Leishmania Treatment Center Walter Reed Army Medical Center Leishmaniasis MAJ Mark Polhemus Leishmania Treatment Center Walter Reed Army Medical Center

Introduction Leishmaniasis is a parasitic disease transmitted by the bite of sand flies. Found in parts of at least 88 countries including the Middle East Three main forms of leishmaniasis Cutaneous: involving the skin at the site of a sandfly bite Visceral: involving liver, spleen, and bone marrow Mucocutaneous: involving mucous membranes of the mouth and nose after spread from a nearby cutaneous lesion (very rare) Different species of Leishmania cause different forms of disease

Introduction In the Middle East L. major and L. tropica are the most common species L. major causes skin infection L. tropica causes skin and visceral infection and rarely causes mucocutaneous infection About 1.5 million new cases of cutaneous leishmaniasis in the world each year 500,000 new cases of visceral leishmaniasis estimated to occur each year also 20 cases of cutaneous leishmaniasis from L. major/ L tropica and twelve cases of visceral infection caused by L. tropica were reported in soldiers from Desert Storm

Endemic Areas for Leishmaniasis Highlighted areas are parts of the world where leishmaniasis has been reported. Taken from British Medical Journal 2003 326:378 BMJ 2003;326:378

Leishmaniasis in the Middle East 90% of cutaneous leishmaniasis occurs in Afghanistan, Iran, Saudi Arabia, Syria, Brazil and Peru 8,779 cases were reported in Iraq in 1992 Sore is commonly called the Baghdad boil At least 20 cases of cutaneous leishmaniasis were reported in Americans from Desert Storm 90% of all visceral leishmaniasis occurs in Bangladesh, Brazil, India, and the Sudan 2893 cases were reported in Iraq in 2001 12 visceral leish cases were reported in Americans in Desert Storm 90% of mucocutaneous leishmaniasis occurs in Bolivia, Brazil and Peru Rarely associated with L tropica which is found in Middle East Data on leishmaniasis is based on voluntary reporting by countries so true incidence may be higher in countries that are not likely to report. Numbers of cases in Iraq come from recent Promed messages (authors Desjeux and Deresinki)

Life Cycle 1- Sandfly bites animal and ingests blood infected with Leishmania 2- Sandfly bites human and injects Leishmania into skin Reservoir: Small animals – including dogs, rats, gerbils, sloths. Vector: Sandflies which become infected by ingesting blood from these small animals. The sandfly is very small and does not make noise when it flies. They are most active at night (from dusk to dawn) and less active during the hottest part of the day. About 1/3 the size of a mosquito, they can fly through the mesh of mosquito nets unless the bed nets are treated with Permethrin. Their mouthparts are too small, however, to bite through clothing. Lifecycle: Leishmaniasis is spread to humans by the bite of some types of sand flies. Sand flies become infected by biting an infected animal (for example, a rodent or dog) or person. When the sandfly bites an infected animal it ingests blood (specifically white blood cells) infected with Leishmania. The Leishmania changes form inside the gut of the sandfly – from amastigote to promastigote. At night, the sandflies slip through untreated bed nets or land on skin without repellent and bite. Leishmania from the gut of the sandfly are are injected into the skin of the human. In the human the Leishmania again change form – back to amastigote. If another sandfly bites the infected human, the sandfly ingests blood infected with Leishmania, becomes infected, and flys off to infect another human or animal. The life cycle continues. Leishmaniasis also can be spread by blood transfusions or contaminated needles. 4- Cycle continues when sandfly bites another human or animal reservoir 3- Another sandfly bites human and ingests blood infected with Leishmania

Cutaneous Leishmaniasis

Photograph provided by COL Naomi Aronson

Photograph provided by COL Naomi Aronson

Cutaneous Leishmaniasis Most common form Characterized by one or more sores, papules or nodules on the skin Sores can change in size and appearance over time Often described as looking somewhat like a volcano with a raised edge and central crater Sores are usually painless but can become painful if secondarily infected Swollen lymph nodes may be present near the sores (under the arm if the sores are on the arm or hand…) Some sores are covered by a scab or have not yet ulcerated so they may look like red raised plaques- sometimes with dry crust/scale

Cutaneous Leishmaniasis Most sores develop within a few weeks of the sandfly bite, however they can appear up to months later Skin sores of cutaneous leishmaniasis can heal on their own, but this can take months or even years Sores can leave significant scars and be disfiguring if they occur on the face If infection is from L. tropica it can spread to contiguous mucous membranes (upper lip to nose)

Small, raised lesion on trunk without significant oozing or scab. Photograph provided by COL Naomi Aronson

Multiple lesions on arm with a variety of appearances. Photograph provided by COL Naomi Aronson

