16. 1. William Leishman, a Glasgwegian Dr served British Army in India. In1. William Leishman, a Glasgwegian Dr served British Army in India. In
Dum Dum, he discovered LD bodies in spleen of a British soldier. HeDum Dum, he discovered LD bodies in spleen of a British soldier. He
called it “Dum Dum Fever” & published it in 1903. 2. Charles Donovancalled it “Dum Dum Fever” & published it in 1903. 2. Charles Donovan
also recognized SS in other KA pts. & published it a few weeks lateralso recognized SS in other KA pts. & published it a few weeks later
17. Leishmaniasis: Key factsLeishmaniasis: Key facts
3 main forms:3 main forms: visceral L.visceral L. (kala-azaar: the most serious),(kala-azaar: the most serious),
cutaneous L.cutaneous L. (the commonest), &(the commonest), & mucocutaneous L.mucocutaneous L.
Transmitted by bite ofTransmitted by bite of inf. female sandfliesinf. female sandflies
Affects the poorest with malnutrition, displacement,Affects the poorest with malnutrition, displacement,
poor housing, a weak immune systempoor housing, a weak immune system
ItIt is linked to environmental changes: deforestation,is linked to environmental changes: deforestation,
building dams, irrigation, & urbanizationbuilding dams, irrigation, & urbanization
700,000 new cases700,000 new cases && 20,000 deaths/y20,000 deaths/y
Only a small fraction of inf. will eventually develop d.Only a small fraction of inf. will eventually develop d.
18. At the end of this session you will learnAt the end of this session you will learn
– L.L. affects the poorest withaffects the poorest with little knowledge about it &little knowledge about it &
unlikely to seek early Rx./cannot afford Rxunlikely to seek early Rx./cannot afford Rx
AA spectrum disease:spectrum disease:
• TheThe commonestcommonest is ~is ~ self-healingself-healing skin lesionskin lesion ((75%)75%)
• The worst/The worst/severest isseverest is visceral d.visceral d. Kala Azaar (Kala Azaar (25%)25%)
60% in our60% in our Sub-continentSub-continent
a neglected ID,a neglected ID, should have been controlledshould have been controlled
1 of the important c/of1 of the important c/of PUOPUO
L. & HIV/TB augments each otherL. & HIV/TB augments each other
It isIt is curablecurable
Our country is leading to control itOur country is leading to control it
19. Prevalence:Prevalence: 12 mln12 mln
350 million at risk350 million at risk
– Cutaneous L (CL)Cutaneous L (CL):: 90% in Afghanistan, Iran, Syria, KSA, S90% in Afghanistan, Iran, Syria, KSA, S
Lanka, Peru, BrazilLanka, Peru, Brazil
– MCLMCL:: 90% in S America90% in S America
– Visceral L (VL)Visceral L (VL) (Kala Azar)(Kala Azar)
60% in BD, India, Nepal. 30% in Brazil, Sudan60% in BD, India, Nepal. 30% in Brazil, Sudan
EndemicEndemic in 88 countries (16 western)in 88 countries (16 western)
Depth of the ProblemDepth of the Problem
25. Bangladesh ScenarioBangladesh Scenario
AA re-emerging IDre-emerging ID since 1990; disappeared duringsince 1990; disappeared during
‘Malaria Eradication Pgm’‘Malaria Eradication Pgm’ (1961-70)(1961-70)
– poor control of vectorpoor control of vector
– lack of access to Rxlack of access to Rx
139 Upazillas in139 Upazillas in 45 districts45 districts
PrevalencePrevalence 45,000.45,000. IncidenceIncidence 10,000/y10,000/y
– 55% in55% in MymensinghMymensingh
– 25% in25% in Pabna, Tangail, JamalpurPabna, Tangail, Jamalpur
BD is committed to eliminate kA/2015 (<1/10k popn. atBD is committed to eliminate kA/2015 (<1/10k popn. at
Upazila level).Upazila level). Now it is almost controlled!Now it is almost controlled!
Only 420 new cases Dx/2015Only 420 new cases Dx/2015
28. SynonymsSynonyms
Kala-azar, visceral L (VL), black fever, leishmaniasis,Kala-azar, visceral L (VL), black fever, leishmaniasis,
Dumdum fever, Assam FDumdum fever, Assam F
Mucocutaneous L, cutaneous L, bay sore,Mucocutaneous L, cutaneous L, bay sore, espundiaespundia,,
mucosal L, post-kala-azar dermal L,mucosal L, post-kala-azar dermal L,
viscerotropic L, forest yaws, Aleppo evilviscerotropic L, forest yaws, Aleppo evil
Baghdad sore, Biskra button, Chiclero ulcer, DelhiBaghdad sore, Biskra button, Chiclero ulcer, Delhi
boil, Oriental sore, Rose of Jericho, Utaboil, Oriental sore, Rose of Jericho, Uta
29. Only a small fraction infected develop the d.Only a small fraction infected develop the d.
A zoonosis; mammalian reservoirsA zoonosis; mammalian reservoirs
Leishmanias areLeishmanias are obligate intracellular parasiteobligate intracellular parasite
– One sp. can cause different syn.One sp. can cause different syn.
– One syn. can be c/by different spp.One syn. can be c/by different spp.
Vector:Vector: femalefemale sand-fly. 2-3mmsand-fly. 2-3mm
Phlebotomus & LutzomyiaPhlebotomus & Lutzomyia
ReservoirReservoir:: Indian KA: humanIndian KA: human
rodents in Africa, foxes in Brazil, C. Asiarodents in Africa, foxes in Brazil, C. Asia
dogs in the Mediterranean, China
EPIDEMIOLOGYEPIDEMIOLOGY
31. The vectorThe vector lives in cracks of mud-houses, heaps of cowlives in cracks of mud-houses, heaps of cow
dung, in rat burrows, bushesdung, in rat burrows, bushes
Feed mainly on cattle.Feed mainly on cattle. We are 2nd choice!We are 2nd choice! MoreMore exposure:exposure:
– extracting timber, mining, building damsextracting timber, mining, building dams
– irrigation, road making in forestsirrigation, road making in forests
Transmission:Transmission: CommonCommon:: bitebite by inf. F.by inf. F.
vector.vector. UncommonUncommon::
– congenital, BT, needle sharingcongenital, BT, needle sharing
– rarely: inoculation from culturerarely: inoculation from culture
IP:IP: Cut. L: ~several weeksCut. L: ~several weeks
Visceral L:Visceral L: 6 w-6 mo (10 d-10 y)6 w-6 mo (10 d-10 y)
32.
