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Cutaneous leishmaniasis clinical spectrum management

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DR RML DELHI
DR RML DELHI

dermatology in general medicine

Health & Medicine
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INTRODUCTION â–ș Leishmaniasis are a group of infections caused by intracellular protozoan parasites belonging to the genus Leishmania, family Trypanosomatidae, order Kinetoplastida. â–ș Different names : Oriental sore, Aleppo evil, Delhi boil, Baghdad sore, Rose of Jericho, Uta, Espundia (mucocutaneous), kala-azar, Black fever (visceral)
CLASSIFICATION â–ș Depending on the extent and severity of involvement, infections in the human host can be classified as ➱ - Cutaneous leishmaniasis â–Ș New world – L.braziliensis, L.mexicana â–Ș Old world – L.major, L.tropica, L.aethiopica, L.infantum ➱ - Diffuse cutaneous leishmaniasis – L.mexicana, L.aethiopica ➱ - Mucocutaneous leishmaniasis – L.braziliensis, L.aethiopica ➱ - Visceral leishmaniasis – L.donovani, L.infantum â–ș Based on the location of enzymatically active proteins (isoenzymes), leishmaniasis has been reclassified into ZYMODEMES. Zymodemes are defined as group of leishmania organisms that share same electrophoretic migration pattern of isoenzyme
EPIDEMOLOGY â–ș VL:- Prevelant in all continents except Australia & Antarctica. â–ș Affects 88 countries worldwide & 350 million people live in these endangered zones â–ș Highest in central & South America, Southern Europe, Central Africa & parts of Southern & central Asia. â–ș CL - 1.5-2 million new cases each year â–ș 90% are in Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, Syria, Brazil and Peru.
EPIDEMOLOGY In India : â–ș VL- 90% cases in Bihar, followed by West Bengal & Eastern UP. â–ș CL – PKDL- North Eastern India â–ș L. Tropica – Delhi, HP, Punjab, Haryana, Rajasthan
TRANSMISSION â–ș Bite of an infected Sand fly â–ș Rarely – 1. Tranfusion 2. Sexual intercourse 3. Placental transfer 4. Lab accident PARASITE â–ș Obligate intracellular parasite â–ș Completes life cycle in two hosts and exists in three morphologic types: Amastogote – Non flagellate form, in macrophage / RE cells of vertebrates. Promastigote – flagellate form, in intestines of invertebrates Paramastigote – Transitional stage between two invertebrates.
VECTOR : Sandflies â–ș Phlebotomine sandfiles of genus: - Phlebotomus – Old world - Lutzomyia and Psychopygu– New World â–ș Only females are hematophagus (blood sucking) â–ș More common in warm months. â–ș Pass through ordinary mesh screens and mosquito nets. â–ș Limited flight range – 250 mt. RESERVOIR â–ș Rodents – Visceral â–ș Dogs – Cutaneous â–ș Others -rats , mice, cats, gerbits. In India, man is the most common reservoir for cutaneous leishmaniasis.
LIFE CYCLE OF LEISHMANIA Amastigate form (Inf. Mammalian tissue or blood) Midgut of female sandfly Promastigate multiplication Migrate to pharynx & proboscis Injected into new mammalian host Enter dermis Phagocytosed by macrophages Amastigate form Multiplication Disrupt macrophages Release amastigotes Enter new macrophages
IMMUNOPATHOGENESIS â–ș Susceptibility to disease depends on the T-cell & macrophage response â–ș Expansion of the Th1 subset with production of IL-2 & IFN-Îł leads to resolution of infection, while Th2 proliferation & IL-4 production leads to progression of the disease â–ș Factors that determine the type of response include ➱ Antigen presenting cells ➱ Antigenic load ➱ Type & amount of cytokines present at the time of inoculation of parasites ➱ Specific leishmanial antigen
ADHESION & ESCAPE MECHANISMS OF LEISHMANIA spp. ➱Binds lectin like binding sites on CD8+ cells & mediates adhesion to macrophages ➱Inhibits insertion of C5b9 complex in membrane, preventing lysis ➱Inhibits generation of respiratory bursts through inhibition of protein kinase C ➱Inhibition of lysosomal ÎČ galactosidase ➱Oxygen radical scavenger â–șLipophosphogly can Mechanism of interaction with host Leishmania
ADHESION & ESCAPE MECHANISMS OF LEISHMANIA spp. ➱Protease capable of degrading lysosomal enzymes ➱Degradation of hydrogen peroxide ➱Inhibition of oxidative burst â–șGlycoprotein 63 â–șSuperoxide dismutase â–șAcid phosphatase Mechanism of interaction with host Leishmania
CLINICAL FEATURES â–ș Infection with Leishmania can either lead to clinically silent disease or a spectrum of clinical signs depending on ➱ Immunological status of the individual ➱ Genetic background ➱ Nutritional status of the host ➱ Number of parasites and their virulence factors ➱ Site of inoculation ➱ Composition of sandfly saliva
Mucocutaneous form ➱Skin lesions- papules, ulcers & nodules ➱Mucosal lesions present with in 2 years of skin lesions in 50% of cases ➱ most common site is nose where it starts as a nodule on the inferior turbinate or septum f/b pharynx,palate, larynx & upper lip l/t destruction of cartilage & disfigurement – ESPUNDIA ➱Earlier seen in 80% cases but now <5% ➱Lutzomya longipalpis ➱Lu. umbratilis ➱Lu. spinicrassa ➱Lu. trapidoi ➱Lu. migonei ➱Phlebotomus yucumensis ➱P.lianosmartinsi ‱L.braziliensis ‱complex ‱L.braziliensis braziliensis ‱L.braziliensis guyanensis ‱L.braziliensis panamensis TYPE OF DISEASEVECTORAGENT
➱Visceral involvement not usually seen but death can occur due to secondary bacterial infection, pharyngeal obstruction & malnutrition TYPE OF DISEASEVECTORAGENT
➱Mucocutaneous form ➱Small erythematous papules occur at site of insect bite – ulcerated nodule – heal leaving behind a depressed scar ➱Ears are involved in 40-55% of cases ➱Cutaneous nodules are the most common presentation in Texas ➱May cause Diffuse cutaneous leishmaniasis ➱Lutzomya anthopora ➱Lutzomya diabolica ➱Lutzomya olmeca olmeca â–șL.mexicana complex â–șL.mexicana amazonensis â–șL.mexicana pifanoi â–șL.mexicana aristedesi â–șL.mexicana garnhami â–șL.mexicana venezuelensis TYPE OF DISEASEVECTORAGENT
➱Two different forma are recognized- ➱Cutaneous Andrean form – c/a UTA ➱Amazonian jungle form – has mucous membrane involvement resembling ESPUNDIA ➱Lutzomya noguchii ➱Lutzomya verrucarum ➱Lutzomya peruensis â–șL.peruviana TYPE OF DISEASEVECTORAGENT
Cutaneous form ➱c/as Oriental sore ( dry), Aleppo button, Jericho boil, Pendinnsk ulcer, Urban or Anthroponotic leishmaniasis ➱Starts as a small brownish nodule after an incubation period of about 2 months ➱Increases in size to 1-2 cms in diameter over 6 months ➱Ulcers & sores may develop which heal by permanent scarring in 8-12 months ➱P.perfiliewi ➱P.pappatasi ➱P.sergenti ➱P.longicuspis L.tropica TYPE OF DISEASEVECTORAGENT
Cutaneous form ➱Wet form of oriental sore, also c/as zoonotic or rural leishmaniasis ➱Starts as a small papule which appears immediately after insect bite or after 2-4 weeks ➱Enlarges in size & becomes crusted in center, which on removal shows an ulcer ➱Heals with depressed scar after 6-12 months but may remain active >24 months – NON HEALING CHRONIC CUTANEOUS LEISHMANIASIS ➱P.duboscqi ➱P.pappatasi ➱P.salehi ➱P.caucasicus L.major TYPE OF DISEASEVECTORAGENT
