Leishmania and Filaria part 1

Class IC2
Module TM
Lecturer Prof Mary Cafferkey
Year 2014
Leishmania & Filaria
Arthropod vectors
Protozoan (Leishmania spp) or nematode
filaria) parasite
Tropics and sub-tropics
Chronic skin and/or systemic diseases
History
39 year old male soldier in the Irish Army
Presented to RCSI travel clinic with a chronic
skin ulcer on the forehead
Began as a slightly itchy papule 3 months ago
Gradually enlarged, ulcerated
History of the Presenting Complaint
On a work trip to the jungle in Belize x 6/52
Exposed to swamps, mosquitoes
Drank river water, swam in lagoons, sleeping on the
ground
Bitten by many things
Noticed a red painless papule on forehead
In 2 3 weeks clear fluid emerged when the lesion
was squeezed
Skin broke down to a 2cm x 2cm ulcer
No response to flucloxacillin and others
Past Medical History
Left cruciate ligament surgery 1990
Social
Finner (Army) Camp in Ballyshannon Co
Donegal
Married, 3 children
Travel History
Belize for 6 weeks
On Examination
2 x 2 cm ulcer on
forehead
raised edge with a
shallow flat base
like a volcano
moist non-purulent base
not tender
no lymphadenopathy
Differential diagnosis
Resistant bacterial infection
Fungal infection coccioidomycosis, histoplasma etc.
Syphilis
Orf
Lupus vulgaris
Pyoderma gangrenosum
Atypical mycobacteria
Mycobacterium marinumor M. ulcerans
Skin cancer: squamous cell carcinoma
Sarcoidosis
Likely diagnosis
Leishmaniasis cutaneous
Of 50 soldiers on the trip to Belize
7 others from UK also develooped
cutaneous leishmaniasis
Differential diagnosis
Tropical ulcer - ? Leishmaniasis
Resistant bacterial infection
Fungal infection coccioidomycosis, histoplasma etc.
Syphilis
Orf
Lupus vulgaris
Pyoderma gangrenosum
Atypical mycobacteria
Mycobacterium marinumor M. ulcerans
Skin cancer: squamous cell carcinoma
Sarcoidosis
H&E x 40
H&E x 2030
H&E x 400
Leishmania
Vector-borne diseases
Protozoan parasites of genus Leishmania
>20 species associated with human disease
Multiple clinical manifestations
Cutaneous
Mucocutaneous
Visceral
Clinical spectrum can range from insignificant pustules to fatal systemic disease
related to T-cell immunity
Therefore also a disease associated with HIV
Cutaneous Leishmania - Geographic distribution
L. tropica
L. major
Cutaneous and
mucocutaneous in New
World
Visceral Leishmaniasis
Worldwide incidence
Visceral leishmaniasis
200,000 to 400,000 new cases occur
worldwide each year
Cutaneous leishmaniasis
estimated 0.7 million to 1.3 million new cases
occur worldwide each year
Geographic distribution
4 continents
Endemic in 88 countries, 72 of which are
developing countries:
90% of cutaneous leishmaniasis cases occur
in Afghanistan, Brazil, Iran, Peru, Saudi
Arabia and Syria
90% of mucocutaneous leishmaniasis occurs
in Bolivia, Brazil and Peru.
90% of all visceral leishmaniasis cases occur
in Bangladesh, Brazil, India, Nepal and
Sudan
Epidemics visceral leishmaniasis
Can cause large-scale epidemics, with high casefatality rates
Libo Kemkem, Ethiopia (200506), Wajir, Kenya (2008), and Upper
Nile, Southern Sudan (2009)
Malnutrition is a well-known risk factor, and the epidemics
flourish under conditions of famine, complex emergencies and
mass population movements
In Sudan a major epidemic of visceral leishmaniasis occurred from
1984 to 1994
As this was the first epidemic in the area, the population was highly susceptible.
100 000 deaths in a population of around 300 000 in the western upper Nile area of the
country. In some villages, more than half of the population died from the disease.
In 1997, a new epidemic caused the number of confirmed cases of visceral leishmaniasis in
Sudan to increase by 400% over the previous year. Treatment centres were overwhelmed and
stocks of first-line drugs were depleted. The migration of seasonal workers and large
population movements caused by civil unrest carried the epidemic into Eritrea and Ethiopia.
Epidemics visceral leishmaniasis
HIV co-infection
One of the major threats to control of visceral leishmaniasis (VL) is its
interaction with HIV infection
In areas endemic for VL, many people have asymptomatic leishmania
infection
A concomitant HIV infection increases the risk of developing active VL by
between 100 and 2320 times
In southern Europe, up to 70% of cases of visceral leishmaniasis in adults
are associated with HIV infection
Leishmaniasis
Transmitted by the bite of female sandflies
Reservoirs
humans (anthroponotic forms)
animals (zoonotic)
(In the New World all the forms are zoonotic,
humans being infected only secondarily)
Sandfly Phlebotomus sp.& Lutzomia sp.
Leishmanial parasites
The species of genus Leishmania are in the family
Trypanosomatidae
They alternate between two hosts:
the vertebrate
amastigotes; intracellular forms
the invertebrate
promastigotes
Incubation period: weeks to months after inoculation
Promastigotes R.L. Jacobson, U. Utah
Amastigotes H. Zaiman, U. Utah
Causative organisms ...