33. 3 syndromes of Leishmaniasis3 syndromes of Leishmaniasis
Cutaneous LCutaneous L
– Old World:Old World: L tropica, L major,L tropica, L major, L aethiopica, L donovaniL aethiopica, L donovani ,, L infantum,L infantum, L mexicanaL mexicana
– New World:New World: L amazonensis, L braziliensis, L panamensis, L guyanensis,L amazonensis, L braziliensis, L panamensis, L guyanensis, L chagasiL chagasi
Mucocutaneous LMucocutaneous L byby L braziliensis, L panamensis, L guyamenis, LL braziliensis, L panamensis, L guyamenis, L
amazonensisamazonensis
Visceral LVisceral L byby L donovani,L donovani, L infantum, L chagasi,L infantum, L chagasi, L tropica,L tropica, LL
amazonensisamazonensis
Post-kala-azar dermal L (PKDL)Post-kala-azar dermal L (PKDL)
Old WorldOld World:: L donovani, L infantumL donovani, L infantum
New World:New World: L donovani chagasi:L donovani chagasi: Central &, S AmericaCentral &, S America
34. Life cycleLife cycle
2 forms2 forms
– amastigoteamastigote (no flagella) in host(no flagella) in host
– promastigotepromastigote in vector &in vector & mediummedium
Amastigotes in blood meal become flagellate in vector &Amastigotes in blood meal become flagellate in vector &
multiply over 6-9dmultiply over 6-9d
Following bite: flagellates enter R.E.S. & change toFollowing bite: flagellates enter R.E.S. & change to
amastigote;amastigote; multiply by binary fissionmultiply by binary fission
35.
36. PathogenesisPathogenesis
R.E.S.R.E.S. is invaded:is invaded: mainlymainly spleen, liver, BMspleen, liver, BM
Monocytes spread parasitesMonocytes spread parasites
Outcome:Outcome: virulence vs immunityvirulence vs immunity
MarkedMarked suppression of C.M.I.suppression of C.M.I. Overproduction of IgOverproduction of Ig
Spleen:Spleen: Bag of parasites!Bag of parasites!
– enlarged, soft, fragile, dilated BVenlarged, soft, fragile, dilated BV
– Billroth cellsBillroth cells are over-parasitized;are over-parasitized; No fibrosisNo fibrosis
Liver:Liver: Kupffer cellsKupffer cells over-parasitizedover-parasitized
BM:BM: parasitized monocytes replace normal tissueparasitized monocytes replace normal tissue
38. Cutaneous L.Cutaneous L.
Bite siteBite site macule/nodulemacule/nodule ⇒⇒ shallow ulcer,shallow ulcer, raised borders:raised borders:
commonly face, limbscommonly face, limbs
May have satellite lesions & LAPMay have satellite lesions & LAP
Self-healingSelf-healing in weeks-years within weeks-years with atrophic (cigaretteatrophic (cigarette
paper) scarpaper) scar
But can causeBut can cause serious disfigurementserious disfigurement
On recovery:On recovery: immunityimmunity to infecting sp.to infecting sp.
CL. MANIFESTATIONSCL. MANIFESTATIONS
48. CL is generally considered toCL is generally considered to
be an innocuous d.; but, inbe an innocuous d.; but, in
some parts of world,some parts of world,
especially in tribal areas,especially in tribal areas,
even CL can have a lifeeven CL can have a life
altering effect on a person.altering effect on a person.
Minimal facial disfiguringMinimal facial disfiguring
can condemn young girls tocan condemn young girls to
life without the prospect oflife without the prospect of
marriage or acceptance inmarriage or acceptance in
societysociety
49. CL with a 1-y h/of asymptomatic pink-erythematous infiltrative plaqueCL with a 1-y h/of asymptomatic pink-erythematous infiltrative plaque
with overlying scale & central crustwith overlying scale & central crust
58. MCL (espundia)MCL (espundia)
Rare in childrenRare in children
InvasiveInvasive disfiguringdisfiguring d.: destroys mucosad.: destroys mucosa
90% in S America90% in S America
Commonly around noseCommonly around nose
Heals withHeals with scarsscars
Significant mortality/morbiditySignificant mortality/morbidity
Mucosa may perforateMucosa may perforate
MCL: mucocut. LMCL: mucocut. L
63. Visceral L. (kala-azar)Visceral L. (kala-azar)
Severest & Progressive.Severest & Progressive. DeathDeath in 2 years if untreatedin 2 years if untreated
Malnourished people are most susceptibleMalnourished people are most susceptible
India-Bangladesh-Nepal: 300k/y.India-Bangladesh-Nepal: 300k/y. 200 million at risk200 million at risk
– 52 districts52 districts of Indiaof India
– 45 ,,45 ,, of Bangladeshof Bangladesh
– 12 ,,12 ,, of Nepalof Nepal
Control program in BD in 2007: new cases droppedControl program in BD in 2007: new cases dropped
from 10k/y to 542 in 2015, MR now close to zero.from 10k/y to 542 in 2015, MR now close to zero.