➱Sub cutaneous nodules develop along lymphatics ➱Lymph nodes are enlarged ➱No mucous membrane involvement TYPE OF DISEASEVECTORAGENT
Cutaneous form ➱Similar to L.major ➱In 20% cases, widespread involvement that resembles lepromatous leprosy â–șL.aethiopica TYPE OF DISEASEVECTORAGENT
➱Viscerocutaneous form ➱Causes MEDITERRANEAN or INFANTILE KALA AZAR ➱90% of affected people are children < 5 years ➱Cutaneous lesions are usually more inflammatory & more likely to be solitary than those caused by L.major ➱P.anasi ➱P.longicuspis ➱P.major ➱P.orientalis ➱P.perniciosus ➱P.tobbi ➱P.martini ➱P.argentipis ➱P.chinensis L.infantum TYPE OF DISEASEVECTORAGENT
LEISHMANIASIS RECIDIVANS â–ș Also c/as recurrent leishmaniasis, Metaleishmaniasis, Leishmaniasis recidiva cutis, lupoid leishmaniasis, Late cutaneous leishmaniasis â–ș Refers to development of new lesions in the center or periphery of a scar of healed lesion of leishmaniasis â–ș First reported by Berlin in cases of oriental sore â–ș Causative organism – L.tropica in middle east L.braziliensis in South America â–ș Rare in the New World, with only 11 cases reported so far â–ș Recurrent disease is due to reactivation of dormant organism, with period of dormancy ranging from 1-15 years
LEISHMANIASIS RECIDIVANS â–ș Leishmania strain in 50% of recurrent lesions are different from the initial strain, suggesting â–Ș Change in immune status of host â–Ș An exogenous re-infection â–ș Presents clinically as scaly, erythematous papules with in the scar of healed lesions â–ș sometimes ulcers, psoriasiform lesions or veruccous lesions may be present â–ș Lesions tend to resist treatment & become chronic
POST KALA AZAR LEISHMANIASIS â–ș PKDL is a complication of VL, seen in patients who have recovered from VL & who are otherwise well â–ș Seen mainly in Sudan & India, where it follows VL in 50% & 5-10% of cases respectively â–ș Causative organism is L.donovani â–ș Important role in inter epidemic periods of VL, acting as reservoir of infection â–ș Pathogenesis is immunologically mediated ➱ High conc. of serum IL-10 in VL patients predict development of PKDL ➱ production of IFN-Îł by PBMC after treatment of VL coincides with appearance of PKDL lesions
POST KALA AZAR LEISHMANIASIS TYPE OF RASH â–ș In Sudan, most common in papular or nodular rash ( 51%) ➱ Other presentstions include – maculopapular (23%) micropapular- measles like (17%) macular (9%) â–ș In India, there are 3 main presentations – ➱ Erythema & induration on butterfly area of face which shows photosensitivity ➱ Multiple symmetric hypopigmented macules which may coalesce ➱ Combination of papules, nodules & plaques
POST KALA AZAR LEISHMANIASIS â–ș Uncommon presentations include – Annular, Warty, Papillomatous, Fibroid or Xanthomatous types â–ș Ulceration is not a feature of Indian or Sudanese PKDL DISTRIBUTION â–ș In Sudanese PKDL, lesions typically appear around mouth & spread to other parts of face, then to upper arms & chest â–ș Indian PKDL also shows predilection for face & less frequently over trunk & arms â–ș After treatment, lesions around mouth remain longest & are first to recur in case of relapse â–ș In severe cases, mucosal lesions may appear on lips & palate â–ș Exposure to uv rays may be important in pathogenesis â–ș Lesions may show koebnerization
POST KALA AZAR LEISHMANIASIS CLINICAL GRADES OF SEVERITY â–ș GRADE 1 – scattered maculopapular or nodular rash over face, with or without some lesions on extremities â–ș GRADE 2 – dense maculopapular or nodular rash over face, extending to chest, back, upper arms & legs with scattered lesions on forearms & legs â–ș GRADE 3 – maculopapular or nodular rash covering most parts of body, including hands & feet; crusting, ulceration, scaling, sloughing and mucosal involvement can occur
INVESTIGATIONS I. Demonstration of parasite â–ș Direct smears – SSS- Giemsa /Wright’s or leishmanin stain. â–ș Tissue smears – from edge of lesion’s â–ș Skin Bx – from edge â–ș FNAC. â–ș Nasal mucosal scrapings –MCL. II. Culture â–ș Promastigste form is seen â–ș Various culture media include â–Ș Novy, Mcneal Nicole (NNN) media â–Ș Schneider’s culture medium. â–Ș Rabbit blood agar.
III. Animal Inoculation â–ș When parasite load in tissues is low â–ș Biopsy or aspirate specimens may be inoculated into ➱ Mouse foot pad – L. tropica L. mexicana ➱ Hamster’s foot pad – other species IV.Leishmanin skin test (Montenegro test) â–ș I/D test – Non-endemic areas – diagnostic Endemic areas – survey work. â–ș 0.1 to 0.2 ml of antigen – 5 x 106 promastigote in 1 ml of 0.5% phenolized saline. Each 0.1 ml = 1 million organisms. INVESTIGATIONS
â–ș Evokes delayed type of hypersensitivity response. â–ș Read after 48-72 hours â–ș Induration > 5mm is positive Grade I : 5-6 mm induration Grade II : 7-8 mm induration Grade III : > 8 mm induration Grade IV : Blisters â–ș Negative in VL, DCL and Indian PKDL â–ș Positive in 90-98% patients of CL, MCL and African PKDL â–ș Cannot distinguish between active & quiescent disease â–ș False +VE – Glandular tuberculosis Lepromatous leprosy INVESTIGATIONS
V. Histopathology â–ș Epidermis – Hyperkeratosis Parakeratosis Follicular plugging Basal cell degeneration - Pigmentary alterations – PKDL/VL - Atrophy – LR/MCL â–ș Dermis – Diffuse granulomas – CL, DCL, MCL, VL - Well organized granulomas – LR, PKDL - Plasma cells lymphocytes, macrophages. - Epitheloid cells – LR - Organisms in macrophages – DCL, VL & early CL INVESTIGATIONS
VI.Polymerase Chain reaction â–ș PCR Assay can detect parasite DNA or RNA a few weeks ahead of appearance of clinical signs and symptoms. â–ș PCR assay has also been used for post therapeutic follow up and for detection of relapse among HIV infected patients. â–ș A PCR-ELISA technique developed recently is reported to be sufficiently sensitive and specific for diagnosis of MCL. â–ș PCR was found to be 100% specific and sensitive method JAAD 2003 INVESTIGATIONS
INVESTIGATIONS VII. Serology â–ș More helpful in VL. â–ș Unreliable in CL – Sensitively ~ 70% Specificity – low 1. Indirect immunofluorescent antibody test (IFAT) – High specificity and sensitivity 2. ELISA – High sensitivity modification of this method – dot – ELISA is a simpler immunoassay. 3. Western blot – sensitive 4. Direct agglutination test (DAT) – specificity similar to IFAT but low sensitivity.
INVESTIGATIONS 5. Indirect immunoperoxidase assay (IPA) More sensitive and specific than IFAT 6. Immunochromatographic ( rk39) test – sensitivity & specificity of strip test are 82.4% & 100% resp. compared to 100% & 92.7% for IFAT test â–ș For cutaneous leishmamasis – diagnosis rests on finding parasite in the stains â–ș PCR is useful for confirming the diagnosis. â–ș IFAT – diagnosis in early stages.
