Protozoa 2a): Visceral Leishmaniasis Flashcards
What are the different clinical pictures of leishmaniasis?
- Cutaneous leishmaniasis
- Muco–cutaneous leishmaniasis
- Visceral leishmaniasis (kala–azar)
Which organisms cause VL and how prevalent is it?
Around 20 different species cause leishmania in humans.
Leishmania donavani complex:
–L. donavanii (India, East Africa)
–L. infantum (Old World)
–L. chagasi (New World)
L. chagasi is virtually confined to the dry, rocky hill country of Central America and especially of South America (Brazil). L. donovani is found in East India and Bangladesh while L. infantum is found in the Mediterranean, East Africa and in pockets throughout Asia as well as in Western India. All three species cause visceral leishmaniasis syn. Kala-Azar (Hindi for ‘black sickness’). Humans are the only known reservoir of L. donovani in the Indian subcontinent. Humans and maybe rodents are the reservoir in East Africa.
500 000 cases reported annually, 50 000 deaths
Reservoir: varies in each location, can be humans only, dogs, or rodents
Kala–azar generally affects poor and neglected populations living in remote rural areas. If not treated, more than 95% of kala–azar cases will eventually result in death
How is VL transmitted?
- Transmitted in blood meal of a female phlebotmus sand fly
- Promastigotes inserted under skin
- Ingested unharmed by macrophages
- Metamorphose into amastigotes
- Distributed in the reticuloendothelial system where they lodge and multiply by binary fission
- Sandfly then bites and takes up amastigote in its blood meal
- Amastigotes released into sandlfy stomach and divide by simple fission, eventually forming flageallated metacyclic promastigotes
What role does HIV co-infection play in VL?
- HIV co-infection 2-30% among VL patients
- Mutually adverse effects on disease progression
- HIV pts 100-2320 times more likely to develop active VL
- Most cases CD4 count under 200
- 40% of patient on ART will still develop relapse
There is a clear reciprocal facilitation of infectivity between HIV and VL. Antiretroviral therapy (ART) has improved matters considerably, but nonetheless VL patients are more likely to develop aggressive HIV than others. Various regimes of anti-leishmanial drugs have been used to reduce relapses of HIV in co-infected patients. Many of these regimes include pentamidine, a drug that is also useful in P. jirovecii, C. albicans, and T. brucei gambiense infections. Unfortunately there are drawbacks to giving pentamidine. For example VL is now widely resistant to it in India and unwanted side effects, such as hypotension and insulin -dependent diabetes, are know to occur. Furthermore pentamidine must be given deep IM not orally.
What is the lifecycle of leishmania?
Transmitted in blood meal of a female phlebotmus sand fly
Promastigotes inserted under skin
Ingested unharmed by macrophages
Metamorphose into amastigotes
Distributed in the reticuloendothelial system where they lodge and multiply by binary fission
Sandfly then bites and takes up amastigote in its blood meal
Amastigotes released into sandlfy stomach and divide by simple fission, eventually forming flageallated metacyclic promastigotes
What are the clinical features of VL?
Visceral Leish [incubation weeks/months, can be years if later immunocompromise]
- Fever, weight loss, splenomegaly > hepatomegaly, pancytopenia, epistaxis, lymphadenopathy. It is usually fatal if not treated.
WHO Case definition of a clinical suspicion of VL:
- History of prolonged fever (more than 2 weeks) AND splenomegaly or wasting (weight loss)
Low-grade fever and progressive hepatosplenomegaly – often developing into a massive spleen – is typical of African VL. Chills, rigors, cough, burning feet, epistaxis, abdominal and joint pain, lassitude and anaemia together with skin pigmentation is most common in India (Kala-Azar, Hindi for ‘black sickness’).
The incubation period is normally less than 3 weeks although some cases may take up to 10 years to become manifest. Untreated disease almost always results in death.
As only 50 – 60% of patients meeting this clinical case definition have kala–azar, the diagnosis needs to be confirmed serologically or parasitologically. The main differential diagnoses for KA patients are:
Malaria
Hyperreactive malarial splenomegaly (HMS): formerly called Tropical Splenomegaly Syndrome (TSS). This condition results from multiple partially treated malaria episodes
Schistosomiasis: the splenomegaly is caused by portal hypertension and the fever is usually caused by another condition (e.g. pneumonia)
Brucellosis: the splenomegaly is usually not massive; hepatomegaly; joint, bone and occasionally neurological involvement
Typhoid fever: high grade fever, bradycardia, duration of illness less than one month, impaired mental status, constipation
Tuberculosis: usually no splenomegaly, but possible in case of miliary tuberculosis; respiratory symptoms
Splenic abscess
Myeloproliferative diseases
Malignancies of lymphoid origin (leukemias and lymphomas) Chronic haemolytic anaemia
How do we diagnose VL?
