Side Effects of Treatment

1) Pentavalent Antimonials – Serious cardiotoxicity is seen in 9-10% of patients. Other side effects are reversible renal insufficiency, pancreatitis, anemia, leukopenia, rash, headache, abdominal pain, nausea, vomiting, arthralgia, myalgia, thrombocytopenia, and transaminase elevation. Effectiveness of treatment increases with longer courses of treatment, however incidence of side effects does as well.

2) Amphotericin B – Infusion-related adverse events can occur with amphotericin B deoxycholate. Toxicities which can be seen are hypokalemia, nephrotoxicity and myocarditis. Liposomal amphotericin B is much safer, with fewer side effects.

3) Miltefosine – Gastrointestinal side effects are the most common and include vomiting. Transient elevation of hepatic enzymes has been observed. The drug is highly teratogenic and as such is contraindicated in pregnant patients and mandatory contraception is recommended for women of child-bearing age through treatment and 2-3 months after.

4) Paromycin – Injection-site pain was the most frequently reported side effect in one study done in India. Ototoxicity and nephrotoxicity are side effects that are common in aminoglycoside antibiotics, however frequency at therapeutic doses is low. Monitoring of hepatic enzymes has been recommended.

5) Pentamidine – The major side effect of pentamidine use is induction of insulin-dependent diabetes mellitus. It a major concern and one of the reasons it is a second line treatment. Other side effects include nausea, vomiting, abdominal pain, and headache.

For more information:

www.cdc.gov

www.rxlist.com

Seifert, K., (2011). Structures, targets and recent approaches in anti-leishmanial drug discovery and development. The Open Medical Chemistry Journal, (5), 31-39.

Distribution Maps from WHO

Geographical distribution of visceral leishmaniasis in the Old and New world

Geographical distribution of cutaneous and mucocutaneous leishmaniasis in the New World

maps from: http://www.who.int/leishmaniasis/leishmaniasis_maps/en/index1.html

Treatment

Since many of those infected with visceral leishmaniasis live in poor, rural areas, availability and cost can significantly limit treatment options. There are several categories of drugs used to treat VL.

1) Pentavalent Antimonials – Includes meglumine antimonite and sodium stibogluconate. These drugs have been used for many years and are still highly effective for previously untreated VL patients. Since they have been a first line treatment for over 60 years resistance has developed in endemic regions. Dosing recommended by the CDC is 20 mg/kg/day of antimony IV or IM for 28-30 days.

2) Amphotericin B – Amphotericin B deoxycholate is an antibiotic that is highly effective and is used as first line treatment where resistance has developed to antimonials and as a second line choice in other areas. The CDC recommends a regimen of 0.75 – 1.0 mg/kg daily for 15-20 days or 0.75-1.0 mg/kg every other day for 30-40 days. A liposomal form of amphotericin B (AmBisome) has been developed and approved for treatment of VL by the FDA and appears to be an effective and simpler alternative. The recommended dose of AmBisome is 3 mg/kg QD on days 1-5, 14 and 21 (total dose of 21 mg/kg). A single dose of 10 mg/kg has been tested and shown to be comparable and less expensive as a treatment option. Cost can be a limiting factor as patients need to be hospitalized and monitored during treatment using Amphotericin B deoxycholate and liposomal amphotericin B (AmBisome) costs around $20 per 50mg vial.

3) Miltefosine – This drug is an alkylphosphocholine and was the first oral anti-leishmanial drug available. Miltefosine (Impavido) is registered to treat VL in India and Germany and in some clinical trials has a cure rate of up to 95%. It is not approved for treatment of leishmaniasis in the United States and as such the CDC has no recommendations for proper doses and treatment regimens.

4) Paromycin – This aminoglycoside antibiotic is another newer anti-leishmanial drug which is registered in India for treatment of VL but not in the United States. A course of 11 mg/kg/day for 21 days was shown to have a cure rate of 92%.

5) Pentamidine – This drug is an aromatic diamidine. It is not often used due to toxicity and side effect issues. It is a second line treatment but is rarely used.

6) Drugs currently being developed – 2-Substituted Quinolines have been shown to be effective in treating new world cutaneious leishmaniasis. 8-Aminoquinolines, such as Sitamaquine, is being developed for oral treatment of VL. Buparvaquone is currently marketed as Butalex for treatment of theileriosis in cattle but has been shown to be highly effective against L. donovani in vitro.  

For more information:

www.CDC.gov

Seifert, K., (2011). Structures, targets and recent approaches in anti-leishmanial drug discovery and development. The Open Medical Chemistry Journal, (5), 31-39.

Diagnostic Tests

Direct Visualization:

A definitive diagnosis of visceral leishmaniasis can be made based on visualization of amastigotes on microscopic examination of Giemsa-stained aspirate from bone marrow, blood, lymph or spleen (the most accurate but also most dangerous due to bleeding complications). The amastigotes are seen in monocytes or macrophages. This method of diagnostic testing however is expensive, complicated and not appropriate for many of the settings in which visceral leishmaniasis is endemic. The search for a cheap, specific and sensitive field test is ongoing.

Serological Tests:

-          Several antibody-detection tests exist and are available for field diagnosis. Although these tests when combined with presentation of clinical signs and symptoms are enough to lead to a safe decision to treat they are not useful for assessing for cure after treatment. These tests are also unreliable in patients who have been treated and later return with symptoms such as fever and splenomegaly as antibodies will be present and the test can’t distinguish between a relapse of visceral leishmaniasis and another pathology.

-          A direct agglutination test (DAT) is available and has both a high sensitivity and high specificity; however it is technically demanding and requires an 8 hour incubation period.

