Dum Dum Fever

~ Son of Pilgrim
The mix of variable pathophysiology, geographic distinctiveness, inconstant clinical penetrance, and complex host-parasite interaction make for a smouldering ‘Neglected Tropical Disease’ affecting 12 million of the world’s poorest.

Leishmania infect phagocytes, outwitting the host immune system. Caught early and trapped locally, the organism replicates within dendritic cells (dermal macrophages) causing only cutaneous disease. Another species (there are 20 that are pathogenic to humans) in a different host in a different region may, however, show a propensity for spread—this time via circulating macrophages to the nasopharynx/oropharynx and urogenital region—causing mucosal disease. And another, spread yet wider still, infiltrating deeper reticuloendothelial cells of the spleen, liver, and bone marrow, manifesting as a visceral leishmaniasis.

Untreated visceral leishmaniasis—hepatosplenomegaly, weight loss, anaemia, and undulating fever—is a uniformly fatal, wasting disease second only to malaria for global human mortality from parasitism. The more limited and rarely lethal mucosal, and mostly limited and never fatal cutaneous, disease, both still cause major morbidity. The good news: leishmaniasis is treatable.

Leish key

The history of leishmania is tortuous but inescapable. According to paleoparasitology, the organism is many millions of years old. Rather than cause population decimation, true to parasite form, leishmania follow human development (‘Red Queen’ Theory). A reptilian zoonosis arising out of the Middle East (earliest fossilised sandflies from Lebanon), leishmania came to the New World across the Bering Strait—before the break-up of Gondwana in the Jurassic age—during the Pangea single landmass of the Triassic era. With its distinctive features, leishmaniasis is readily identifiable even in the seventh-century-BC Assyrian records of King Ashurbanipal, while molecular amplification techniques demonstrate leishmania DNA in Nubian mummies (Zink et al, 2006). The disease, moreover, spread to Brazil via seafaring Phoenicians and Syrians. And the distinctly deformed faces of first-century Incan pottery likely merely depict a mucocutaneous leishmaniasis.

Recognised far and wide throughout history, over time leishmaniasis gains many a pseudonym—Baghdad Boil, Jericho Button, many others. To tenth-century Muslim physicians, it is Balkh sores. From central Asian zoonotic reservoirs, disease transfers, around the fourteenth-century, also to the Indian subcontinent. By mid-eighteenth century, visceral leishmaniasis is being described in Africa. Kala-azar (Hindi: “Black-Fever”) is first recognised in Jessore in 1824 in febrile patients thought to have malaria but who fail to respond to quinine. By 1862, the disease reaches epidemic levels in Burdwan, yet still mostly attributed to a virulent form of malaria.

During a 13-year residence stationed in Aleppo with the Levant Company, in 1756, Edinburgh born physician Alexander Russell—The Natural History of Aleppo and parts adjacent—characterises what he calls an “Aleppo Boil” in a Turkish man:

After it is cicatrised, it leaves an ugly scar, which remains through life, and for many months has a livid colour. When they are not irritated, they seldom give much pain.

David Cunningham (1885), a Scottish physician, and later a Harvard pathologist, James Homer Wright, discover the cutaneous parasite. Meanwhile, Russian military surgeon, Peter Borovski, publishes his discovery of the visceral parasite in a lesser-fancied journal, in 1898.

Scotsman William Boog Leishman, a British army doctor stationed at Dum Dum near Calcutta, founds the leishmania parasite during histological examination of the swollen spleen of a British soldier who died amidst bouts of fever, anaemia, and wasting in 1903. Leishman identifies, and implicates, ovoid bodies in “Dum Dum fever”. Weeks later, Charles Donovan, professor of physiology at Madras University, recognises these symptoms in patients with kala-azar. Receiving coincidental reports from both Leishman and Donovan, then BMJ senior-editor in London, Ronald Ross syncretises each man’s separate discovery into “Leishman-Donovan bodies”, later Leishmania donovani. Finally, in 1921, brothers Edouard and Etienne Sergent experimentally prove human transmission of leishmania from a Phlebotomus (genus) sandfly, and transmission via arthropod bite confirmed in 1941. By then, cutaneous leishmaniasis is increasingly seen in American expats returning from a nascent Saudi oil industry.

