleviating the problem have been promising. This area accounts for about 90 percent of the visceral leishmaniasis cases in India, due in part to the lifestyle its citizens have no choice but to maintain. They’re extremely poor and rely on cows not only for milk but also for dung, which they use to plaster their walls and roofs. Living in the dung, though, are millions of tiny sandflies, which come out at night and bite the inhabitants of the house, spreading the parasite into human hosts. Of the estimated 250,000 cases of VL in the region, most go unreported and untreated. Treatment is often prohibitively expensive, especially when multiple members of a family contract the disease [2].

Even so, Bihar is lucky in that it’s a good candidate region for the elimination of leishmaniasis. In some regions, both dogs and people are reservoirs for Leishmania, but here people are the only reservoir, and the population is highly concentrated and not widely distributed. Additionally, only one species of sandfly transmits L. donovani (the only Leishmania species responsible for VL in India), and these flies are sensitive to insecticides [6]. Simple lifestyle changes – using bed nets and keeping cattle and dung away from homes – in combination with an affordable treatment and spraying insecticides could significantly reduce the number of cases in the area [2].

Of course, none of these are simple solutions, least of all the elusive affordable treatment. Currently, amphotericin B is the standard treatment, and although effective, it’s nephrotoxic and can only be administered in a hospital. Liposomal amphotericin B is safer and can be given in a single dose, but it’s much more expensive. Miltefosine is administered orally, but presents a host of problems, including high costs, risks of birth defects, and the potential for developing resistance if the treatment course isn’t completed [7]. One drug that shows some promise, though, is paromomycin, developed by the nonprofit organization OneWorld Health. It’s administered through intramuscular injections, and like amphotericin B and miltefosine, it requires approximately 3 weeks of treatment, decreasing the likelihood that people will complete the full treatment. It is, however, as effective as amphotericin B, and is significantly more affordable [2, 7].

Clinical trials comparing two combination paromomycin treatments, one with miltefosine and one with liposomal amphotericin B, to amphotericin B and combination miltefosine and liposomal amphotericin B found that the combination treatments were effective and less toxic than amphotericin B alone, and required a shorter duration of treatment. This increases the likelihood that patients will complete the treatment, reducing the risk of the Leishmania parasites developing drug resistance [8]. Another study showed that a 21-day regimen of paromomycin resulted in a definitive cure at six months post-treatment in 92% of patients and that side effects were mild [9]. Because of its low cost and high efficacy and safety, paromomycin has the potential to make leishmaniasis treatment in Bihar much more accessible, helping to reduce the burden of the disease on the population [2].

Once a patient has had visceral leishmaniasis, though, they’re at risk for post-kala-azar dermal leishmaniasis (PKDL). PKDL cases can act as reservoirs for Leishmania, making it critical that these patients also seek treatment to prevent potential outbreaks of VL. The impact of the disease is, unfortunately, intensified by the lack of reliable health systems and the cost of treating it. In a rural region of Bangladesh, a study found that people with PKDL often didn’t pursue treatment at all, a potentially dangerous route, as PKDL can provide a means for Leishmania to reenter sandflies. Those that did faced the cost of the drug, the bureaucracy of the health system, and, crucially, the immense loss of productivity as a result of the lengthy treatment regimen – patients lost a median of 123 days of work.  Even worse, because PKDL generally occurs in patients who have already been treated for VL, this is often their second round of costs. It was estimated that the direct costs associated with PKDL treatment – about $367 USD – were over twice the per capita annual income of the population in that area [10].

Leishmaniasis is a devastating disease both physically and economically. Despite being the second deadliest parasitic disease, it suffers from minimal national and international recognition. Strategies to eliminate it in India have been developed, however, and it’s possible that if they’re successful, they could be used as a model for other regions. Improved surveillance – making sure that cases are reported and treated thoroughly – research, control of sandflies, and promoting social mobility to raise more people out of poverty could in combination address the debilitating physical and social aspects of leishmaniasis [11].

Submitted by Amelia Haj

[1]        "Neglected Tropical Diseases." Centers for Disease Control and Prevention, 2011. 

[2]        Kill or Cure? Visceral Leishmaniasis. BBC World News, 2007. 

[3]        Chappuis, François et al. “Visceral Leishmaniasis: What Are the Needs for Diagnosis, Treatment and Control?” Nature Reviews. Microbiology 5.11 (2007) : 873-82. 23 Jul.          2011.

[4]        Boelaert, M et al. “Socio-economic Aspects of Neglected Diseases: Sleeping Sickness and Visceral Leishmaniasis.” Annals of Tropical Medicine and Parasitology 104.7 (2010) : 535-42. 13 Nov. 2011.

[5]        "Disease considered as candidates for global eradication by the International Task Force for Disease Eradication." The Carter Center, 2008.

[6]        Matlashewski, Greg et al. “Visceral Leishmaniasis: Elimination with Existing Interventions.” The Lancet Infectious Diseases 11.4 (2011) : 322-5. 4 Aug. 2011.

[7]        Hailu, Asrat et al. “Visceral Leishmaniasis: New Health Tools Are Needed.” PLoS Medicine 2.7 (2005) : e211. 25 Nov. 2011.

[8]        Sundar, Shyam et al. “Comparison of Short-course Multidrug Treatment with Standard    Therapy for Visceral Leishmaniasis in India: An Open-label, Non-inferiority, Randomised Controlled Trial.” Lancet 377.9764 (2011) : 477-86. 7 Aug. 2011.

[9]        Sundar, Shyam et al. “Short-course Paromomycin Treatment of Visceral Leishmaniasis   in India: 14-day Vs 21-day Treatment.” Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America 49.6 (2009) : 914-8. 1 Dec.   2011. 

[10]      Ozaki, Masayo et al. “Economic Consequences of Post-kala-azar Dermal Leishmaniasis in a Rural Bangladeshi Community.” The American Journal of Tropical Medicine and Hygiene 85.3 (2011) : 528-34. 15 Nov. 2011.

[11]      Aagaard-Hansen, Jens, Nohelly Nombela, and Jorge Alvar. “Population Movement: A Key Factor in the Epidemiology of Neglected Tropical Diseases.” Tropical Medicine & International Health 15.11 (2010) : 1281-1288. 5 Jul. 2011.

[12]      Gupta, Suman. “Visceral Leishmaniasis: Experimental Models for Drug Discovery.” The Indian Journal of Medical Research 133 (2011) : 27-39. 25 Nov. 2011.