Cutaneous leishmaniasis
Localized cutaneous leishmaniasis
Old World -Leishmania major and others
New World L. mexicana and others
Diffuse cutaneous leishmaniasis
Old World L. aethiopica
New World L. mexicana and others
Recidivans cutaneous leishmaniasis
Old World L. tropica
New World L. braziliensis
Mucocutaneous leishmaniasis
New World L. mexicana, L. brazielensis and others
Visceral leishmaniasis
Old World L. donovani, L. infantum, L. tropica
New World L. chagasi
Cutaneous/muco-cutaneous disease
Skin ulcer on exposed skin in a few weeks
Face commonly
Ear, fingertip
Can often be multiple
Regional lymphadenopathy
Subcutaneous nodules
WHO data and image
Lancet1999 Dr RReves
Natural history
Varies by species
Proportion healed at 3 months
L. major 34%
L. mexicana 68%
L. braziliensis 6%
Usually leaves a scar
Pre-Inca pottery from Peru
showing lesions of mucocutaneous
leishmaniasis
Iran Derm
Variants - important
Mucocutaneous disease e.g., L. braziliensis
Sores on mouth and nose years later (espundia)
Diffuse cutaneous leishmaniasis
L. viannia
chronic progressive poly-parasitic, widespread plaques
Much worse with HIV
Visceral Leishmaniasis
Most devastating and fatal form
kala-azar or black fever
Systemic infection of the liver, spleen, and bone marrow
Massive hepatomegaly, splenomegaly
May seem like a leukaemia
Pentad
Fever
weight loss
Hepatosplenomegaly
Pancytopenia
Hypergammaglobulinemia
Visceral disease
Night sweats, weakness, and anorexia
characteristic skin hyperpigmentation
Death from secondary infection due
to immunosuppression
Disease of poverty
Disease mainly of children
e.g., Bangladesh, India, Sudan
Diagnosis
Histopathology-
biopsy and impression smear
Culture at Liverpool School of Hygiene and Tropical Medicine & London School of Hygiene
and Tropical Medicine
PCR is available at CDC and Liverpool School of Hygiene and Tropical Medicine
Antigen detection tests for Visceral disease
Amastigotes in a macrophage from skin From CDC
Investigations
Cutaneous - Treatment of severe disease
Pentavalent antimony compounds/antimonials
(painful, reversible hepatitis, pancreatitis, cardiotoxicity)
sodium stibogluconate [Pentostam, GSK] intralesional,
slow iv or im
meglumine antimoniate [Glucantime, Aventis]
20mg/kg/day im/iv for 20-28 days
Imiquimod topically [Aldara, 3M]
topical
an immune response modifier
Image from www.iranderm.net
Cutaneous - Alternative Treatments
Pentamidine iv
Amphoteracin B iv
Oral azoles
ketoconazole
fluconazole
itraconazole
Oral miltefosine
Topical paromomycin
Cryotherapy, battery acid
Family in Kabul seeking treatment
Lancet 1999 B Herwaldt
from Dr. R.W. Ashford
Cutaneous - treatment
If localised disease and not likely to become
systemic
fluconazole treatment
Cheap
Safe
Well tolerated
Treatment of Visceral disease
BEST TREATMENT IS AMPHOTERICIN B
Lipid associated amphotericin
Alternatives:
Stibogluconate
Paromomycin (cheaper)
Miltefosine (oral)
Sudanese woman with
visceral Leishmaniasis
Lancet 1999 B Herwaldt
Long sleeves, long trousers, socks
Avoid outside from dusk to dawn
N,N-diethylmetatoluamide: DEET 30-50% on
skin
Permethrin on clothes
Impregnated fine-mesh bed nets
Screens, A/C
Spray living area
with insecticide
Prevention
Control
To achieve this, the WHO has adopted a five-pronged approach:
facilitation of early diagnosis and prompt treatment
support for control of sandfly populations through residual insecticide
spraying of houses and use of insecticide-impregnated bednets
provision of health education and production of training materials
detection and containment of epidemics in the early stages &
early diagnosis and effective management of leishmania/HIV co-
infections
References
WHO
http://www.who.int/leishmaniasis/burden/en/
Abdulrahman Alrajhi et al. NEJM 346:891
Randomised double-blind clinical trial of topical imiquimod
5%. C Miranda-Verastigui et al. Clinical Infectious
Diseases 2005 40:1395
Barbara Herwaldt
Lancet 2 Oct 1999 1191-9
Mansons Tropical Diseases 21
st
Ed
Saunders Oct 2002
Sir William Boog Leishman
1865 1926
Indian Medical Service
Medical Director General
of Army Medical Service
-
Charles Donovan
1863-1915,
Physician in the
Indian Medical
service
Leishmania - summary
Cutaneous
Non healing ulcer
Visceral
Severe immunosuppressing disease
Sandfly vector
Biopsy or serological diagnosis
Treatment options
Cutaneous Leishmaniasis is transmitted through the
bite of an infected female phlebotomine sand fly.
The risk is highest from dusk to dawn because sand
flies typically feed (bite) at night and during twilight
hours. Although sand flies are less active during the
hottest time of the day, they may bite if they are
disturbed (for example, if hikers brush against tree
trunks or other sites where sand flies are resting).
Vector activity can easily be overlooked: sand flies do
not make noise, they are small (approximately one-
third the size of mosquitoes), and their bites might not
be noticed.
cdc.gov/travel/yellow book/2014
Basic immunological insights
L. major in a murine model illustrates Th1/Th2
polarisation: c57Bl/6 or BALB/c
Early IFN-g and IL-2 -> Th1 T-cell response; this is
required for protection
Activated macrophages then kill the pathogen
Th2 response with IL-4 leads to progressive disease
Rhee et al J Exp Med 2002:195;1565-1573
Fluconazole for cutaneous disease?
A clinical trial
In Saudi Arabia, n=209
Outcome sought complete healing of all lesions
At 3 month follow up: healing in 63/80 (79%) fluconazole
vs 22/65 (34%) placebo
Sodium stibogluconate for non-healers
Faster healing with fluconazole vs placebo
8.5 versus 11.2 weeks