TREATMENT OF CUTANEOUS LEISHMANIASIS â–ș CL heals spontaneously in 6 months – 1 yr without treatment, so expectant approach may be appropriate particularly in endemic area. â–ș Patients requiring active treatment are : â–Ș Lesions on cosmetically or functionally important sites such as face or hands â–Ș Associated lymphangitis â–Ș Multiple or persistant lesions â–Ș L. braziliensis/ panamensio –change into MCL. â–Ș Lesions are large or overlie a joint. Patients with MCL, DCL, PKDL do not heal without treatment and require adequate systemic therapy
TREATMENT Pentavalent antimony â–ș Antimony was first used in treatment of leishmaniasis in 1912 & in its current formulation since 1945 â–ș Only agent with clearly favourable therapeutic index â–ș Both trivalent and pentavalent compounds tried – pentavalent is less cardiotoxic. â–ș Route – I/M or I/V â–Ș I/M is preferred – ease of administration Less toxic effects. ‱ Oral and rectal route – often not tolerated by patients.
TREATMENT â–ș Preparations â–Ș Sodium stibugluconate – pentostam (UK) [100mg/ml] sodium antimony gluconate - India (SAG) â–Ș Meglumine antimonate – (85 mg/ml] Glucantime. â–Ș These two drugs are equivalent in terms of efficacy and toxicity. â–ș Dose : 20 mg/kg/day â–ș To minimize phlebitis – given as an I/V infusion in 150 ml of 5% dextrose over 2 hours.
TREATMENT Duration of treatment â–ș CL – 20 days â–ș VL – 28 days â–ș Early MCL – 28 days â–ș PKDL – at least 4 months Patient should be examined for clinical response 6 weeks after completing therapy and for 1 year for overt sign of relapse Mode of Action 1. Inhibition of synthesis of proteins, RNA and DNA – Interfering with phosphorylation of ATP and GTP which interferes with glycolysis and fatty acid oxidation. 2. Anti-inflammatory effect
TREATMENT ADVERSE EFFECTS â–ș Well tolerated , both in children and adults â–ș Common side effects include - Nausea, headache, lethargy, myalgia, arthralgia. â–ș Pain at injection site â–ș Chemical pancreatitis (increase lipase/amylase)
TREATMENT â–ș Cardio toxicity : monitered by ECG changes â–Ș Decrease T wave amplitude â–Ș T-wave inversion â–Ș Concave ST segment â–Ș QT prolongation â–ș T/T should be interrupted if : â–Ș QT > 0.5 secs. â–Ș Significant arrhythmias â–Ș 5 fold elevation of LFT â–Ș Concave ST â–ș Can be resumed cautiously after 1-2 days to avoid resistance â–ș Recurrent episodes of toxicity – switch to alternate drug.
TREATMENT â–ș Transient increase in liver enzymes â–ș Can be given safely in pregnancy Monitoring â–ș HMG, S. biochem., ECG, Amylase –twice a week Resistance 1. Primary resistance – Bihar (>30% pts. Of VL) 2. Secondary resistance – due to inadequate doses and/or duration of treatment
â–ș Intralesional treatment - For solitary uncomplicated CL lesions antimonials can be injected intralesionally. - Undiluted solution is infiltrated into the base and edges of the ulcer or nodule so that blanching occurs. - Injections are repeated every 2-3 days for 2-3 weeks. TREATMENT
TREATMENT Amphotericin B. â–ș TOC in antimony resistant patients. â–ș Polyene antibiotic from Streptomyces nodosus. â–ș Route – slow i/v with 5% dextaose. Mechanism of action : 1. Interference with permeability of cell membrane. 2. Immuno modulatory effects. Dose â–ș intital test dose – 1 mg â–ș usual daily dose ; started with 250 ”g / kg/ day – gradually increased to 1mg/kg/day infused over 2-4 hours.
TREATMENT Adverse effects ➱ Hypersensitivity reactions – fever, rigors, hypotension, nausea, vomiting, tinitus, bronchospasm, anaphylactoid reaction. ➱ Phelbitis at site of injection ➱ Nephrotoxicity : in almost 100% patients â–Ș Both glomerular and tubular damage â–Ș RTA â–Ș Incresed excretion of K & Mg l/t hypokalemia & hypomagnesiumia â–Ș Nephrocalcinosis . ➱ Reversible normocytic normochromic anaemia ➱ Visual disturbances ➱ Ventricular arrhythmias – sudden cardiac arrest – with high dose or rapid infusion
TREATMENT LIPID – associated Amphotericin B â–ș Three formulations are available i) Liposomal (Am Bisome) ii) Colloidal dispersion (ABCD) iii) Lipid complex (ABLC) â–ș Advantages ➱ Rapidly effective ➱ Taken up by macrophages and reaches high concentration at infection site ➱ Less s/e - no nephrotoxicity - no local toxicity ➱ Can be used at higher doses – 3-4 mg/kg â–ș Disadvantages : More expensive
TREATMENT Physical Modalities â–ș Local heat : attractive, non toxic, inexpensive & simple treatment option ‱ infrared radiation used to raise the skin temperature to 55 C for 5 min â–ș L. braziliensis and L. mexicana are particularly heat sensitive. â–ș Mechanism of action Inhibition of amastigote replication 90% cure rate with single treatment with infra-red radiation 99% cure rate with two treatments.
TREATMENT â–ș Cryotherapy : Useful for small lesions (<1 cm diameter) â–Ș 30-90 sec cryoapplications performed with CO2 cryosurgical machine with 1 cm cryoprobe tip, include the skin 2 mm outside the lesions â–Ș Complete response reported with average of 2 treatments. â–Ș A large controlled study in Saudi Arabia showed the success rate to be <30% with NO cryomachine â–Ș Combination of cryotherapy & I/L stibugluconate superior to either alone â–ș Other physical modalities used are ➱ CO2 laser ➱ curretage ➱ electrodessication ➱ surgical excision
TREATMENT TRADITIONAL ANTI-INFECTIVE AGENTS â–ș Dapsone : 200 mg/day for 45 days cure rate – 82% (Dogra et al) ➱ Exact mechanism not known, thought to decrease phospholipid synthesis and /or interfere with folic acid synthesis. â–ș Rifampin : 600-1200 mg/day (0-80% cure rate) â–ș Metronidazole : 250 mg tds for 10 days,3 cycles with 10 days rest (Pederson et al) ➱ 78% recovery rate with 250 mg bd for 15 days in L.mexicana infection ( Beltran et al,1967 ) ➱ subsequent studies – no clinical improvement.
TREATMENT â–ș Cotrimoxazole : 160/ 800 mg BD for 4 weeks ➱ 33 of 36 pts. showed resolution in 3-14 weeks (Kandil, 1973) ➱ Efficacy similar to placebo in subsequent studies. ‱ Allopurinol : 20 mg/kg/day for 28 days ➱ A large placebo controlled double blinded study from Colombia concluded that allopurinol monotherapy is ineffective against Colombian cutaneous disease and is unlikely to be effective against cutaneous disease due to other organisms ➱ Combined therapy with allopurinol & meglumine antimoniate has shown better response than either of the two drugs used alone JAAD 2002
TREATMENT Oral Azoles â–ș Ketoconazole : 200-400 mg /day x 4 wks. â–Ș 70% cure rate – L. major (Weinrauch et al) â–Ș ineffective in – L. tropica and aethiopica. â–Ș 89% cure rate – L. mexicana â–ș Itraconazole : 200 mg/ day x 4-8 wks â–Ș 79% cure rate – old world CL (IJD – 1994) â–Ș 66% cure rate from India (Dogra et al – IJD 1990)
TREATMENT â–ș TOPICAL AGENTS â–ș Topical paromomycin 15% in methylbenzethoniumchloride applied twice daily for 10-30 days is effective in Israel in L.major CL â–ș In open study, topical paromomycin was found to be equally effective as i/l meglumine antimoniate for treatment of L.major CL Euj J Dermatol 2005
â–ș Pentamidine â–ș For cutaneous leishmaniasis the high cure rate associated with low dose of pentamidine given for a shorter period makes it an attractive alternative to sodium stibugluoconate and treatment of choice in cases of Stibugluconate treatment failure. â–ș Pentamidine mesylate and isethionate are safe and effective drugs in treatment of New World CL (Esther J.S. et al ) 32/38 (84)2 mg/kg q.o.d., 4Open-label nonrandomized 23/24 (96)2 mg/kg q.o.d., 7Open-label nonrandomized No. of patients cured/total no. of patents (%) Dosage/no. of injections Study design Efficacy of pentamidine regimens for the treatment of cutaneous leishmaniasis in Colombia.