Epidemiology

Visceral leishmaniasis involves cells of the reticuloendothelial system—liver, spleen, and bone marrow—of some 200,000 to 400,000 new cases (and 20,000-30,000 deaths) worldwide each year. The disease splits geographically into Old and New World types with multiple parasite species implicated for each, suggesting a common ancestor vector prior to a continental separation. Global travel and military conflict has since seen the disease spread more widely, including emergence of resistance strains in those with HIV co-infection.

A disease feature is its distribution in rural or semi-urban areas associated with malnutrition, displacement, poor infrastructure, and weakened immunity, and also areas of deforestation and urbanisation. Over 90% of visceral disease occurs in the Indian subcontinent (India and Bangladesh, but also Nepal), in East Africa (Sudan, South Sudan, Ethiopia), and in Brazil. Most of the remainder is concentrates about the Mediterranean basin.

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Biology

Of this obligate intracellular protozoan, 31 species have now been implicated with human disease with L. donovani and L. infantum / L. chagasi the commonest variants in visceral leishmaniasis.

Wellcome Images – cc-by 4.0 licence

Intermediate Host: Infection is transmitted from the bite of phlebotomine sand fly, an arthropod with a habitat spanning the world’s inter-tropical and temperate regions between latitudes 50°N and 40°S, sparing the Pacific Islands and New Zealand. The sand-fly is found at the opening of the burrows of certain rodents (with specie-host specificity), in the bark of old trees, ruined buildings, cracks in house walls, animal shelters, household rubbish—in short, wherever humidity allows for organic matter to enrich larvae. The Lutzomyia (a New World) genus of sandfly may be found in and around caves, feeding off bats.

1280px-Leishmaniasis_life_cycle_diagram_en_svg
Life cycle of Leishmania donovani [Wikimedia Commons]
From here the sand-fly roams, dusk to dawn, across a span of several hundred metres in search of a blood meal. A single blood meal can support the production of 100 eggs. Occasionally the same species will bite both animal and human, enabling a zoonotic reservoir to exist. At a third the size of a mosquito, the noiseless phlebotomine sandfly may present a bite that goes unnoticed. Hours or days later, an itchy papule develops at the site of the sting.

The first non-sandfly specie transmission of leishmaniasis was identified in the Northern Territory, Australia (Rose et al, 2004)—an as yet undescribed specie of day-feeding midge (subgenus Forcipomyia (Lasiohelea)) was likely infecting the red kangaroo with a parasite strain most closely related to Leishmania enriettii (Dougall et al, 2011).

Over 70 animal species have been identified as the natural reservoir hosts for the parasite: humans, which are the parasite’s definitive host; and dogs a common reservoir host. Sporadic infection is now seen in returned travellers from Eastern Europe or soldiers from the Middle East, otherwise infection is not seen in Americans. There is, however, an endemic cycle in dogs (L. tropica, from middle Europe) in the Unites States, particularly along the eastern seaboard.

A congenital transmission and transmission parenterally through blood transfusion or needle sharing have also been reported in leishmania cases.

Clinical Presentation

There are three main presentations of leishmaniasis: a visceral, cutaneous, and mucosal form. Manifestations depend on host immune factors and the pathogenic strain implicated, with a distinct geography: disease in the Old World is principally due to L. donovani and spread via the Phlebotomus sand fly, causing widespread infection of the reticuloendothelial system; in the New World, L braziliensis spreads via the sting of Lutzomyia sand flies and affects the naso-oropharynx and urogenital tract.

Cutaneous leishmaniasis

The result of local infection of dermal macrophages, this is the most common form of leishmaniasis. It newly affects about one million people each year. Almost all cases occur in the Americas, the Mediterranean basin, Middle East, and Central Asia — mostly from the six countries of Afghanistan, Algeria, Brazil, Colombia, Iran, and Syria.