Diagnostic techniques involve serological and parasitological tests:
Serological tests:
- Rapid diagnostic test (RDT) (rK39 dipsticks – Inbios® and DiaMed – IT LEISH® also known as Opti–Leish®
- Direct agglutination test (DAT)
- Caveat: serological tests can only be used in primary VL and are not very sensitive in immunosuppressed individuals
The clinical indications for parasitological diagnosis (spleen, bone marrow or lymph node aspiration) are the following: - Clinical suspect with a prior history of kala–azar (suspicion of relapse) VL patient not responding to anti–Leishmania treatment (test of cure)
- Clinical suspect with a borderline DAT result (1:400–1:1600) Clinical suspect with a negative rK39 dipstick or DAT results but with strong clinical suspicion of kala–azar AND absence of alternative diagnosis or no response to treatment of alternative diagnosis.
Parasitological tests (GOLD STANDARD):
- Giemsa-stained parasites in smears of lymph node/splenic (best)/bone marrow aspirate
Others (not frequently used in guidelines):
- PCR
- Fast agglutination screening test (FAST)
- ELISA
- Indirect fluorescent antibody test (IFAT)
- Pancytopaenia + deranged LFTs
How do you perform a splenic aspirate?
Moeschlin’s technique
https://www.bmj.com/content/1/4766/987
What are the different drugs available to treat VL?
Treatment decisions are nuanced and depend on: the patient, Leishmania species, disease manifestation, geographic region, patterns of resistance etc. Cutaneous Leish is not always treated: Treatment reduces the risk of mucosal disease (in relevant species), relapse, morbidity/cosmetics, reservoir of infection (in relevant species), etc.
Systemic therapy (parenteral)
- Pentavalent antimonial [sodium stibogluconate or meglumine antimoniate] is used for cutaneous, mucosal and visceral disease: typically 2 weeks for cutaneous and 4 weeks for mucosal/visceral. This is usually first line.
- Liposomal Amphotericin B is used for all 3: typically 1-2 weeks.
- Paromomycin [Animoglycoside] IM for 3 weeks is an option for visceral leish. Systemic therapy (oral)
- Miltefosine is used for all 3 in the non-pregnant/breastfeeding population Local therapy. It is the first highly effective oral treatment for VL
How do you treat VL in East Africa?
How do you treat VL in South Asia?
How does PKDL present?
- Post Kala-Azar Dermal Leish [PKDL] is a complication of Old World Visceral Leish during/after treatment [especially L Donovani, especially in Sudan (50%), 10-20% in Bangladesh].
- Variable appearance: macules, papules, nodules.
- Lesions are loaded with amastigotes and are important reservoirs of infection. It is not a sign of resistance. In some regions it can resolve without treatment. It can be treated the same as primary visceral disease.
- It is treated if (a) part of elimination programme (to treat the reservoir) or (b) severe i.e. cosmetic reasons.
- PKDL is commoner following VL treatment with SbV and is uncommon in patients treated with miltefosine or amphotericin B
- Diagnosed by identifying leishmania amastigotes in skin tissue biopsy/aspirate
- 50% recover spontaneously without treatment in SUdan, however treatment usually needed in India in all cases
PKDL is primarily a complication of treated L. donovani VL. It is thus found mostly in the ‘Old World’ and is extremely rare in the ‘New World’. It has the same appearance and progression in India as in North/East Africa (Sudan, Kenya). Reports of PKDL have also come from China and the Middle East.
In many cases the lesions are self-limiting but, when they persist for longer than 6 months, treatment with pentavalent antimonials or miltefosine is needed.
The development of PKDL is likely due the release of excessive amounts of pro-inflammatory cytokines from circulating monocytes.
PKDL often arises in cases of ‘cured VL’ sometimes with a gap of 3–8 years.
In India VL occurs in approximately 2-5% of cases.
Occasionally PKDL occurs in the absence of a history of overt VL
How do you treat PKDL?
Treated the same as primary visceral disease
What are effective measures in eliminating VL?
- Eliminate or treat the reservoir host
- Kill dogs if dogs the reservoir
- Where human reservoir, find and treat
- Eliminate or avoid vector
- Sandflies breed in dark most habitats and don;t fly far from their habitat
- nets can still be penetrated by the fly
- succumb to DDT
Early diagnosis and treatment of infection is key to reducing morbidity and mortality but also to reducing the spread of infection.
- Vector control includes IRS, ITNs and personal protection.
- Disease surveillance systems is important for outbreak protection.
- Control of reservoir host depends on species and geography o L. infantum in Europe, dogs serve as the main reservoir hosts e.g. insect repellant dog collars can be used, infected dogs destroyed etc.
o L. donovani in the Indian subcontinent, early detection and treatment of human infection including PKDL also controls the reservoir of infection.
Leishmania amstaigotes microscopy
What do we know about the phlebotomus sandlfy?
- It’s only the female sandlfies that transmit leishmaniasis because it is only the females that feed on blood every 3 or 4 days -> they need the proteins for producing eggs so it is related to the gonadotrophic cycle
- Leishmaniasis is a zoonosis
- Rodents and dogs can be reservoir hosts and dogs are important reservoir hosts in the mediterranean
- Signs of infection
- Overgrowth of nails
- Loss of hair around eyes, ears and mouth
- Ulceration of ears
- General loss of condition
- L. infantum in the dog affects both viscera and skin
Morphology promastigotes
Picture amastigotes in macrophages