TREATMENT â–ș ADVERSE EFFECTS â–ș Hypotension, hypoglycemia, severe myalgias, intractable headaches â–ș GI s/e – nausea, vomiting â–ș Leukopenia â–ș Neuropathy â–ș Hepatotoxicity
TREATMENT Miltefosine â–ș Phosphorylcholine ester of hexadecanol, a membrane active alkylphospholipid â–ș First effective oral agent for VL, including antimony resistant cases. â–ș Topical treatment with miltefosine has been shown to efficiently reduce parasite load in experimental cutaneous leishmaniasis. â–ș In an open label study in Colombia, 4 weeks treatment with 133 and 150 mg of miltefosine daily cured 100% and 89% respectively – American cutaneous leishmaneasis (Soto J et al 2001)
TREATMENT â–ș In a controlled study in Columbia & Guatemala, miltefosine given in a dose of 2.5 mg/kg body weight for 28 days produced 91% cure rate for L.panamensis infection and 50% cure rate for L. braziliensis & L. mexicana compared to 38% & 20% for placebo respectively â–ș Was well tolerated, adverse effects seen were mostly nausea, mild elevation in creatinine levels Trans R Soc Trop Med Hyg. 2006
TREATMENT â–ș In a trial comparing the efficacy of miltefosine & sodium stibugluconate in treatment of VL in an Ethopian population with high prevelance of HIV infection, there was 88% initial cure rate in both the groups, mortality was 2% & initial treatment failure 8% with miltefosine compared to 8% & 1% resp with SSG â–ș Among HIV+ patients, cure rate, relapse rate & mortality in miltefosine group was 60%, 10% & 6% compared to 65%, 2% & 12% with SSG. â–ș In HIV+ patients, miltefosine is a much safer, though slightly less effective than SSG in treatment of leishmaniasis Clin Infect Dis,2006
TREATMENT Photodynamic Therapy â–ș In a randomized placebo controlled trial, efficacy of Photodynamic therapy was compared with paromomycin & placebo â–ș Group 1 was treated with weekly topical PDT, and groups 2 and 3 received twice-daily topical paromomycin and placebo, respectively. The duration of treatment was 4 weeks for all groups. These groups were followed for 2 months after the end of treatment. â–ș At the end of the study, complete improvement was seen in 29 of 31 (93.5%), 14 of 34 (41.2%) and 4 of 30 lesions (13.3%) in groups 1, 2 and 3, respectively (P<0.001). At the same time point, 100%, 64.7% and 20% of the lesions had parasitological cure in group 1, 2 and 3, respectively (P<0.001)
TREATMENT Immunotherapy ‱ Interferon-Îł – Intralesional treatment has been tried for cutaneous lesions ➱ In one study in L. braziliensis infection, 12 of 13 lesions became smaller after injection. ➱ IFN-Îł was also compared with antomony. â–Ș I/L infiltration once a week x 5 weeks â–Ș 100% cure rate with antomony treated lesions Vs 38% of IFN-Îł treated lesions – L. tropica ‱ Recombinent IL-2 has been used to treat a few patients with disseminated cutaneous leishmaniasis.
TREATMENT Immunochemotherapy In a double-blind placebo controlled study of 102 patients with American CL, combination of a single –strain leishmania amazonensis killed promastiote vaccine with half dose of amtimonial – 100% cure rate after 4 series of treatments [10-day series at an interval of 10 days] compared to 82% in control group. IJD 2002
TREATMENT â–ș Imiquimod ➱ Another topical agent under investigation for cutaneous leishmaniasis ➱ Immunomodulator developed to geintal warts. ➱ It produced 90% cure rate in patients who had failed to respond to antimonials alone when it was used in conjunction with antimonials in peru. (Arevaloi et al) Clin Infect Dis 2001 ➱ 5% Imiquomod with or without I/L meglumine antimoniate is more effective than I/L meglumine antimoniate alone in treatment of old world CL JAAD 2005
LEISHMANIASIS IN HIV INFECTION â–ș VL is the fourth most common opportunistic parasitic disease in HIV-positive individuals â–ș VL promotes the development of AIDS-defining conditions and HIV infection increases the development of VL by 100-1000 times in endemic areas, reduces the therapeutic response & increases the relapse rate â–ș Leishmania/HIV co-infection has so far been reported from 33 countries worldwide, most commonly from Brazil (in Americas) and India ( in Asia) â–ș Introduction of HAART decreases the incidence of leishmania infection in HIV positive patients
LEISHMANIASIS IN HIV INFECTION â–ș Cutaneous involvement is seen in 2-12% of patients with leishmania/HIV co-infection â–ș Causes a variable spectrum of lesions – papular, maculopapular & nodular â–ș Leishmania amastigotes have been found in apparently normal skin, infestating sweat ducts, & co-existing with lesions of KS, HSV & HZV â–ș Leishmania is also associated with changes attributable to other dermatological processes like dermatofibroma, psoriasis, Reiters disease, bacillary angiomatosis, cryptococcosis & oral aphthae
LEISHMANIASIS IN HIV INFECTION â–ș Can present as dermatomyositis like eruption ➱ mucocutaneous & mucosal leishmaniasis ➱ post kala-azar leishmaniasis â–ș Primary cutaneous lesions can visceralize in severely immunodepressed patients
LEISHMANIASIS IN HIV INFECTION DIAGNOSIS â–ș Gold standard for diagnosis of leishmsniasis in HIV infected individuals remains the isolation or identification of parasite from appropriate tissue â–ș Detection of leishmania amastigotes & antigens in peripheral blood has sensitivity of 50% which increases to 70% after culture â–ș New PCR techniques like detecting highly variable regions of kinetoplast DNA & nested PCR have a sensitivity of 95.45% in peripheral blood & 100% in bone marrow
LEISHMANIASIS IN HIV INFECTION TREATMENT â–ș Duration of treatment has to be prolonged until 4 weeks â–ș More likely to suffer from adverse events â–ș Low rate of clinical & parasitological response – 60% with antimonials or with amphoterecin B â–ș 25-60% patients experience relapse during first year after completing treatment â–ș Combining antimonials with allopurinol/IFN-Îł useful in refractory cases or in relapses
LEISHMANIASIS IN HIV INFECTION SECONDARY PROPHYLAXIS â–ș Antimonials 20 mg/kg once a month – some degree of efficacy is seen â–ș Pentamidine every 3-4 weeks â–ș liposomal AMB every 2 weeks â–ș Allopurinol/ itraconazole Usually withdrawn when CD4+ cell count > 200/”l
â–ș My references are :- ➱ Textbook of dermatology –Rook Fitzpatrick ➱ J Postgrad Med 2003 ➱ J Am Acad Dermatol 1994, 1996 ➱ Clin Infect Dis. 1997, 2001, 2006 ➱ Drugs 1998; 56: 1009-1018 ➱ Int. J. Dermatol 1994, 1998, 2002 ➱ Trans R Soc Trop Med Hyg. 2006 ➱ Clin Exp Dermatol 2006

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Cutaneous leishmaniasis clinical spectrum management

  • 1. INTRODUCTION â–ș Leishmaniasis are a group of infections caused by intracellular protozoan parasites belonging to the genus Leishmania, family Trypanosomatidae, order Kinetoplastida. â–ș Different names : Oriental sore, Aleppo evil, Delhi boil, Baghdad sore, Rose of Jericho, Uta, Espundia (mucocutaneous), kala-azar, Black fever (visceral)
  • 2. CLASSIFICATION â–ș Depending on the extent and severity of involvement, infections in the human host can be classified as ➱ - Cutaneous leishmaniasis â–Ș New world – L.braziliensis, L.mexicana â–Ș Old world – L.major, L.tropica, L.aethiopica, L.infantum ➱ - Diffuse cutaneous leishmaniasis – L.mexicana, L.aethiopica ➱ - Mucocutaneous leishmaniasis – L.braziliensis, L.aethiopica ➱ - Visceral leishmaniasis – L.donovani, L.infantum â–ș Based on the location of enzymatically active proteins (isoenzymes), leishmaniasis has been reclassified into ZYMODEMES. Zymodemes are defined as group of leishmania organisms that share same electrophoretic migration pattern of isoenzyme
  • 3. EPIDEMOLOGY â–ș VL:- Prevelant in all continents except Australia & Antarctica. â–ș Affects 88 countries worldwide & 350 million people live in these endangered zones â–ș Highest in central & South America, Southern Europe, Central Africa & parts of Southern & central Asia. â–ș CL - 1.5-2 million new cases each year â–ș 90% are in Afghanistan, Algeria, Iran, Iraq, Saudi Arabia, Syria, Brazil and Peru.