  • L. major (Old World): L. major, L. tropica, L aethiopica, L. infantum, L. donovani
  • L. mexicana (New World): L. mexicana, L. amazonensis, and L. venezuelensis

Unless superinfected, or near a joint, lesions are generally painless, persisting months to years after their progression from papule to nodule to ulcer, to scab or crust, before leaving behind an atrophic scar. Multiple (sometimes hundreds) of primary and satellite, often disfiguring, skin lesions can be seen often with an associated regional adenopathy.

Then, a cutaneous form of the disease, caused by L. tropica, suddenly “visceralises” in American troops during Operation Desert Storm, demonstrating unique pathophysiology (and parasite-host immunogenicity) upon introduction of a naïve host to an old disease. But because it is essentially non-life threatening, an oft disfiguring cutaneous disease has been neglected by funding agencies and pharmaceutical companies.

Mucosal leishmaniasis (espundia)

Mucosal disease is predominantly caused by L. braziliensis, a species felt to proliferate (and lesions slowly advance) early in the course of the disease in the lower heat and relatively acellular cartilaginous nasal areas presenting a dearth of cellular immunity (Gerszten et al, 2012). Mucosal disease is felt to be the delayed metastatic sequelae of untreated or poorly treated cutaneous or visceral disease. Disease causes a gradually disabling and personally degrading partial or total destruction of the mucosa. Almost 90% of mucosal leishmaniasis occur in Bolivia, Brazil, and Peru.

Visceral leishmaniasis

Here, again, the permutations are many, not least of all in clinical presentation and spectrum of disease severity, due to a widespread infection of macrophages throughout the reticuloendothelial system. Over 90% of new cases occur in just six countries: Bangladesh, Brazil, Ethiopia, India, South Sudan and Sudan. Visceral leishmaniasis can present acutely, subacutely, or chronically, with an incubation period between weeks and months. Alternatively, it presents from latent infection manifesting opportunistically years to decades later. L. donovani or L. infantum (Old World) or L. chagasi (New World) are the major species to cause visceral leishmaniasis. Atypical manifestations, including gastrointestinal tract involvement and drug-resistance, is commonly seen in HIV-coinfected patients.

Thankfully, amidst all this variability, there is a patterned presentation of visceral disease to guide the clinician:

  • Fever: usually described as undulating (dromedary or ‘camel-back’)
  • Weight loss: cachexia, wasting
  • Hepatosplenomegaly: spleen usually more prominent than liver
  • Pancytopenia
  • Hypergammaglobulinemia — high-protein, low-albumin state
  • Lymphadenopathy: especially seen in Sudan

A secondary cutaneous eruption complicating visceral leishmaniasis in areas of L. donovani endemicity, and seen particular after partial treatment, is the post kala-azar dermal leishmaniasis (PKDL) which presents as pale maculopapular or nodular (and not ulcerative) lesions that, but for infections endemic to India, heal spontaneously. PKDL is thought to act as an important reservoir of leishmania infection.

PATHOPHYSIOLOGY — A “Trojan Horse”

Upon taking a blood meal, the sandfly injects the flagellated promastigote along with chemoattractants into the subcutaneous tissue. Unlike plasmodia, which are directly injected into blood stream, leishmania parasites depend on host-cell phagocytosis for their life-cycle. Dendritic cells quickly engulf the parasite after which, depending upon parasite-host response, they decide on one of two actions:

  1. migrate away from the site of infection to reticuloendothelial organs; or
  2. remain locally, entering a ‘parasitophorous vacuole’—a phagosome protected, by way of parasitic connivance, from lysosomal degradation.

In the case of T. gondii, recall the parasite prevents lysosomal fusion with phagosome. Leishmania also does this but beyond even this has developed a further mechanism of host immune evasion, producing potent lytic enzymes that hydrolyse phagocyte lysosomal hydrolases before they can enzymatically destroy the parasite. Rather than destroying the invader, phagocytes end up aiding and abetting it: harbouring, nurturing, and transporting it instead.

