Cutaneous leishmaniasis in Pakistan
Published Web Locationhttps://doi.org/10.5070/D325b5x6b4
Cutaneous leishmaniasis in Pakistan
Gomal Medical College
Shiraz Jamal Khan, and Syed Muneeb
Dermatology Online Journal 11 (1): 4
Leishmaniasis is a major health problem worldwide. It is also a particular problem in the rural areas of Pakistan. The disease occurs in varying presentations, from the self-limited and even self-healing cutaneous forms to fatal systemic disease. Lesions of cutaneous leishmaniasis may occur anywhere on the body but the most likely sites are the exposed parts. The initial papule rapidly gives rise to an ulcer. Systemic leishmaniasis is rarer in Pakistan and invariably fatal if not treated promptly. It affects the internal body organs, particularly the spleen and the liver. Leishmaniasis is transmitted by an infected female sandfly. Cutaneous lesions are usually single and often self-healing, but a presentation with multiple ulcers resulting from multiple bites from the sandfly is not rare in Pakistan. The disease has a very long history and lesions like leishmaniasis have been described dating back to the ninth century (Balkan sore). Cutaneous leishmaniasis has been given various names in different civilizations such as "Delhi boil" in India, "Baghdad boil" in Iraq, and "saldana" in Afghanistan. The organism responsible for leishmaniasis was discovered 100 years ago but the disease has not been eradicated; rather it is on rise in many parts of the world. If control measures are not taken, it might emerge as a major health problem. Pakistan has a burden of cutaneous and visceral leishmaniasis, the mucocutaneous form being almost nonexistent. The physicians need to know the diagnostic criteria as well as the treatment of the disease. Because of a scarcity of dermatologists in the rural areas, most of these cases present to general practitioners. Control of this disease is further complicated by an inadequate supply of appropriate drugs.
There are about 1.5 million cases of cutaneous Leishmaniasis each year worldwide, with the bulk reported from Afghanistan, Iran, Iraq, Algeria, Saudi Arabia, Peru, and Pakistan. According to the World Health Organization (WHO), leishmaniasis is endemic in 88 countries, with a total of 350 million people at risk. It is believed that worldwide 12 million people are affected by leishmaniasis. It is very prevalent in Pakistan and has been reported from all the provinces and almost all the major cities. It is endemic at Baluchistan, Interior Sind, and Multan [1, 2, 3, 4, 5, 6, 7]. It has also been reported in Pakistanis working abroad . In Pakistan the disease has been described in its classic form and as variants of the classic variety. Some rare manifestations have also been described. These include acute paronychial, chancriform, annular, palmoplantar, zosteriform and erysipeloid forms . Careful review of the literature confirms that it is present in almost all parts of Pakistan but is more prevalent in the hilly areas [10, 11, 12]. The WHO has been working with local health authorities in the Northwest Frontier Province of Pakistan to control the outbreak. It has reported a total of 738 cases, mostly in children under age 15; these cases have mainly been found in Kurram agency and are among the local population, in addition to 1,500 cases in Afghan refugee camps [13, 14, 27]. At least 72 percent of the affected are unable to access medical treatment because of multiple factors such as poverty, lack of health education, and lack of health facilities.
Leishmaniasis is caused by a parasite transmitted between infected individuals by the sandfly. The cases can be divided into urban and rural. The most common type in Pakistan is called "urban" or "anthroponotic leishmaniasis". The disease is transmitted from human to human, but rural or zoonotic leishmaniasis comes from the interaction of man with animals. The cutaneous variety can present in various unusual clinical variants that can be difficult to diagnose, such as paronychial, chancriform, annular, palmoplantar, zosteriform and erysipeloid forms [9, 15].
The geographic distribution of cutaneous leishmaniasis is mainly determined by the sandfly vectors (Phlebotomus sp. and Lutzomyia sp.) . They live in dark, damp places; these vectors do not fly high or far and they have a range of only 50 meters from their breeding site. Sandflies become infected through feeding on infected animals. Once a sandfly is infected, it can transmit the parasite to both humans and animals for the rest of its life . Unlike mosquitoes, they fly silently and their small size (2-3 mm) allows them to penetrate through mosquito nets. They are most active in the evening and at night. Most infections exist as zoonoses among wild animals, such as rodents and dogs, and are most prevalent in rural or forest areas. Although man is usually an incidental host, such infections are by no means uncommon. In endemic areas, up to 9 percent of the healthy population may have a positive Leishmanin skin test, indicative of an earlier, often asymptomatic infection. In India and Pakistan simple cutaneous leishmaniasis is usually caused by Leishmania tropica , and man is the most common reservoir.