  • 4. EPIDEMOLOGY In India : â–ș VL- 90% cases in Bihar, followed by West Bengal & Eastern UP. â–ș CL – PKDL- North Eastern India â–ș L. Tropica – Delhi, HP, Punjab, Haryana, Rajasthan
  • 5. TRANSMISSION â–ș Bite of an infected Sand fly â–ș Rarely – 1. Tranfusion 2. Sexual intercourse 3. Placental transfer 4. Lab accident PARASITE â–ș Obligate intracellular parasite â–ș Completes life cycle in two hosts and exists in three morphologic types: Amastogote – Non flagellate form, in macrophage / RE cells of vertebrates. Promastigote – flagellate form, in intestines of invertebrates Paramastigote – Transitional stage between two invertebrates.
  • 6. VECTOR : Sandflies â–ș Phlebotomine sandfiles of genus: - Phlebotomus – Old world - Lutzomyia and Psychopygu– New World â–ș Only females are hematophagus (blood sucking) â–ș More common in warm months. â–ș Pass through ordinary mesh screens and mosquito nets. â–ș Limited flight range – 250 mt. RESERVOIR â–ș Rodents – Visceral â–ș Dogs – Cutaneous â–ș Others -rats , mice, cats, gerbits. In India, man is the most common reservoir for cutaneous leishmaniasis.
  • 7. LIFE CYCLE OF LEISHMANIA Amastigate form (Inf. Mammalian tissue or blood) Midgut of female sandfly Promastigate multiplication Migrate to pharynx & proboscis Injected into new mammalian host Enter dermis Phagocytosed by macrophages Amastigate form Multiplication Disrupt macrophages Release amastigotes Enter new macrophages
  • 8. IMMUNOPATHOGENESIS â–ș Susceptibility to disease depends on the T-cell & macrophage response â–ș Expansion of the Th1 subset with production of IL-2 & IFN-Îł leads to resolution of infection, while Th2 proliferation & IL-4 production leads to progression of the disease â–ș Factors that determine the type of response include ➱ Antigen presenting cells ➱ Antigenic load ➱ Type & amount of cytokines present at the time of inoculation of parasites ➱ Specific leishmanial antigen
  • 9. ADHESION & ESCAPE MECHANISMS OF LEISHMANIA spp. ➱Binds lectin like binding sites on CD8+ cells & mediates adhesion to macrophages ➱Inhibits insertion of C5b9 complex in membrane, preventing lysis ➱Inhibits generation of respiratory bursts through inhibition of protein kinase C ➱Inhibition of lysosomal ÎČ galactosidase ➱Oxygen radical scavenger â–șLipophosphogly can Mechanism of interaction with host Leishmania
  • 10. ADHESION & ESCAPE MECHANISMS OF LEISHMANIA spp. ➱Protease capable of degrading lysosomal enzymes ➱Degradation of hydrogen peroxide ➱Inhibition of oxidative burst â–șGlycoprotein 63 â–șSuperoxide dismutase â–șAcid phosphatase Mechanism of interaction with host Leishmania
  • 11. CLINICAL FEATURES â–ș Infection with Leishmania can either lead to clinically silent disease or a spectrum of clinical signs depending on ➱ Immunological status of the individual ➱ Genetic background ➱ Nutritional status of the host ➱ Number of parasites and their virulence factors ➱ Site of inoculation ➱ Composition of sandfly saliva
  • 12. Mucocutaneous form ➱Skin lesions- papules, ulcers & nodules ➱Mucosal lesions present with in 2 years of skin lesions in 50% of cases ➱ most common site is nose where it starts as a nodule on the inferior turbinate or septum f/b pharynx,palate, larynx & upper lip l/t destruction of cartilage & disfigurement – ESPUNDIA ➱Earlier seen in 80% cases but now <5% ➱Lutzomya longipalpis ➱Lu. umbratilis ➱Lu. spinicrassa ➱Lu. trapidoi ➱Lu. migonei ➱Phlebotomus yucumensis ➱P.lianosmartinsi ‱L.braziliensis ‱complex ‱L.braziliensis braziliensis ‱L.braziliensis guyanensis ‱L.braziliensis panamensis TYPE OF DISEASEVECTORAGENT
  • 13. ➱Visceral involvement not usually seen but death can occur due to secondary bacterial infection, pharyngeal obstruction & malnutrition TYPE OF DISEASEVECTORAGENT
  • 14.
  • 15.
  • 16. ➱Mucocutaneous form ➱Small erythematous papules occur at site of insect bite – ulcerated nodule – heal leaving behind a depressed scar ➱Ears are involved in 40-55% of cases ➱Cutaneous nodules are the most common presentation in Texas ➱May cause Diffuse cutaneous leishmaniasis ➱Lutzomya anthopora ➱Lutzomya diabolica ➱Lutzomya olmeca olmeca â–șL.mexicana complex â–șL.mexicana amazonensis â–șL.mexicana pifanoi â–șL.mexicana aristedesi â–șL.mexicana garnhami â–șL.mexicana venezuelensis TYPE OF DISEASEVECTORAGENT
  • 17.
  • 18. ➱Two different forma are recognized- ➱Cutaneous Andrean form – c/a UTA ➱Amazonian jungle form – has mucous membrane involvement resembling ESPUNDIA ➱Lutzomya noguchii ➱Lutzomya verrucarum ➱Lutzomya peruensis â–șL.peruviana TYPE OF DISEASEVECTORAGENT
  • 19.
  • 20. Cutaneous form ➱c/as Oriental sore ( dry), Aleppo button, Jericho boil, Pendinnsk ulcer, Urban or Anthroponotic leishmaniasis ➱Starts as a small brownish nodule after an incubation period of about 2 months ➱Increases in size to 1-2 cms in diameter over 6 months ➱Ulcers & sores may develop which heal by permanent scarring in 8-12 months ➱P.perfiliewi ➱P.pappatasi ➱P.sergenti ➱P.longicuspis L.tropica TYPE OF DISEASEVECTORAGENT
  • 21.
  • 22. Cutaneous form ➱Wet form of oriental sore, also c/as zoonotic or rural leishmaniasis ➱Starts as a small papule which appears immediately after insect bite or after 2-4 weeks ➱Enlarges in size & becomes crusted in center, which on removal shows an ulcer ➱Heals with depressed scar after 6-12 months but may remain active >24 months – NON HEALING CHRONIC CUTANEOUS LEISHMANIASIS ➱P.duboscqi ➱P.pappatasi ➱P.salehi ➱P.caucasicus L.major TYPE OF DISEASEVECTORAGENT
  • 23. ➱Sub cutaneous nodules develop along lymphatics ➱Lymph nodes are enlarged ➱No mucous membrane involvement TYPE OF DISEASEVECTORAGENT
  • 24.