BD is on track to eliminate VL/2015BD is on track to eliminate VL/2015
64. Typical PresentationTypical Presentation
Chr. F: double rise, good appetite, HSM, progressive pallor,Chr. F: double rise, good appetite, HSM, progressive pallor,
weakness, wt. loss, darkening skinweakness, wt. loss, darkening skin
Panacytopenia, LAPPanacytopenia, LAP
⇓⇓ albumin,albumin, ⇑⇑ ImmunoglobulinsImmunoglobulins
2y infx. common2y infx. common
Co-morbidity withCo-morbidity with HIV, TB, orHIV, TB, or
Immunodeficiencies:Immunodeficiencies: more severemore severe
66. JaundiceJaundice (10%)(10%) is rare:is rare: Bad prognosisBad prognosis
Immune complexes: mild GNImmune complexes: mild GN
Rh. Factor may be positiveRh. Factor may be positive
Fulminant formFulminant form mainly in children: pancytopenia & ac. livermainly in children: pancytopenia & ac. liver
failurefailure
Skin in VLSkin in VL
dark, dry, thin, scalydark, dry, thin, scaly
diffuse wartydiffuse warty
petechiae, bruisespetechiae, bruises
hair losshair loss
edemaedema
67. Atypical presentations of KAAtypical presentations of KA
PUO/FUO:PUO/FUO: an important causean important cause
Pancytopenia without splenomegalyPancytopenia without splenomegaly
Immune hemolysisImmune hemolysis
Generalized LAP with/-out HSMGeneralized LAP with/-out HSM
Massive hepatic necrosisMassive hepatic necrosis
Retinal bleedRetinal bleed
Severe Anemia in KASevere Anemia in KA
BM replaced by parasitesBM replaced by parasites
BM depression, splenic sequestration, hge, hemolysis, 2y inf.BM depression, splenic sequestration, hge, hemolysis, 2y inf.
68. Case definition for KACase definition for KA
Residing/travelling in endemic areasResiding/travelling in endemic areas
F. for >2w & any 1:F. for >2w & any 1:
Splenomegaly or wt. loss or anemiaSplenomegaly or wt. loss or anemia
And ‘rk39’ test positiveAnd ‘rk39’ test positive
Case definition for PKDLCase definition for PKDL
Residing/travelling in endemic areasResiding/travelling in endemic areas
Rx of KA any time in pastRx of KA any time in past
Skin lesion lesions (macular, papular, nodular, or mixed)Skin lesion lesions (macular, papular, nodular, or mixed)
without loss of sensationwithout loss of sensation
Exclusion of other c/of skin d.Exclusion of other c/of skin d.
‘‘rk39’rk39’ positive/slit skin smear positive/PCR positivepositive/slit skin smear positive/PCR positive
69. DefinitionsDefinitions
Primary KA (PKA)Primary KA (PKA)
KA as case definition & not treatedKA as case definition & not treated
KA treatment failure (KATF)KA treatment failure (KATF)
Case defined. Rx within last 1y. All efforts should be made to DxCase defined. Rx within last 1y. All efforts should be made to Dx
parasitologically by splenic/BM smear or PCRparasitologically by splenic/BM smear or PCR
Relapse KARelapse KA
Dx KA with case defn. & Rx in past but not within last 1y. All effortsDx KA with case defn. & Rx in past but not within last 1y. All efforts
are made to Dx parasitologically by splenic/BM smear or PCRare made to Dx parasitologically by splenic/BM smear or PCR
70. DxDx
Showing MOShowing MO
CL/MCL:CL/MCL: biopsy, scrapings, FNAC,biopsy, scrapings, FNAC, LN:LN:
aspiration/aspiration/ biopsy,biopsy, tissuetissue punch biopsypunch biopsy
VL:VL: spleen, BM, liver, LN puncturespleen, BM, liver, LN puncture
Blood culture may help (~1 mo): Novy-McNeal-Blood culture may help (~1 mo): Novy-McNeal-
Nicolle medium (3N medium). Blood smears fromNicolle medium (3N medium). Blood smears from
buffy-coat in HIVbuffy-coat in HIV
Immunological tests:Immunological tests:
71. Immunological testsImmunological tests
Specific: RDTSpecific: RDT (recombinant Ag.(recombinant Ag. rk39rk39), DAT (IgM) at), DAT (IgM) at
early stage; ICT: highly sensitiveearly stage; ICT: highly sensitive
NonspecificNonspecific
– CIE, CFT, IF Ab test:CIE, CFT, IF Ab test: cross-react with leprosy, Chaga,cross-react with leprosy, Chaga,
malaria, schistosomiasismalaria, schistosomiasis
– Detection of hyper-Ig: AT. CT (3 mo)Detection of hyper-Ig: AT. CT (3 mo)
A negative serology does not exclude LA negative serology does not exclude L..
72. rK39rK39
Rapid dipstick testRapid dipstick test
Based on theBased on the
recombinant k39recombinant k39
proteinprotein
77. Peripheral Blood PicturePeripheral Blood Picture
Severe normocytic-chromic anemiaSevere normocytic-chromic anemia
LeukopenicLeukopenic relative lymphocytosisrelative lymphocytosis
ThrombocytopeniaThrombocytopenia
Raised ESRRaised ESR
High Ig with reversal of AG ratioHigh Ig with reversal of AG ratio
BM aspirationBM aspiration
Commonest method. Sensibility 86%. Safer than splenic p.Commonest method. Sensibility 86%. Safer than splenic p.
Splenic puncture:Splenic puncture: 98%.98%. Risk: bleedRisk: bleed
If BM is inconclusiveIf BM is inconclusive
78. DrugsDrugs
Liposomal Amphotericin BLiposomal Amphotericin B
LABLAB is now DoC; single dose works (97%)is now DoC; single dose works (97%)
Amphotericin BAmphotericin B
Na stibogluconate (SSG): IMNa stibogluconate (SSG): IM
MiltefosineMiltefosine is new: p.o.is new: p.o.
PentamidinePentamidine
Paromomycin in VL. It is low-costParomomycin in VL. It is low-cost
Ketoconazole, ItraconazoleKetoconazole, Itraconazole
The commonest drug for VL wasThe commonest drug for VL was SSGSSG x 4w; now variablyx 4w; now variably
resistant in many countriesresistant in many countries
79. Amphotericin BAmphotericin B
an antifungal, used for serious mycosis & leishmaniasisan antifungal, used for serious mycosis & leishmaniasis
Aspergillosis, blastomycosis, candidiasis, cryptococcosisAspergillosis, blastomycosis, candidiasis, cryptococcosis
coccidioidomycosiscoccidioidomycosis
Typically IVTypically IV
Lower SE.Lower SE. Common:Common: F, chills, HA, kidney problems,F, chills, HA, kidney problems,
anaphylaxis, hypotension, myocarditis. Safe in preg. Itanaphylaxis, hypotension, myocarditis. Safe in preg. It
works in part by interfering with the cell membraneworks in part by interfering with the cell membrane
It was isolated fromIt was isolated from Streptomyces nodosusStreptomyces nodosus
Cost in the developing world: 162-229 USDCost in the developing world: 162-229 USD
80. TREATMENTTREATMENT
CLCL may heal spontaneously.may heal spontaneously. TreatTreat ifif
– disabling/disfiguring ulcers, late healing, MCLdisabling/disfiguring ulcers, late healing, MCL
S. American CL:S. American CL: ketoconazole, itra-, paromomycin, plusketoconazole, itra-, paromomycin, plus
local heatlocal heat
VLVL
Bangladesh: most are still sensitive to SSGBangladesh: most are still sensitive to SSG
DoC: LABDoC: LAB
MiltefosineMiltefosine is taken p.o.is taken p.o.