-          An enzyme-linked immunosorbent assay (ELISA) and immunochromatographic strip test based on a 39-amino-acid-repeat recombinant leishmanial (rK39) antigen has proven a better alternative for field testing. It can also be used after treatment and levels decrease rapidly.

Urine Tests:

-          A latex agglutination test (KAtex) which detects antigen in a patient’s urine has shown promise but is continuing to be evaluated.

Molecular Diagnostics:

-          There are several tests but they are complex and expensive and so are limited to research centers and some teaching hospitals and are not widely used to diagnose patients in many endemic areas.


Bone marrow biopsy specimen from a patient
with visceral leishmaniasis showing a macrophage
containing Leishmania amastigotes. CDC photo

Signs and Symptoms

Signs and symptoms of visceral leishmaniasis may be mild or severe and appear after the incubation period of the leishmania parasite, which can be anywhere from several weeks to 6 months. Occasionally the parasite may remain dormant in an infected individual for years and multiply when the individual’s immune system becomes compromised.

Cardinal signs and symptoms: weight loss, pancytopenia, hepatosplenomegaly, intermittent fever (usually rising and falling 2 times a day), hypergammaglobulinemia

Other signs and symptoms: adenopathy, hypoalbuminemia, hyperpigmentation of the forehead, abdomen, hands and feet (seen only in India), dizziness, cough, diarrhea, jaundice, ascites, skin lesions. Patients often progress to cachexia, multisystem disease, bleeding disorders, secondary infections and death.




Photo showing marked enlargement of the spleen
in patient with visceral leishmaniasis. CDC photo.

Basic Pathophysiology

The various forms of Leishmaniasis (cutaneous, visceral, mucocutaneous and post-kala-azar dermal) are caused by more than 20 different species of protozoa belonging to the genus Leishmania. Visceral Leishmaniasis is caused by L. donovani, L. infantum and L. chagasi. Some who are infected remain asymptomatic while others progress to serious illness and death, at risk are those who are immunocompromised or malnourished. The promastigote (flagellated) form of the parasite multiplies in the gut of female sand flies after it has ingested the amastigote form from another person (or animal). The promastigotes, which are injected into a human host while the sand fly is feeding, are phagocytised by macrophages where they return to an amastigote form. The amastigotes multiply within the macrophage’s phagolysosomes, protected from an immune response by the host.

The incubation period within a human host can range from 10 days up to 2 years. In visceral leishmaniasis the parasite is able to multiply without suppression from the host’s immune system leading to complications affecting the spleen, liver, intestinal mucosa, bone marrow and lymph nodes. Hematopoiesis is depressed leading to pancytopenia, prothrombin becomes depleted (leading to bleeding complications when combined with thrombocytopenia), and decreased albumin predisposes the patient to edema. The host’s immune system becomes severely compromised as infection spreads and, if left untreated, most patients will die within 2-3 years often from secondary infections such as tuberculosis, pneumonia or dysentery.

Leishmania life cycle:

diagram from: http://www.sciencephoto.com/media/151986/enlarge#

Leishmaniasis: intro and stats

I have chosen to investigate the infectious disease Leishmaniasis, it is a disease that is strongly linked to poverty and as such is relatively unknown in the developed world. Leishmaniasis is a vector-borne parasitic disease caused by over 20 species of the protozoa Leishmania. Leishmaniasis is transmitted through the bite of an infected sand fly. The promasitgote form of the parasite is phagocytized by macrophages where it develops into the amastigote form, multiplies and infects other cells. It is possible for the more severe form of leishmaniasis, visceral leishmaniasis, to be transmitted through transfusions and needle sharing, congenital transmission appears to be very rare.

There are several forms of Leishmaniasis. Cutaneous leishmaniasis is the most common form of the disease; it is rarely fatal and involves skin sores which often resolve on their own without treatment. Mucocutaneous leishmaniasis is a possible complication of cutaneous leishmaniasis, usually due to L. braziliensis, which can cause destruction of mucosal structures such as the nasal septum and soft palate. My focus in this blog will be on the most deadly form of leishmaniasis which is visceral leishmaniasis, also known as kala-azar in parts of the world.

Leishmaniasis is found in 88 countries and as many as 12 million are currently infected. There are 1-2 million new cases each year. Of these 1-2 million new leishmaniasis cases a year and estimated 1.5 million are cutaneous leishmaniasis with the more severe visceral form accounting for about 500,000 new cases. Over 90% of visceral leishmaniasis cases occur in India, Bangladesh, Nepal, Sudan and Brazil. Visceral leishmaniasis is most often caused by L. donovani and L. infantum and without proper treatment it is fatal in >90% of cases. There have been several epidemics of visceral leishmaniasis. Malnutrition, displacement, poor housing and immunosuppresion are known risk factors and thus epidemics tend to occur in hard to reach places that are suffering from famine, war or mass population movements. In Southern Sudan a major epidemic occurring from 1984 to 1994 was estimated to have killed 100,000 in a population of about 300,000 in the upper Nile region. Most cases of leishmaniasis in the United States reflect individuals who were infected during travel or who immigrated to the U.S after they were infected. There have been a few cases of cutaneous leishmaniasis infections in Texas and Oklahoma but there have been no known cases of visceral leishmaniasis acquired in the United States.

There is no prophylactic medication to take if you are traveling to a part of the world where leishmaniasis is endemic. Disease prevention involves avoiding being bitten by the sand fly which hosts the Leishmania genus through use of bug spray, mosquito nets, clothing which covers extremities and avoiding being outside in the evening when the sand fly is most active.

For more information visit: www.cdc.gov

                                                  www.who.org