Both lesions are leishmaniasis Note the raised border and wet appearance of the sore on the back of the hand. Sores over joints are very concerning as scarring with healing can lead to limited movement of joint. Photograph provided by COL Charles Oster

Back of hand. Note raised border and wet appearance. Patient has bacitracin ointment applied to lesion. Photograph provided by COL Naomi Aronson

Upper Eyelid. Note the dry, crusted/scabbed appearance which is different than previous sores shown. Photograph provided by COL Naomi Aronson

Close up of another dry, crusted lesion with concentric surrounding scale. This is a typical appearance for Old World Leishmaniasis. Photograph provided by COL Charles Oster

Three lesions on face. Raised and dry but not scabbed. Another different presentation. This was Leishmania tropica. Photograph provided by COL Charles Oster

Visceral Leishmaniasis

Two children with visceral leishmaniasis Two children with visceral leishmaniasis. The size of the spleen is marked on the abdomen. Normally the spleen does not protrude below the bottom rib. Photograph provided by COL Charles Oster

Visceral Leishmaniasis Most severe form of the disease, may be fatal if left untreated Usually associated with fever, weight loss, and an enlarged spleen and liver Anemia (low RBC), leukopenia (low WBC), and thrombocytopenia (low platelets) are common Lymphadenopathy may be present Visceral disease from the Middle East is usually milder with less specific findings than visceral leishmaniasis from other areas of the world Based on our experience with Desert Storm, well nourished American soldiers generally have a less symptomatic, relatively oligoparasitic infection that was not life threatening but posed some diagnostic challenges

Visceral Leishmaniasis in Desert Storm The following symptoms were found in eight visceral leishmaniasis patients returning from Desert Storm Fevers: 6 of 8 Weight loss: 2 of 8 Nausea, vomiting, low-grade watery diarrhea: 2 of 8 Lymphadenopathy: 2 of 8 Hepatosplenomegly: 2 of 8 Anemia: 3 of 8 Leukopenia or thrombocytopenia: 0 of 8 Elevated liver enzymes: 6 of 8 No symptoms: 1 of 8 Summary of the presenting symptoms of eight soldiers with visceral leishmaniasis from Desert Storm. The summary is from an New England Journal of Medicine article by COL Alan Magill and others from the Walter Reed Army Medical Center Infectious Disease Service. Magill et al, NEJM 1993:328(19)

Visceral Leishmaniasis Symptoms usually occur months after sandfly bite - Soldiers from Desert Storm presented up to five months after leaving the Persian Gulf Because symptoms are non-specific and often start after redeployment there is usually a delay in diagnosis Visceral leishmaniasis should be considered in any chronic FEVER patient returning from an endemic area. From the Desert Storm experience, would also consider visceral leishmaniasis in patients with low grade elevated temperature, chronically elevated liver function tests and mild anemia

Mucocutaneous Leishmaniasis

Mucocutaneous Leishmaniasis Occurs with Leishmania species from Central and South America Very rarely associated with L. tropica which is found in the Middle East - This type occurs if a cutaneous lesion on the face spreads to involve the nose or mouth - This rare mucosal involvement may occur if a skin lesion near the mouth or nose is not treated May occur months to years after original skin lesion Hard to confirm diagnosis as few parasites are in the lesion Lesions can be very disfiguring Much of the destruction is from a hyperimmune reaction to the Leishmania infection. There are not many parasites in the affected tissue so confirming the diagnosis can be difficult. This form of leishmaniasis would be unusual in soldiers infected in South West Asia.

Photograph provided courtesy of COL Donald Skillman

Prevention Suppress the reservoir: dogs, rats, gerbils, other small mammals and rodents Suppress the vector: Sandfly Critical to preventing disease in stationary troop populations Prevent sandfly bites: Personal Protective Measures Most important at night Sleeves down Insect repellent w/ DEET Permethrin treated uniforms Permethrin treated bed nets Sandflies bite dusk to dawn so personal protection is most important during these times. Even light clothing covering skin is sufficient to prevent the bite of the sandfly. DEET is the most effective insect repellent. Sandflies are small enough to fly through bed netting unless it is treated with permethrin.