ParomomycinParomomycin has excellent safetyhas excellent safety
Always treat if MCL or VLAlways treat if MCL or VL
81. VL: Supportive RxVL: Supportive Rx
– RestRest
– High-calorie dietHigh-calorie diet
– BTBT
– Rx secondary inf.Rx secondary inf.
Symptoms rapidly improveSymptoms rapidly improve
Spleen regresses over monthsSpleen regresses over months
Patients must be counseled about the importance ofPatients must be counseled about the importance of
FU for relapseFU for relapse
82. Post KA Dermal L (PKDL) (10%)Post KA Dermal L (PKDL) (10%)
1-2y follows1-2y follows completecomplete Rx;Rx; may last up to 20ymay last up to 20y
No disability!No disability!
Seek Rx for social stigma!Seek Rx for social stigma!
SSG x 4 mo is potentially toxic & cumbersomeSSG x 4 mo is potentially toxic & cumbersome
MiltefosineMiltefosine x12w is effective (93%)x12w is effective (93%)
LAB 2 doses:LAB 2 doses: 5 mg/kg/w x 3w is successful5 mg/kg/w x 3w is successful
Consider combinations of LAB & miltefosine, miltefosine &Consider combinations of LAB & miltefosine, miltefosine &
paromomycin, or miltefosine & SSGparomomycin, or miltefosine & SSG
83.
84.
85. DD of VLDD of VL
Malaria, tropical splenomegaly syn.Malaria, tropical splenomegaly syn.
EF, Portal HTNEF, Portal HTN
Leukemias & lymphomasLeukemias & lymphomas
Chr. hemolytic anemiaChr. hemolytic anemia
DD ofPKDLDD ofPKDL
Yaws; Syphilis; LeprosyYaws; Syphilis; Leprosy
DD of CL:DD of CL: traumatic ulcerstraumatic ulcers
DD of MCL:DD of MCL: Leprosy; Sarcoidosis; Midline granuloma,Leprosy; Sarcoidosis; Midline granuloma,
Histoplasmosis; Syphilis, tertiary yawsHistoplasmosis; Syphilis, tertiary yaws
86. PROGNOSISPROGNOSIS
CL:CL: may be self-limiting. Excellentmay be self-limiting. Excellent
Diffuse CL & MCL:Diffuse CL & MCL: good on Rxgood on Rx
VL:VL: fatal if untreated: mortality 10% in Rxfatal if untreated: mortality 10% in Rx
Causes of death in VLCauses of death in VL
2y infx.: pneumonia; septicemia2y infx.: pneumonia; septicemia
DysenteryDysentery
TB, HIVTB, HIV
Cancrum oris, uncontrolled hgeCancrum oris, uncontrolled hge
87. KA elimination in SEA is possibleKA elimination in SEA is possible
Confined to 3 countriesConfined to 3 countries
Humans are the only reservoirHumans are the only reservoir
A RDT is availableA RDT is available
Only 1 vector: control by indoorOnly 1 vector: control by indoor residualresidual sprayspray
Permethrin treated nets, good housing, screen,Permethrin treated nets, good housing, screen, clothing,clothing,
repellent, minimum outdoor exposuresrepellent, minimum outdoor exposures dusk-dawndusk-dawn
LAB & Miltefosine are safe & effectiveLAB & Miltefosine are safe & effective
Strong political willStrong political will
88. Target:Target:
To reduce incidence of KA &PKDL to <1/10k popn.:To reduce incidence of KA &PKDL to <1/10k popn.:
Early DxEarly Dx & complete Rx:& complete Rx: stops transmissionstops transmission
Surveillance; health educationSurveillance; health education
Reducing incidence in endemic communitiesReducing incidence in endemic communities
Reducing CFR (case fatality rates)Reducing CFR (case fatality rates)
Rx PKDL to reduce the parasite reservoirRx PKDL to reduce the parasite reservoir
Px & Rx of KA-HIV-TB co-inf.Px & Rx of KA-HIV-TB co-inf.
Integrated vector managementIntegrated vector management
89.
90. Integrated vector Mx (IVM)Integrated vector Mx (IVM)
Indoor Residual Spray (IRS):Indoor Residual Spray (IRS):
Insecticide Deltamethrin; 6 rounds; 1 round inInsecticide Deltamethrin; 6 rounds; 1 round in
moderate & low endemic areasmoderate & low endemic areas
Piloting was done at Fulbaria in 2011Piloting was done at Fulbaria in 2011
90
IRSAT DHANIKHOLAVILLAGE OFTRISHAL UPAZILLA
Dr.Shah
Golam Nabi,
DPM,KEP,
CDC,DGHS
with the IRS
Team ( Spray
man,Team
leader & 1st
Line
Supervisor) at
Dhanikhola
Village,Trishal
Upazilla.