  • 25.
  • 26. Cutaneous form ➱Similar to L.major ➱In 20% cases, widespread involvement that resembles lepromatous leprosy â–șL.aethiopica TYPE OF DISEASEVECTORAGENT
  • 27.
  • 28. ➱Viscerocutaneous form ➱Causes MEDITERRANEAN or INFANTILE KALA AZAR ➱90% of affected people are children < 5 years ➱Cutaneous lesions are usually more inflammatory & more likely to be solitary than those caused by L.major ➱P.anasi ➱P.longicuspis ➱P.major ➱P.orientalis ➱P.perniciosus ➱P.tobbi ➱P.martini ➱P.argentipis ➱P.chinensis L.infantum TYPE OF DISEASEVECTORAGENT
  • 29. LEISHMANIASIS RECIDIVANS â–ș Also c/as recurrent leishmaniasis, Metaleishmaniasis, Leishmaniasis recidiva cutis, lupoid leishmaniasis, Late cutaneous leishmaniasis â–ș Refers to development of new lesions in the center or periphery of a scar of healed lesion of leishmaniasis â–ș First reported by Berlin in cases of oriental sore â–ș Causative organism – L.tropica in middle east L.braziliensis in South America â–ș Rare in the New World, with only 11 cases reported so far â–ș Recurrent disease is due to reactivation of dormant organism, with period of dormancy ranging from 1-15 years
  • 30. LEISHMANIASIS RECIDIVANS â–ș Leishmania strain in 50% of recurrent lesions are different from the initial strain, suggesting â–Ș Change in immune status of host â–Ș An exogenous re-infection â–ș Presents clinically as scaly, erythematous papules with in the scar of healed lesions â–ș sometimes ulcers, psoriasiform lesions or veruccous lesions may be present â–ș Lesions tend to resist treatment & become chronic
  • 31.
  • 32. POST KALA AZAR LEISHMANIASIS â–ș PKDL is a complication of VL, seen in patients who have recovered from VL & who are otherwise well â–ș Seen mainly in Sudan & India, where it follows VL in 50% & 5-10% of cases respectively â–ș Causative organism is L.donovani â–ș Important role in inter epidemic periods of VL, acting as reservoir of infection â–ș Pathogenesis is immunologically mediated ➱ High conc. of serum IL-10 in VL patients predict development of PKDL ➱ production of IFN-Îł by PBMC after treatment of VL coincides with appearance of PKDL lesions
  • 33.
  • 34. POST KALA AZAR LEISHMANIASIS TYPE OF RASH â–ș In Sudan, most common in papular or nodular rash ( 51%) ➱ Other presentstions include – maculopapular (23%) micropapular- measles like (17%) macular (9%) â–ș In India, there are 3 main presentations – ➱ Erythema & induration on butterfly area of face which shows photosensitivity ➱ Multiple symmetric hypopigmented macules which may coalesce ➱ Combination of papules, nodules & plaques
  • 35.
  • 36. POST KALA AZAR LEISHMANIASIS â–ș Uncommon presentations include – Annular, Warty, Papillomatous, Fibroid or Xanthomatous types â–ș Ulceration is not a feature of Indian or Sudanese PKDL DISTRIBUTION â–ș In Sudanese PKDL, lesions typically appear around mouth & spread to other parts of face, then to upper arms & chest â–ș Indian PKDL also shows predilection for face & less frequently over trunk & arms â–ș After treatment, lesions around mouth remain longest & are first to recur in case of relapse â–ș In severe cases, mucosal lesions may appear on lips & palate â–ș Exposure to uv rays may be important in pathogenesis â–ș Lesions may show koebnerization
  • 37. POST KALA AZAR LEISHMANIASIS CLINICAL GRADES OF SEVERITY â–ș GRADE 1 – scattered maculopapular or nodular rash over face, with or without some lesions on extremities â–ș GRADE 2 – dense maculopapular or nodular rash over face, extending to chest, back, upper arms & legs with scattered lesions on forearms & legs â–ș GRADE 3 – maculopapular or nodular rash covering most parts of body, including hands & feet; crusting, ulceration, scaling, sloughing and mucosal involvement can occur
  • 38. INVESTIGATIONS I. Demonstration of parasite â–ș Direct smears – SSS- Giemsa /Wright’s or leishmanin stain. â–ș Tissue smears – from edge of lesion’s â–ș Skin Bx – from edge â–ș FNAC. â–ș Nasal mucosal scrapings –MCL. II. Culture â–ș Promastigste form is seen â–ș Various culture media include â–Ș Novy, Mcneal Nicole (NNN) media â–Ș Schneider’s culture medium. â–Ș Rabbit blood agar.
  • 39.
  • 40. III. Animal Inoculation â–ș When parasite load in tissues is low â–ș Biopsy or aspirate specimens may be inoculated into ➱ Mouse foot pad – L. tropica L. mexicana ➱ Hamster’s foot pad – other species IV.Leishmanin skin test (Montenegro test) â–ș I/D test – Non-endemic areas – diagnostic Endemic areas – survey work. â–ș 0.1 to 0.2 ml of antigen – 5 x 106 promastigote in 1 ml of 0.5% phenolized saline. Each 0.1 ml = 1 million organisms. INVESTIGATIONS
  • 41. â–ș Evokes delayed type of hypersensitivity response. â–ș Read after 48-72 hours â–ș Induration > 5mm is positive Grade I : 5-6 mm induration Grade II : 7-8 mm induration Grade III : > 8 mm induration Grade IV : Blisters â–ș Negative in VL, DCL and Indian PKDL â–ș Positive in 90-98% patients of CL, MCL and African PKDL â–ș Cannot distinguish between active & quiescent disease â–ș False +VE – Glandular tuberculosis Lepromatous leprosy INVESTIGATIONS
  • 42. V. Histopathology â–ș Epidermis – Hyperkeratosis Parakeratosis Follicular plugging Basal cell degeneration - Pigmentary alterations – PKDL/VL - Atrophy – LR/MCL â–ș Dermis – Diffuse granulomas – CL, DCL, MCL, VL - Well organized granulomas – LR, PKDL - Plasma cells lymphocytes, macrophages. - Epitheloid cells – LR - Organisms in macrophages – DCL, VL & early CL INVESTIGATIONS
  • 43.
  • 44.
  • 45. VI.Polymerase Chain reaction â–ș PCR Assay can detect parasite DNA or RNA a few weeks ahead of appearance of clinical signs and symptoms. â–ș PCR assay has also been used for post therapeutic follow up and for detection of relapse among HIV infected patients. â–ș A PCR-ELISA technique developed recently is reported to be sufficiently sensitive and specific for diagnosis of MCL. â–ș PCR was found to be 100% specific and sensitive method JAAD 2003 INVESTIGATIONS
  • 46. INVESTIGATIONS VII. Serology â–ș More helpful in VL. â–ș Unreliable in CL – Sensitively ~ 70% Specificity – low 1. Indirect immunofluorescent antibody test (IFAT) – High specificity and sensitivity 2. ELISA – High sensitivity modification of this method – dot – ELISA is a simpler immunoassay. 3. Western blot – sensitive 4. Direct agglutination test (DAT) – specificity similar to IFAT but low sensitivity.
  • 47. INVESTIGATIONS 5. Indirect immunoperoxidase assay (IPA) More sensitive and specific than IFAT 6. Immunochromatographic ( rk39) test – sensitivity & specificity of strip test are 82.4% & 100% resp. compared to 100% & 92.7% for IFAT test â–ș For cutaneous leishmamasis – diagnosis rests on finding parasite in the stains â–ș PCR is useful for confirming the diagnosis. â–ș IFAT – diagnosis in early stages.