Diagnosis Heightened awareness of individuals, small unit leaders, and medical personnel is critical Sores that will not heal have to be referred for evaluation – even if not “typical” for leishmaniasis Individuals with fevers, weight loss, gastrointestinal complaints, anemia, abnormal liver tests should be referred for evaluation When soldiers present to medical personnel they should volunteer that they were in South West Asia

Diagnosis: Cutaneous Leishmaniasis Biopsy is required for diagnosis Biopsy can be done locally if trained medical personnel are available AND Leishmania diagnostic capability present If trained personnel and diagnostic capability are not available, patient should be referred to Walter Reed Army Medical Center Biopsy specimens should be sent to Walter Reed (WRAIR) for diagnosis -Leishmania Diagnostics Laboratory - Special laboratories will do microscopy, culture and PCR - Mail out kits/instructions available Preliminary results should be ready in less than two weeks On occasion, a deep scraping of a skin lesion can be sufficient when the tissue scraping is subjected to giemsa stain, Leishmania culture and/or PCR.

Diagnosis: Cutaneous Leishmaniasis Patients with any of the following findings should be referred early to avoid long term complications: Big lesions (greater than an inch in size) Many lesions (3 or more) Sores on the face Sores on the hands and feet Sores over joints

Diagnosis:Visceral Leishmaniasis Must be considered if diagnosis is to be made Presentation is usually very non-specific and should be considered in febrile patients in / returned from SWA Antibodies to Leishmania may be present in patient’s serum but this will not confirm or exclude the diagnosis Diagnosis requires finding Leishmania on biopsy of bone marrow, liver, enlarged lymph node, or spleen Patients should be referred to a Medical Center, for referral on to Walter Reed Army Medical Center for definitive diagnosis and management if other etiologies excluded Methods available in the US for antibody detection in the serum - IFA test - rk39 dipstick (Kalazar DetectTM)

Diagnosis Mucocutaneous Leishmaniasis Early diagnosis and treatment is critical to avoid disfigurement Patients should be referred to Walter Reed Army Medical Center Biopsies should be done but require special training to avoid further disfigurement Biopsies will be evaluated by the same methods and special laboratories as for cutaneous lesion Because few parasites are present, PCR may be particularly useful

Diagnosis Mail-out diagnostic kits with instructions are available upon request from the Walter Reed Army Institute of Research Limited to CONUS facilities and Landstuhl POC: Dr Coyne/ Dr Weina Phone: 301-319-7155/9956 DSN 285-7155/9956 Return kit and specimen to: Commander, WRAIR Attn: Leishmania Diagnostics Laboratory Division of Experimental Therapeutics 503 Robert Grant Avenue Silver Spring, MD 20910-7500 If kit is not available, place biopsy samples in formalin and send for histopathology review. This may be a less sensitive diagnostic method than above. For expert second level review, slides of potential leishmaniasis cases can be forwarded to Armed Forces Institute of Pathology, AFIP, Geographic Pathology Division, Washington DC Patient may be referred to Walter Reed Army Medical Center for assistance with diagnosis.

Treatment Cutaneous and Mucocutaneous Antimony (Pentostam®, Sodium stibogluconate) is the drug of choice Given under an experimental protocol at Walter Reed Army Medical Center (WRAMC) 20 days of intravenous therapy Available at WRAMC for all branches of the military Requires patient to come to WRAMC Fluconazole may decrease healing time in L. major infection Biopsy and culture to determine species is required Six weeks of therapy is needed Since L tropica is of more concern in the SWA theatre (because of potential visceralizing infection, rare mucocutaneous involvement, and chronic (recidivans) skin infection) , would not advocate use of azoles routinely as there is not data to support their use in L.tropica and speciation can not be reliably made using clinical appearance. Mucocutaneous infection is treated with a longer treatment course (28 days)

Treatment Visceral Leishmaniasis Liposomal amphotericin-B (AmBisome®) is the drug of choice 3 mg/kg per day on days 1-5, day 14 and day 21 Pentostam® is an alternative therapy 28 days of therapy is required Although AmBisome® is widely available, the difficulty of accurate diagnosis and the potential severity of visceral infection suggest possible patients be referred to the Leishmania Treatment Center at WRAMC for maximal diagnostic efficiency It is not known what species of visceral leishmaniasis is present in Iraq – WHO reports that children have L. infantum. During Desert Storm some of American soldiers were found to have visceral infection with L. tropica. Published studies of liposomal amphotericin for visceral leishmaniasis have not included patients with L. tropica so it is not known for sure that it would be effective but it is expected likely.

Points of Contact

Points of Contact Clinical questions or patient referral LTC Glenn Wortmann, COL Naomi Aronson, COL Charles Oster Leishmania Treatment Center Infectious Disease Service Walter Reed Army Medical Center Comm: 202-782-1663/8695/8691 DSN: 662-1663/8695/8691 To request Diagnostic Kits CPT Eric Fleming, LTC Peter Weina, CAPT Philip Coyne Walter Reed Army Institute of Research Comm: 301-319-9206/9956/7155 DSN: 285-9206/9956/7155 Email for all is first.lastname@na.amedd.army.mil