92. Larvicide Spray in Cow & chicken shadeLarvicide Spray in Cow & chicken shade
93. Effective surveillanceEffective surveillance
National ConsultantNational Consultant
Surveillance Medical OfficerSurveillance Medical Officer
Data ManagerData Manager
Regular collection of Data fromRegular collection of Data from
all KA Endemic UHCall KA Endemic UHC
Case detectionCase detection
96. MCQMCQ
In L. spectrum d. the commonest is Kala AzarIn L. spectrum d. the commonest is Kala Azar
KA, is 2nd
biggest parasitic killer after malaria
KA is spread by infected mosquitoKA is spread by infected mosquito
Thrombocytopenia is a common featureThrombocytopenia is a common feature
Reservoir in Indian KA is dogReservoir in Indian KA is dog
LAB single dose is effectiveLAB single dose is effective
97. MCQMCQ
DAT is a specific test for KADAT is a specific test for KA
ICT is a non-specific test for KAICT is a non-specific test for KA
Splenic puncture more sensitive than BMSplenic puncture more sensitive than BM
Most VL in Bangladesh is sensitive to SSGMost VL in Bangladesh is sensitive to SSG
Severe anemia is common in KASevere anemia is common in KA
HIV, TB & VL augments each otherHIV, TB & VL augments each other
Charles Donovan MD (1863 – 1951) was an Irish MO in the Indian Medical Service. He discovered LD as the cause of VL, and Klebsiella granulomatis as that of donovanosis. The son of a judge in India, he was born in Calcutta. He graduated in medicine from Trinity College, Dublin and joined the IMS. He participated in British expeditions to Mandalay in Burma, Royapuram and Mangalore in India, Afghanistan, and finally Chennai, where he spent the rest of his service. He was professor at Madras Medical College from 1898 until his retirement in 1919
Phlebotomus: vein cutting
Visceral L (VL), also known as kala-azar is fatal if left untreated in over 95% of cases. It is characterized by irregular bouts of fever, weight loss, enlargement of the spleen & liver, & anaemia. Most cases occur in Brazil, East Africa & in South-East Asia. An estimated 50 000 to 90 000 new cases of VL occur worldwide each year. In 2015, more than 90% of new cases reported to WHO occurred in 7 countries: Brazil, Ethiopia, India, Kenya, Somalia, South Sudan & Sudan.
Cutaneous L (CL) is the most common form of leishmaniasis & causes skin lesions, mainly ulcers, on exposed parts of the body, leaving life-long scars & serious disability. About 95% of CL cases occur in the Americas, the Mediterranean basin, the Middle East & Central Asia. In 2015 over two thirds of new CL cases occurred in 6 countries: Afghanistan, Algeria, Brazil, Colombia, Iran (Islamic Republic of) & the Syrian Arab Republic. It is estimated that between 600 000 to 1 million new cases occur worldwide annually.
Mucocutaneous L leads to partial or total destruction of mucous membranes of the nose, mouth & throat. Over 90% of mucocutaneous leishmaniasis cases occur in Bolivia (the Plurinational State of), Brazil, Ethiopia & Peru.
Transmission. The epidemiology of leishmaniasis depends on the characteristics of the parasite species, the local ecological characteristics of the transmission sites, current & past exposure of the human population to the parasite, & human behaviour. Some 70 animal species, including humans, have been found as natural reservoir hosts of Leishmania parasites.
WHO regional specificities
WHO African Region
Visceral, cutaneous & mucocutaneous leishmaniasis are endemic in Algeria & countries in East Africa which are highly endemic. In East Africa, outbreaks of visceral leishmaniasis occur frequently.
WHO Region of the Americas
The epidemiology of cutaneous leishmaniasis in the Americas is very complex, with variations in transmission cycles, reservoir hosts, sandfly vectors, clinical manifestations & response to therapy, & multiple circulating Leishmania species in the same geographical area. Brazil represents over 90% of the VL cases in that region.
WHO Eastern Mediterranean Region
This region accounts for 70% of the cutaneous leishmaniasis cases worldwide. Visceral leishmaniasis is highly endemic in Iraq, Somalia & Sudan.
WHO European Region
Cutaneous & visceral leishmaniasis are endemic in this region. There are also imported cases mainly from Africa & the Americas.
WHO South-East Asia Region
Visceral leishmaniasis is the main form of the disease in this region, also endemic for cutaneous leishmaniasis. The region is the only one with a regional initiative to eliminate visceral leishmaniasis as a public health problem.
Post-kala-azar dermal leishmaniasis (PKDL)
Post-kala-azar dermal leishmaniasis (PKDL) is usually a sequel of visceral leishmaniasis that appears as macular, papular or nodular rash usually on face, upper arms, trunks & other parts of the body. It occurs mainly in East Africa & on the Indian subcontinent, where 5–10% of patients with kala-azar develop the condition. It usually appears 6 months to 1 or more years after kala-azar has apparently been cured, but can occur earlier. People with PKDL are considered to be a potential source of kala-azar infection.
Leishmania-HIV co-infection
Leishmania-HIV coinfected people have high chance of developing the full-blown clinical disease, & high relapse & mortality rates. Antiretroviral treatment reduces the development of the disease, delays relapses & increases the survival of the coinfected patients. High Leishmania-HIV coinfection rates are reported from Brazil, Ethiopia & the state of Bihar in India.
Major risk factors
Socioeconomic conditions
Poverty increases the risk for leishmaniasis. Poor housing & domestic sanitary conditions (such as a lack of waste management or open sewerage) may increase sandfly breeding & resting sites, as well as their access to humans. Sandflies are attracted to crowded housing as these provide a good source of blood-meals. Human behaviour, such as sleeping outside or on the ground, may increase risk.
Malnutrition
Diets lacking protein-energy, iron, vitamin A & zinc increase the risk that an infection will progress to kala-azar.
Population mobility
Epidemics of both cutaneous & visceral leishmaniasis are often associated with migration & the movement of non-immune people into areas with existing transmission cycles. Occupational exposure as well as widespread deforestation remain important factors.
Environmental changes
The incidence of leishmaniasis can be affected by changes in urbanization, & the human incursion into forested areas.
Climate change
Leishmaniasis is climate-sensitive.and affect the epidemiology of leishmaniasis in a number of ways:
changes in temperature, rainfall & humidity can have strong effects on vectors & reservoir hosts by altering their distribution & influencing their survival & population sizes;
small fluctuations in temperature can have a profound effect on the developmental cycle of Leishmania promastigotes in sandflies, allowing transmission of the parasite in areas not previously endemic for the disease;
drought, famine & flood can lead to massive displacement & migration of people to areas with transmission of Leishmania, & poor nutrition could compromise their immunity.