Leishmaniasis usually presents to the general practitioner or physician most probably because of lack of experienced dermatologists in far-flung rural areas where this disease is most prevalent. It is therefore essential for the general physicians to have a clear idea about the diagnosis and treatment besides a fair knowledge about its pathophysiology [22, 23, 24]. The drugs used for treatment usually are not available on the open market. Until very recently, despite the surge of this disease in various areas from all over Pakistan, antimony compounds were rarely available. These drugs were smuggled from Iran and were so scarce that they would not suffice for the needs of the community. Newer drugs are not available in Pakistan and therefore there are no local studies.
The lifecycle starts with inoculation by promastigotes that are phagocytosed by macrophages; once inside they shed their flagella and become amastigotes that multiply by binary fission. Infected macrophages are physically destroyed by these rapidly dividing amastigotes. After a macrophage breaks down these amastigotes are released to enter other macrophages and divide and redivide unabated, thereby destroying these immunocompetent cells and leading to immunosuppressionl. The subsequent fate of the amastigotes depends on parasite and host factors, which are poorly understood. Viscerotrophic species, such as Leishmania donovani, migrate throughout the reticuloendothelial system, giving rise to visceral leishmaniasis; whereas dermotrophic species, such as Leishmania major, usually remain close to the inoculation site, giving rise to cutaneous disease. The skin variety can disseminate however and can lead to systemic manifestations. Any spread of dermotrophic species tends to be late, however, and only to adjacent skin (producing satellite lesions), or to lymphatics only to get trapped at regional lymph nodes . Leishmania braziliensis is able to migrate to the oropharyngeal mucosa where it may remain dormant for many years before reactivating to give rise to the destructive mucocutaneous form, espundia . There are reports of Leishmania tropica causing visceral disease. In post-kala-azar dermal leishmaniasis the viscerotrophic parasite becomes dermotrophic as a consequence of treatment.
Most infections follow a bite from an infected sandfly and remain subclinical. However, in some cases, after an incubation period of 1-12 weeks, a papule develops that enlarges and ulcerates. A typical lesion is a painless ulcer with a raised, indurated margin and a necrotic base. Most patients have one or two lesions but the lesions may be multiple and occur in crops. Lesions are usually present on the exposed sites. Their sizes also vary from 0.5 cm to 3 cm in diameter. Some lesions do not ulcerate at all and remain as bluish papules; others develop sporotrichoid nodular lymphangitis. Secondary bacterial infection is common and must always be suspected if the painless lesion becomes painful. Most lesions heal over months or years, leaving an atrophic scar. In general 50 percent of those lesions associated with Leishmania major will have healed in 3 months; those associated with Leishmania tropica take about a year, and those associated with Leishmania brazilienesis persist much longer. Natural resolution leads to partial resistance to reinfection, which is why certain clinicians avoid therapy early, adopting a wait-and-see policy. Drug-induced resolution does not promote subsequent immunity, at least as complete as that provided by natural and spontaneous resolution.
Gallery of cutaneous leishmaniasis
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The diagnosis is often made by the trained eye of a careful physician based on the typical lesion in conjunction with an appropriate history of exposure, usually in an endemic area. However, to the unwary, there are a number of mimics; leishmaniasis may be underdiagnosed or overdiagnosed and treated unnecessarily. The treatment is toxic, so pathological confirmation should be sought, preferably by demonstrating the organism in tissue and culture . Unfortunately, this is not always possible in clinical practice. The parasite may not be found by the most adequate methods.
A full-thickness biopsy is taken from an infiltrated margin of the lesion and divided into three parts: to prepare an impression smear, for histological examination, and for culture. Usually a lesion is selected that is not secondarily infected. It is cleaned with 0.9 percent saline or 70 percent ethyl alcohol. If all lesions appear secondarily infected, a second cleansing is given with 6 percent hydrogen peroxide. These cleansing agents will remove any crust from the lesion. Afterward, 2 percent lidocaine with epinephrine is injected around the lesion, and a biopsy taken. Although a punch may be used, an elliptical biopsy taken with a scalpel is much easier.
Impression smears are made by gently pressing the skin biopsy against a glass microscope slide four or five times, after which the slide is air dried, fixed in 95 percent ethanol for 3 minutes, stained with Giemsa or H & E, and examined for the presence of amastigotes.
Specimens for culture should be transported in "sloppy Evans" media and subsequently cultured on Evans Modified Tobies media or Novy-Nicolle-MacNeal media. Cultured organisms may be typed by isoenzyme analysis.
Alternatively, needle aspirates and slit-skin smears may be useful. A needle aspirate is obtained by using a 2-ml syringe with a 20-gauge needle, containing 0.3 ml normal saline. The needle is inserted through intact skin, and 0.1 ml is injected into the edge of the lesion. The needle is then moved back and forth, rotating it and applying suction at the same time to cut small pieces of tissue from the edge of the needle track, which are then aspirated. The aspirate can be used to inoculate cultures and prepare smears. Slit-skin smears are made by squeezing the edge of the lesion between thumb and forefinger, making a shallow slit 1-mm deep in the pinched skin with a scalpel, and then scrapping the cut edge. A sharp lancet may be all that is needed to obtain a small tissue piece from the edge of the lesion.