  • 48. TREATMENT OF CUTANEOUS LEISHMANIASIS â–ș CL heals spontaneously in 6 months – 1 yr without treatment, so expectant approach may be appropriate particularly in endemic area. â–ș Patients requiring active treatment are : â–Ș Lesions on cosmetically or functionally important sites such as face or hands â–Ș Associated lymphangitis â–Ș Multiple or persistant lesions â–Ș L. braziliensis/ panamensio –change into MCL. â–Ș Lesions are large or overlie a joint. Patients with MCL, DCL, PKDL do not heal without treatment and require adequate systemic therapy
  • 49. TREATMENT Pentavalent antimony â–ș Antimony was first used in treatment of leishmaniasis in 1912 & in its current formulation since 1945 â–ș Only agent with clearly favourable therapeutic index â–ș Both trivalent and pentavalent compounds tried – pentavalent is less cardiotoxic. â–ș Route – I/M or I/V â–Ș I/M is preferred – ease of administration Less toxic effects. ‱ Oral and rectal route – often not tolerated by patients.
  • 50. TREATMENT â–ș Preparations â–Ș Sodium stibugluconate – pentostam (UK) [100mg/ml] sodium antimony gluconate - India (SAG) â–Ș Meglumine antimonate – (85 mg/ml] Glucantime. â–Ș These two drugs are equivalent in terms of efficacy and toxicity. â–ș Dose : 20 mg/kg/day â–ș To minimize phlebitis – given as an I/V infusion in 150 ml of 5% dextrose over 2 hours.
  • 51. TREATMENT Duration of treatment â–ș CL – 20 days â–ș VL – 28 days â–ș Early MCL – 28 days â–ș PKDL – at least 4 months Patient should be examined for clinical response 6 weeks after completing therapy and for 1 year for overt sign of relapse Mode of Action 1. Inhibition of synthesis of proteins, RNA and DNA – Interfering with phosphorylation of ATP and GTP which interferes with glycolysis and fatty acid oxidation. 2. Anti-inflammatory effect
  • 52. TREATMENT ADVERSE EFFECTS â–ș Well tolerated , both in children and adults â–ș Common side effects include - Nausea, headache, lethargy, myalgia, arthralgia. â–ș Pain at injection site â–ș Chemical pancreatitis (increase lipase/amylase)
  • 53. TREATMENT â–ș Cardio toxicity : monitered by ECG changes â–Ș Decrease T wave amplitude â–Ș T-wave inversion â–Ș Concave ST segment â–Ș QT prolongation â–ș T/T should be interrupted if : â–Ș QT > 0.5 secs. â–Ș Significant arrhythmias â–Ș 5 fold elevation of LFT â–Ș Concave ST â–ș Can be resumed cautiously after 1-2 days to avoid resistance â–ș Recurrent episodes of toxicity – switch to alternate drug.
  • 54. TREATMENT â–ș Transient increase in liver enzymes â–ș Can be given safely in pregnancy Monitoring â–ș HMG, S. biochem., ECG, Amylase –twice a week Resistance 1. Primary resistance – Bihar (>30% pts. Of VL) 2. Secondary resistance – due to inadequate doses and/or duration of treatment
  • 55. â–ș Intralesional treatment - For solitary uncomplicated CL lesions antimonials can be injected intralesionally. - Undiluted solution is infiltrated into the base and edges of the ulcer or nodule so that blanching occurs. - Injections are repeated every 2-3 days for 2-3 weeks. TREATMENT
  • 56. TREATMENT Amphotericin B. â–ș TOC in antimony resistant patients. â–ș Polyene antibiotic from Streptomyces nodosus. â–ș Route – slow i/v with 5% dextaose. Mechanism of action : 1. Interference with permeability of cell membrane. 2. Immuno modulatory effects. Dose â–ș intital test dose – 1 mg â–ș usual daily dose ; started with 250 ”g / kg/ day – gradually increased to 1mg/kg/day infused over 2-4 hours.
  • 57. TREATMENT Adverse effects ➱ Hypersensitivity reactions – fever, rigors, hypotension, nausea, vomiting, tinitus, bronchospasm, anaphylactoid reaction. ➱ Phelbitis at site of injection ➱ Nephrotoxicity : in almost 100% patients â–Ș Both glomerular and tubular damage â–Ș RTA â–Ș Incresed excretion of K & Mg l/t hypokalemia & hypomagnesiumia â–Ș Nephrocalcinosis . ➱ Reversible normocytic normochromic anaemia ➱ Visual disturbances ➱ Ventricular arrhythmias – sudden cardiac arrest – with high dose or rapid infusion
  • 58. TREATMENT LIPID – associated Amphotericin B â–ș Three formulations are available i) Liposomal (Am Bisome) ii) Colloidal dispersion (ABCD) iii) Lipid complex (ABLC) â–ș Advantages ➱ Rapidly effective ➱ Taken up by macrophages and reaches high concentration at infection site ➱ Less s/e - no nephrotoxicity - no local toxicity ➱ Can be used at higher doses – 3-4 mg/kg â–ș Disadvantages : More expensive
  • 59. TREATMENT Physical Modalities â–ș Local heat : attractive, non toxic, inexpensive & simple treatment option ‱ infrared radiation used to raise the skin temperature to 55 C for 5 min â–ș L. braziliensis and L. mexicana are particularly heat sensitive. â–ș Mechanism of action Inhibition of amastigote replication 90% cure rate with single treatment with infra-red radiation 99% cure rate with two treatments.
  • 60. TREATMENT â–ș Cryotherapy : Useful for small lesions (<1 cm diameter) â–Ș 30-90 sec cryoapplications performed with CO2 cryosurgical machine with 1 cm cryoprobe tip, include the skin 2 mm outside the lesions â–Ș Complete response reported with average of 2 treatments. â–Ș A large controlled study in Saudi Arabia showed the success rate to be <30% with NO cryomachine â–Ș Combination of cryotherapy & I/L stibugluconate superior to either alone â–ș Other physical modalities used are ➱ CO2 laser ➱ curretage ➱ electrodessication ➱ surgical excision
  • 61. TREATMENT TRADITIONAL ANTI-INFECTIVE AGENTS â–ș Dapsone : 200 mg/day for 45 days cure rate – 82% (Dogra et al) ➱ Exact mechanism not known, thought to decrease phospholipid synthesis and /or interfere with folic acid synthesis. â–ș Rifampin : 600-1200 mg/day (0-80% cure rate) â–ș Metronidazole : 250 mg tds for 10 days,3 cycles with 10 days rest (Pederson et al) ➱ 78% recovery rate with 250 mg bd for 15 days in L.mexicana infection ( Beltran et al,1967 ) ➱ subsequent studies – no clinical improvement.
  • 62. TREATMENT â–ș Cotrimoxazole : 160/ 800 mg BD for 4 weeks ➱ 33 of 36 pts. showed resolution in 3-14 weeks (Kandil, 1973) ➱ Efficacy similar to placebo in subsequent studies. ‱ Allopurinol : 20 mg/kg/day for 28 days ➱ A large placebo controlled double blinded study from Colombia concluded that allopurinol monotherapy is ineffective against Colombian cutaneous disease and is unlikely to be effective against cutaneous disease due to other organisms ➱ Combined therapy with allopurinol & meglumine antimoniate has shown better response than either of the two drugs used alone JAAD 2002
  • 63. TREATMENT Oral Azoles â–ș Ketoconazole : 200-400 mg /day x 4 wks. â–Ș 70% cure rate – L. major (Weinrauch et al) â–Ș ineffective in – L. tropica and aethiopica. â–Ș 89% cure rate – L. mexicana â–ș Itraconazole : 200 mg/ day x 4-8 wks â–Ș 79% cure rate – old world CL (IJD – 1994) â–Ș 66% cure rate from India (Dogra et al – IJD 1990)
  • 64. TREATMENT â–ș TOPICAL AGENTS â–ș Topical paromomycin 15% in methylbenzethoniumchloride applied twice daily for 10-30 days is effective in Israel in L.major CL â–ș In open study, topical paromomycin was found to be equally effective as i/l meglumine antimoniate for treatment of L.major CL Euj J Dermatol 2005
  • 65. â–ș Pentamidine â–ș For cutaneous leishmaniasis the high cure rate associated with low dose of pentamidine given for a shorter period makes it an attractive alternative to sodium stibugluoconate and treatment of choice in cases of Stibugluconate treatment failure. â–ș Pentamidine mesylate and isethionate are safe and effective drugs in treatment of New World CL (Esther J.S. et al ) 32/38 (84)2 mg/kg q.o.d., 4Open-label nonrandomized 23/24 (96)2 mg/kg q.o.d., 7Open-label nonrandomized No. of patients cured/total no. of patents (%) Dosage/no. of injections Study design Efficacy of pentamidine regimens for the treatment of cutaneous leishmaniasis in Colombia.