Diagnosis & treatment
In visceral leishmaniasis, diagnosis is made by combining clinical signs with parasitological, or serological tests (such as rapid diagnostic tests). In cutaneous & mucocutaneous leishmaniasis serological tests have limited value & clinical manifestation with parasitological tests confirms the diagnosis.
The treatment of leishmaniasis depends on several factors including type of disease, concomitant pathologies, parasite species & geographic location. Leishmaniasis is a treatable & curable disease, which requires an immunocompetent system because medicines will not get rid of the parasite from the body, thus the risk of relapse if immunosuppression occurs. All patients diagnosed as with visceral leishmaniasis require prompt & complete treatment. Detailed information on treatment of the various forms of the disease by geographic location is available in the WHO technical report series 949, &quot;Control of leishmaniasis&quot;.
Prevention & control
Prevention & control of leishmaniasis requires a combination of intervention strategies because transmission occurs in a complex biological system involving the human host, parasite, sandfly vector & in some causes an animal reservoir host. Key strategies for prevention are listed below:
Early diagnosis & effective treatment reduces the prevalence of the disease & prevents disabilities & death. Early detection & prompt treatment of cases help to reduce transmission & to monitor the spread & burden of disease. Currently there are highly effective & safe anti-leishmanial medicines particularly for visceral leishmaniasis. Access to these medicines has significantly improved thanks to a WHO-negotiated price scheme & a medicine donation programme through WHO.
Vector control helps to reduce or interrupt transmission of disease by controlling sandflies. Control methods include insecticide spray, use of insecticide–treated nets, environmental management & personal protection.
Effective disease surveillance is important to promptly monitor & take action during epidemics & situations with high case fatality rates under treatment.
Control of animal reservoir hosts is complex & should be tailored to the local situation.
Social mobilization & strengthening partnerships – mobilization & education of the community with effective behavioural change interventions must always use locally tailored communication strategies. Partnership & collaboration with various stakeholders & other vector-borne disease control programmes is critical.
WHO response
WHO&apos;s work on leishmaniasis control involves:
Supporting national leishmaniasis control programmes technically & financially to produce updated guidelines & make disease control plans, including sustainable, effective surveillance systems, & epidemic preparedness & response systems.
Monitoring disease trends & assessing the impact of control activities which will allow raising awareness & advocacy on the global burden of leishmaniasis, & promoting equitable access to health services.
Developing evidence-based policy guidelines, strategies & standards for leishmaniasis prevention & control, & monitoring their implementation.
Strengthening collaboration & coordination among partners, stakeholders & other bodies.
Promoting research & use of effective leishmaniasis control including safe, effective & affordable medicines, as well as diagnostic tools & vaccines.
KA: colour of skin becomes a strange earthy-gray. First noted in India in 1880. Epidemics have occurred/15-20y
Cords of Billroth (aka splenic cords/red pulp cords) are found in red pulp between sinusoids, consisting of fibrils & con. tis. cells with a large popn. of macrophages (50% of total monocytes) as a reserve so that after tissue injury they can move in for healing
RBC pass through the cords of Billroth before entering the sinusoids; the passage is seen as a bottleneck, where RBC need to be flexible in order to pass through. If RBC are abnormal in shape and/or flexibility, like spherocytosis, they fail & get phagocytosed, causing extravascular hemolysis
Red pulp (80% of a normal spleen): many sinuses engorged with blood, giving it a red color. White pulp mainly contains lymphocytes like T cells. Red pulp has several different blood cells: platelets, granulocytes, RBC, plasma
A sinusoid is an open pore capillary lacking a diaphragm (greatly increased permeability). In addition, permeability is increased by large inter-cellular clefts & fewer tight junctions. They allow small & medium-sized proteins like albumin to readily enter & leave the blood. They are found in the liver, lymphoid tissue, endocrine organs, & hematopoietic organs. Sinusoids found in terminal villi of the placenta are not comparable to these because they possess a continuous endothelium & complete basal lamina
Kupffer cells, aka stellate macrophages & Kupffer-Browicz cells, are specialized macrophages located in liver, lining sinusoids that form part of the mononuclear phagocyte system
Reticular cell
1. An undifferentiated cell of spleen, BM, lymphatic t. that can develop into several types of con. tis. cells or into a macrophage
2. A cell of reticular con. tis.; with processes making contact with those of other similar cells to form a cellular
network, making stroma of all lymphoid organs except thymus
Reticular tissue: A type of CT consisting of delicate fibers forming interlacing networks. Fibers stain selectively
with silver stains & are called argyrophil fibers. RT supports blood cells in LN, BM, & spleen
Sporotrichosis (aka &quot;rose gardener&apos;s d&quot;) is c/by fungus Sporothrix schenckii. This usually affects the skin, although other rare forms can affect the lungs, joints, bones, and even the brain
Leishmaniasis recidivans. A CL c/by L tropica & characterized by a partially healing lesion, intense granulomatous tissue that does not heal sometimes for many years
During the past 5 y, &gt;15k have been treated in BD, a country where detection was a challenge. In 2013, a total of 1284 cases were reported vs 4293 cases in 2009, a reduction of &gt;70%.
Dx in BD is based on CF & a recombinant Ag (rk39) RDT. Miltefosine was introduced in 2007 as a first-line oral Rx to replace SSG. Now LAB is used
Rh. factor (RF) is the Ab directed against an own tissues; first found in RhA. It is an Ab against the Fc of IgG & different RFs can recognize different parts of the IgG-Fc. RF & IgG join to form immune complexes that contribute to the d. process
RF can also be a cryoglobulin (Ab that precipitates on cooling). It is predominantly IgM, but can be IgA, IgG, IgE, or IgD
Warthin–Finkeldey giant cell is a giant multinucleate cell a large, grape-like cluster of nuclei found in hyperplastic LN early in measles & also in HIV-inf pts, also in Kimura disease, & more rarely in lymphomas & non-neoplastic LN d. Their origin is uncertain, but they stain with markers similar to those of follicular dendritic cells, including CD21
A liposome is a tiny bubble, made out of the same material as a cell membrane. Liposomes can be filled with drugs, & used to deliver drugs for cancer & other d. Membranes are usually made of phospholipids, which are molecules that have a head group & a tail group.