Monoclonal antibodies can demonstrate parasites. Methods using PCR for confirming the diagnosis and are more sensitive than microscopy and culture. However, problems exist with the identification of individual species.
Serology is unhelpful for cutaneous disease because antibodies tend to be undetectable or present in low titer. The leishmanin skin test is an old test analogous to the tuberculin test, and detects cell-mediated immunity; it becomes positive once the lesions begin to crust and remains so indefinitely. It cannot distinguish between past and present infection and may be useful only for epidemiological studies.
The situation is complicated by the self-healing nature of cutaneous leishmaniasis. Adequately controlled therapeutic trials are therefore essential to assess the efficacy of any new treatment. Unfortunately, the trials done on drugs are few and inconsistent, uncontrolled, and sometimes biased. Furthermore, the drugs that work reasonably well in one endemic area may not be efficacious in another area. Natural healing is so common that it is uncertain whether therapy will be justified at some stage.
Fortunately, there are some guiding principles. Because most lesions heal rapidly without treatment, a wait-and-see approach for spontaneous cure may be appropriate, particularly for those patients living in endemic areas because spontaneous healing is associated with the development of protective immunity. Lesions on cosmetically or functionally important sites, such as the face or hands, those with associated lymphangitis, and those with multiple or persistent lesions are best given active treatment. Local treatment is appropriate for those with early noninflamed lesions and systemic therapy for those with multiple or more complicated lesions.
The pentavalent antimony derivatives sodium stibogluconate (Pentostam, Glaxo Wellcome, UK) and meglumine antimoniate (Glucantime, Rhone-Poulenc Rorer, France), developed in the 1940s, remain the mainstay of systemic treatment. They are similar in both efficacy and toxicity. Their mode of action is not known, although they inhibit glycolysis and fatty acid oxidation in leishmania. Their efficacy is well established, provided they are given in adequate doses and for an adequate length of time.
Sodium stibgluconate is best given once daily by slow IV (or IM) injection for up to 2 weeks, depending on the severity of the lesions. Toxicity is common, and appears dose related; most patients develop malaise, anorexia, myalgia and arthralgia after 14 days treatment. These symptoms are associated with elevations in serum aminotransferases, chemical pancreatitis, mild leukopenia, thrombocytopenia, and flattening of the T waves on the ECG. It is therefore advisable to stop therapy once a near-adequate response is achieved or toxicity has developed. Patients under treatment should be monitored, but in most cases these abnormalities resolve rapidly once treatment is stopped. Lesions will become less indurated, flattened, and less scarred and will stop enlarging with adequate treatment. Healing, however, continues after treatment has been stopped, so evaluation of the need for additional treatment should be delayed for 4-6 weeks. This allows patients to recover from the toxicity.
Rifampicin has been reported to be efficacious but there are no good controlled trials to support its use. Furthermore its use in areas where tuberculosis and leprosy are endemic should be avoided. It should almost never be used in Pakistan for leishmaniasis for fear of developing resistant organisms and losing this wonderful drug that is still the cornerstone of therapy against tuberculosis. Alternative systemic agents include aminosidine  (paromomycin), pentamidine, and ketoconazole. However, they are not used routinely. The most promising oral drug today is miltefosine. In an open-label study in Colombia, 4 week's treatment with 133 or 150 mg of miltefosine daily cured 100 percent or 89 percent, respectively .
Local and topical therapy is an important option for those patients not at risk of mucocutaneous disease. Local injection of sodium stibogluconate, or meglumine antimoniate, is useful for early, noninflamed lesions. The most important thing about local therapy is the technique of administration of these drugs. Infiltrating 1-3 ml around the lesion to produce complete blanching at the base of the lesion. It may be repeated on alternate days or given weekly until complete or near-complete healing occurs. Aminosidine (paromomycin) ointment (15 percent paromomycin, 12 percent methyl benzethonium chloride in white soft paraffin) applied twice daily for 10 days is effective for Leishmania major and may also be useful for Leishmania mexicana. It causes considerable local irritation, and less irritant derivatives have been less effective. Cryotherapy is also useful for small lesions (< 1-cm diameter). Lesions can also be treated by local excision, by curettage, or by electrodesiccation but are probably associated with a higher risk of relapse. The most recent topical agent to be investigated is the topical immunomodulator, imiquimod, which was developed to treat genital warts. It produced a 90-percent cure rate in patients who had failed to respond to antimonials alone when it was used in conjunction with antimonials .
Most relapses occur within 3-6 months after successful treatment, so a followup visit at 6 months is appropriate. Thereafter patients should be warned that relapse is possible and to observe their scars for thickening, crusting, or ulceration. Those who relapse should be given a full course of systemic antimony in the first instance. Patients should be monitored until the lesions have fully healed and the infiltration has resolved.
(for clinical images, see associated file)
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