  • 66. TREATMENT â–ș ADVERSE EFFECTS â–ș Hypotension, hypoglycemia, severe myalgias, intractable headaches â–ș GI s/e – nausea, vomiting â–ș Leukopenia â–ș Neuropathy â–ș Hepatotoxicity
  • 67. TREATMENT Miltefosine â–ș Phosphorylcholine ester of hexadecanol, a membrane active alkylphospholipid â–ș First effective oral agent for VL, including antimony resistant cases. â–ș Topical treatment with miltefosine has been shown to efficiently reduce parasite load in experimental cutaneous leishmaniasis. â–ș In an open label study in Colombia, 4 weeks treatment with 133 and 150 mg of miltefosine daily cured 100% and 89% respectively – American cutaneous leishmaneasis (Soto J et al 2001)
  • 68. TREATMENT â–ș In a controlled study in Columbia & Guatemala, miltefosine given in a dose of 2.5 mg/kg body weight for 28 days produced 91% cure rate for L.panamensis infection and 50% cure rate for L. braziliensis & L. mexicana compared to 38% & 20% for placebo respectively â–ș Was well tolerated, adverse effects seen were mostly nausea, mild elevation in creatinine levels Trans R Soc Trop Med Hyg. 2006
  • 69. TREATMENT â–ș In a trial comparing the efficacy of miltefosine & sodium stibugluconate in treatment of VL in an Ethopian population with high prevelance of HIV infection, there was 88% initial cure rate in both the groups, mortality was 2% & initial treatment failure 8% with miltefosine compared to 8% & 1% resp with SSG â–ș Among HIV+ patients, cure rate, relapse rate & mortality in miltefosine group was 60%, 10% & 6% compared to 65%, 2% & 12% with SSG. â–ș In HIV+ patients, miltefosine is a much safer, though slightly less effective than SSG in treatment of leishmaniasis Clin Infect Dis,2006
  • 70. TREATMENT Photodynamic Therapy â–ș In a randomized placebo controlled trial, efficacy of Photodynamic therapy was compared with paromomycin & placebo â–ș Group 1 was treated with weekly topical PDT, and groups 2 and 3 received twice-daily topical paromomycin and placebo, respectively. The duration of treatment was 4 weeks for all groups. These groups were followed for 2 months after the end of treatment. â–ș At the end of the study, complete improvement was seen in 29 of 31 (93.5%), 14 of 34 (41.2%) and 4 of 30 lesions (13.3%) in groups 1, 2 and 3, respectively (P<0.001). At the same time point, 100%, 64.7% and 20% of the lesions had parasitological cure in group 1, 2 and 3, respectively (P<0.001)
  • 71. TREATMENT Immunotherapy ‱ Interferon-Îł – Intralesional treatment has been tried for cutaneous lesions ➱ In one study in L. braziliensis infection, 12 of 13 lesions became smaller after injection. ➱ IFN-Îł was also compared with antomony. â–Ș I/L infiltration once a week x 5 weeks â–Ș 100% cure rate with antomony treated lesions Vs 38% of IFN-Îł treated lesions – L. tropica ‱ Recombinent IL-2 has been used to treat a few patients with disseminated cutaneous leishmaniasis.
  • 72. TREATMENT Immunochemotherapy In a double-blind placebo controlled study of 102 patients with American CL, combination of a single –strain leishmania amazonensis killed promastiote vaccine with half dose of amtimonial – 100% cure rate after 4 series of treatments [10-day series at an interval of 10 days] compared to 82% in control group. IJD 2002
  • 73. TREATMENT â–ș Imiquimod ➱ Another topical agent under investigation for cutaneous leishmaniasis ➱ Immunomodulator developed to geintal warts. ➱ It produced 90% cure rate in patients who had failed to respond to antimonials alone when it was used in conjunction with antimonials in peru. (Arevaloi et al) Clin Infect Dis 2001 ➱ 5% Imiquomod with or without I/L meglumine antimoniate is more effective than I/L meglumine antimoniate alone in treatment of old world CL JAAD 2005
  • 74. LEISHMANIASIS IN HIV INFECTION â–ș VL is the fourth most common opportunistic parasitic disease in HIV-positive individuals â–ș VL promotes the development of AIDS-defining conditions and HIV infection increases the development of VL by 100-1000 times in endemic areas, reduces the therapeutic response & increases the relapse rate â–ș Leishmania/HIV co-infection has so far been reported from 33 countries worldwide, most commonly from Brazil (in Americas) and India ( in Asia) â–ș Introduction of HAART decreases the incidence of leishmania infection in HIV positive patients
  • 75. LEISHMANIASIS IN HIV INFECTION â–ș Cutaneous involvement is seen in 2-12% of patients with leishmania/HIV co-infection â–ș Causes a variable spectrum of lesions – papular, maculopapular & nodular â–ș Leishmania amastigotes have been found in apparently normal skin, infestating sweat ducts, & co-existing with lesions of KS, HSV & HZV â–ș Leishmania is also associated with changes attributable to other dermatological processes like dermatofibroma, psoriasis, Reiters disease, bacillary angiomatosis, cryptococcosis & oral aphthae
  • 76. LEISHMANIASIS IN HIV INFECTION â–ș Can present as dermatomyositis like eruption ➱ mucocutaneous & mucosal leishmaniasis ➱ post kala-azar leishmaniasis â–ș Primary cutaneous lesions can visceralize in severely immunodepressed patients
  • 77. LEISHMANIASIS IN HIV INFECTION DIAGNOSIS â–ș Gold standard for diagnosis of leishmsniasis in HIV infected individuals remains the isolation or identification of parasite from appropriate tissue â–ș Detection of leishmania amastigotes & antigens in peripheral blood has sensitivity of 50% which increases to 70% after culture â–ș New PCR techniques like detecting highly variable regions of kinetoplast DNA & nested PCR have a sensitivity of 95.45% in peripheral blood & 100% in bone marrow
  • 78. LEISHMANIASIS IN HIV INFECTION TREATMENT â–ș Duration of treatment has to be prolonged until 4 weeks â–ș More likely to suffer from adverse events â–ș Low rate of clinical & parasitological response – 60% with antimonials or with amphoterecin B â–ș 25-60% patients experience relapse during first year after completing treatment â–ș Combining antimonials with allopurinol/IFN-Îł useful in refractory cases or in relapses
  • 79. LEISHMANIASIS IN HIV INFECTION SECONDARY PROPHYLAXIS â–ș Antimonials 20 mg/kg once a month – some degree of efficacy is seen â–ș Pentamidine every 3-4 weeks â–ș liposomal AMB every 2 weeks â–ș Allopurinol/ itraconazole Usually withdrawn when CD4+ cell count > 200/”l
  • 80. â–ș My references are :- ➱ Textbook of dermatology –Rook Fitzpatrick ➱ J Postgrad Med 2003 ➱ J Am Acad Dermatol 1994, 1996 ➱ Clin Infect Dis. 1997, 2001, 2006 ➱ Drugs 1998; 56: 1009-1018 ➱ Int. J. Dermatol 1994, 1998, 2002 ➱ Trans R Soc Trop Med Hyg. 2006 ➱ Clin Exp Dermatol 2006