Paromomycin (monomycin/aminosidine) is an aminoglycoside, isolated from Streptomyces krestomuceticus. WHO Essential Medicine. Used to Rx gut inf. like cryptosporidiosis & amoebiasis; & leishmaniasis. It is effective in CL. Given IM & PO. Topical cream with/-out gentamicin is effective in ulcerative CL. It is a protein synthesis inhibitor. Soluble in water, it is v similar to neomycin. Effective against E coli & S aureus
Miltefosine is hexadecylphosphocholine, an alkyl phospholipid, originally intended for Ca breast & other solid T; a white powder freely soluble in water. Indicated in adults & adolescents ≥12yoa, ≥30 kg for KA, Cutaneous L., & Mucosal L. There may be geographic variation in clinical response. It has excellent antileishmanial activity
It is active against Trypanosoma sp., Entamoeba sp., Acanthamoeba sp., Schistosoma worms, pathogenic bacteria & various fungi.
Common SE: ANVD, dizziness, motion sickness, HA, weakness, AP, malaise, F, drowsiness, itching, & testicular pain
The dose is one 50 mg capsule two or three times daily (based on patient&apos;s weight) daily with food for 28 consecutive days. It may interact with other drugs. It is not recommended for use during pregnancy. It may harm a fetus. Breastfeeding should be avoided for 5 months after therapy.
Oral miltefosine effective in 85% in BD. 20% relapsed after 1y, with a final cure of 79%. the drug was not recommended in preg. So, not ideal for large-scale programs
Single-dose LAB, (AmBisome) is safe & effective &gt;97%. But, it requires cold chain.
Pentamidine is used for Px & Rx of pneumocystis pneumonia (PCP) (P jirovecii), a severe interstitial pn. often seen in HIV. It is also the mainstay of Rx for stage I inf with Trypanosoma brucei gambiense (W African). It is a WHO Essential drug. It is also used as Px against PCP in chemo- & in some organ transplantation, as they also have a depressed immunity. The mortality of untreated PCP is v high. Additionally, pentamidine has good clinical activity in L, & C albicans. It is also used as Px for leukemia. The exact mechanism of its anti-protozoal action is unknown, despite the fact that it is a basic therapeutic modality (in concurrence with multiple antifungal medications) when treating Acanthamoeba in the immunocompromised. It is currently designated an orphan drug by the FDA
Medical Care
SSG resistance is 43% in the Bihar province of India, where VL is endemic. LAB is the DoC.
The earliest s/of improvement is an improvement SS. Regression of splenomegaly takes a few mo.
Supportive Rx includes rest, high-calorie diet, BT, & Rx of 2y inf.
Resistant VL: DR can be primary or secondary. Resistance can be caused by delayed diagnosis (prolonged duration of illness), interrupted & low-dose treatment, immunological failure, emergence of resistant strains of parasites, & leishmaniasis associated with AIDS. Visceral leishmaniasis is an important opportunistic inf.associated with AIDS. Leishmaniasis in AIDS, mainly reported in southern Europe, is now observed in other parts of the world, including South America, Asia, & North Africa. Patients co-infected with HIV can develop unusual manifestations of leishmaniasis. Parasitologic diagnosis using peripheral blood smear & buffy coat smear is easier in patients with HIV co-inf.because parasites are more commonly found in the circulating monocytes of these patients.
Patients resistant to stibogluconate should be treated with alternative agents, such as liposomal amphotericin (0.5-3 mg/kg) on alternate days until a dose of 20 mg/kg or pentamidine (2-4 mg/kg) on alternate days for 15 doses. Pentamidine is available in 2 preparations: pentamidine isethionate (Pentam 300) & pentamidine dimethane sulphonate (Lomidine). However, the effectiveness of pentamidine has recently declined. Other alternatives include miltefosine, the first oral antileishmanial agent licensed for use in India.
Liposomal amphotericin is a lipid complex with amphotericin that is more active than amphotericin B. The 3 preparations formulated include amphotericin B lipid complex, liposomal amphotericin B, & amphotericin B colloidal dispersion. Cure rates of more than 90% have been observed in various studies. The high cost of this drug is a disadvantage to its use in areas where visceral leishmaniasis is prevalent.
Combination of stibogluconate with drugs, such as aminosidine & interferon gamma, has also produced good results in patients who with a poor response to stibogluconate therapy alone. Other alternatives include miltefosine, the first oral antileishmanial drug that has been licensed for use in India. Aminosidine, an aminoglycoside identical to paromomycin, has also been found to be effective in trials in India. A shift from monotherapy to multidrug combinations in short courses delivered at no or affordable cost, through directly observed therapy, appears to be the only way to effectively treat & prevent drug resistance.
Cutaneous leishmaniasis: Rx. essentially remains the same; sodium antimony gluconate & pentamidine are the drugs of choice, although some authors have indicated that a shorter course of pentamidine for 4 days has been effective in Colombia.1 Oral drugs such as ketoconazole, itraconazole, & allopurinol are also effective but only in combination with the first-line drugs. Other approaches include local application of paromomycin & intralesional stibogluconate, but these are of limited value only.
Mucocutaneous leishmaniasis: This responds to a 20-day course of sodium antimony gluconate (ie, sodium stibogluconate); resistant cases are treated with amphotericin
PKDL is a chr but not life-threatening d; pts generally do not demand Rx, but deserve much more attention as PKDL is highly relevant in the context of VL elimination. There is no standard guideline for DX & Rx for it. A species-specific PCR on slit skin smear demonstrated a sensitivity of 93.8%, but it has not been applied routinely
Guidelines for Rx of PKDL (WHO). These Guidelines are valid for BD, India, Nepal
Miltefosine is a relatively safe oral drug for PKDL. It is the preferred first-line drug. Dosage: Adults (&gt;12y; &gt;25kg: 100mg/d 1 cap (50 mg) x2, pc x 12w. &gt;12y &lt;25 kg: 50mg od in the morning pc x12w. 2-11y: 2.5 mg/kg od pc x12w. It is not to be used &lt;2y, pregnant & lactating women & women CBA who refuse to use contraceptives up to 2mo after completion of Rx & in HIV. SE: mild. 98% are not likely to present with any SE. Should any rashes or GI develop the doctor may consider stoppage & refer. Renal & hepatic functions is recommended as 1% may develop nephrotoxicity or hepatotoxicity. Amphotericin B. (2nd line drug) is recommended: if not responding, pregnancy, breast-feeding moms, children &lt;2y
PKDL with liver or kidney d: 1mg/kg/d. Route: IVI in 5% DA, over 6-8h
3 CI: CKD, severe liver & HD
Precautions: Stop if s/of renal failure & hypokalaemia. Make available emergency drugs to guard against hypersensitivity reactions. Drugs are also responsible for renal & cardiac toxicity. Therefore, the Rx of the patients under strict supervision & on indoor basis should be undertaken. Duration of Rx: Amphotericin B for up to 60-80 doses over 4 months
VL can be eliminated from Indian sub- as a PH problem due to its unique epidemiology, Dx with a RDT & an effective single dose drug (AmBisome). To do this, Gov of BD, India & Nepal signed a MoU to eliminate KA as a PHP (&lt;1/10,000, at the sub-district level) by 2015, later extended to 2017
BD leads the way in combating KA: The success of the national KA elimination program in BD offers valuable lessons for other endemic countries. KA, is the world’s 2nd biggest parasitic killer after malaria; a major NTD. But in the last few years considerable progress has been made in BD, one of the most heavily affected countries. A nation-wide elimination program initiated in 2007 has resulted in the rapid decline of new cases & CFR has dropped to almost zero. The BD experience shows that a comprehensive strategy of early Dx, Rx, surveillance & measures to control the d. can produce impressive results within a few years. In addition, clinical trials in BD led by researchers at icddr,b have provided proof that a new easy to administer & effective drug can be used on a large scale in remote, resource poor settings. But, research also points out the need for constant vigilance & greater efforts to increase detection, particularly among vulnerable groups, as the disease is likely to be underreported currently.
WHO: 200k-400k new cases of VL occur worldwide/y; 60% in our subcontinent where 186 million people are at risk. The disease burden is highest in India, followed by Bangladesh & Nepal.
KA is also notoriously difficulty to eradicate. After being cured some patients can develop PKDL (parasite lies dormant inside skin lesions). Otherwise healthy, these pts. are not likely to seek medical Rx & they can trigger a new outbreak in a few years.
Bangladesh’s three-pronged approach to eliminating KA
In 2005, with support from WHO, a National VL Elimination Program was launched to eliminate VL from subcontinent by 2015. The Bangladesh program, which kicked off in 2007, has so far seen remarkable success with new cases dropping from 10k/y before to 1463 in 2012, & a CFR now close to zero. WHO considers Bd on track to eliminate VL by 2015.
The VL elimination program in Bd has 3 main components: early detection, Rx & controlling transmission by sandflies. icddr,b scientists advised the technical working group for VL elimination & contributed to the development of the National KA Elimination guidelines & strategic plan. Scientists from icddr,b are also contributing to the dev of WHO guidelines for L control & the regional strategic plan for VL elimination from Indian subcontinent.
Early detection on a broad scale has been crucial to the success of the VL elimination program as it allows for Rx to start before pt. can transmit. The gov. has been conducting active detection of cases of VL & PKDL through “house-to-house” searches, a labour intensive but highly effective method. RDT rK39 provided a better option, enabling Dx at the community level & reaching a much larger popn. in endemic areas.
For Rx, the program adopted a number of drugs, most importantly miltefosine, which was an easy to administer, relatively safe oral Rx. provided free.
Last but not least, an integrated approach to controlling sandflies has been key to the success of program in Bd. Distribution of long-lasting insecticide-treated bed nets or mass bed net impregnation programs with slow-release insecticide tablets in the communities reduced VL incidence by 66.5%. The gov. also undertook indoor residual spraying of insecticide (deltamethrin) in endemic areas & conducted awareness raising in communities on the dangers of sandfly bites.
Researchers in Bangladesh also provided evidence on the mass usability at primary health-care centres of a more effective new Rx. that has been hailed by WHO as the preferred Rx. for VL. While oral miltefosine was considered to be the most realistic option for treating, its effectiveness is 85%. 20% relapsed after 12 mo, with a final cure rate of only 79%. It is not recommended in pregnancy & caution was advised for women of CBA. These limitations made miltefosine less than ideal. Recently an alternative single-dose LAB (AmBisome); effective in VL, with a cure rate of &gt;95% & minor SE. Combined with its relative ease of administration – a single IV infusion – it offered considerable advantages over miltefosine. Previously LAB was prohibitively expensive but in 2007 the manufacturer, Gilead, announced a price reduction of 90% (US$18/50 mg vial. Dose:10mg/kg ) for L&MIC. But, its distribution requires refrigeration. Indeed, there was little evidence to show that the drug could be effectively distributed & administered through primary health care centres in remote areas.
It is feasible to use single-dose LAB in rural PHC. While some training was needed for the paramedic staff to administer the intravenous infusion, this was found to be feasible even in the remote areas.
Pts. can now be Dx & treated for VL in 1 day. GoB decided to adopt LAB as a DoC & this Rx. will now be implemented in Nepal & India as well.
But is eradication really possible when it comes to KA?
Persistence of PKDL threatens new outbreaks of KA. Within the Indian subcontinent PKDL burden is highest in Bangladesh & therefore ongoing vigilance is needed to prevent a recurrence of KA in Bd.
In 2011 a LA Research Centre was estd. in Northern Bd. It is expected that BD will continue to lead the global conversation on KA in the years to come
National Guideline: Inj. LAB or Cap. Miltefosine
All KA & PKDL are Rx in UHC with LAB or Miltefosine
GoB received 14500 vials AmBisome from WHO
10 Upazilas are using it for Primary KA
In 2013: 554 PKA were Rx with it
730 cases of PKDL Rx with Miltefosine
Training on KA Mx. for Drs. & Nurses are going on
LAB: Liposomal Amphotericin B UHC: Upazila Health Complexes. RDT: Rapid Diagnostic test