As its flagellum disappears, the amastigote now begins to reproduce. Visceral and cutaneous forms of the disease remain, as yet, indistinguishable. A distinction exists, however, in the immune response induced by the differing parasites: parasites causing the cutaneous form of disease remain locally while inhibiting a host inflammatory response; while parasites that cause mucocutaneous disease disseminate to the nasopharynx amid a strong inflammatory response. For each event Toll-like receptors have been implicated.

Another female phlebotominae comes along and takes the blood meal she requires for egg production and inadvertently picks up infected dendritic cells; either from the living edge of a cutaneous wound or from circulating macrophages harbouring the parasite, depending on which form of disease is present. Either way, the sand fly takes up amastigotes into its gut. There amastigotes undergo transform into promastigotes, ready for inoculation into another host.

Uncommon in the United States, cases of lesihmaniasis are mostly seen in tourists to southern Europe or expatriates and deployed soldiers to the Mediterranean and Middle East. That said, the odd case of endogenous cutaneous leishmaniasis has been reported in Texas and Oklahoma but there has never been a documented case of endemic spread within the United States.

Diagnosis

A clinician’s index of suspicion should be raised for a parasitic infection more generally, and leishmania more specifically, by clinical presentation within the appropriate context of travel, recent or remote, to endemic regions. Sample suspect tissue for parasite or its DNA. Serology, which is both geographic and host-dependent, acts as corroborative evidence, failing as it does to distinguish between active and quiescent infection. Specie identification by molecular methods or isozyme analysis of culture have therapeutic and prognostic implications.

  • Serology (including rapid diagnostic tests): antibody produced against the parasite can be detected in cases of visceral leishmaniasis
  • Blood, skin or lymph node biopsy, or bone marrow (safer than splenic) aspirate:
    • Light Microscopy of stained tissue smear
    • Molecular methods: PCR for parasite DNA
    • Culture in Schneider’s ‘insect-cell’ medium: amastigotes transform into promastigotes and start to reproduce
Treatment

Treatment depends on type of disease (not all cutaneous disease needs treatment), species of parasite, geographical location, any concomitant illness and the immune status of host. Infectious Disease or Tropical Medicine referral individualises therapy for cases of visceral disease, taking into account both host and parasite factors. Traditional drugs used in treating leishmaniasis can be problematic and therapeutic regimens transfer poorly across geographic regions, clinical disease, or parasite species. Treatment of visceral disease includes the supportive cares of therapy for malnutrition, treatment of anaemia and bleeding, and treatment of intercurrent infection. Though relatively toxic, antimonials are curative and help induce lifelong immunity against visceral disease in most patients.

Liposomal amphotericin B (AmBisome ®), given as intravenous infusion, is the drug of choice for visceral leishmaniasis. It is better tolerated than conventional amphotericin B:

  • Immunocompetent: 3 mg/kg daily IV infusion on Days 1-5, 14, and 21 (total dose 21 mg/kg)
  • Immunosuppressed: 4 mg/kg daily IV infusion on Days 1-5, 10, 17, 24, 31, and 38 (total dose 40 mg/kg) or higher doses and/or secondary prophylaxis (chronic maintenance therapy), especially in HIV positive patients with CD4 counts < 200 cells/mm3.

The dose of liposomal amphotericin B for cutaneous disease is 3 mg / kg daily, given as an intravenous infusion, for 6-10 or more doses.

Miltefosine (Impavido ®) is an orally active agent (capsule) for cutaneous, mucosal, and visceral disease from New World species and L. donovani in patients ≥ 12 years of age (≥ 30 kg) and dosed according to weight:

  • 30 – 44 kg: 50 mg BD x 28 days
  • ≥ 45 kg: 50 mg TID x 28 days

Sodium stibogluconate (Pentostam ®) of the pentavalent antimonial (SbV) drug class, available under an investigational new drug protocol, has, in fact, been used to treat leishmaniasis since the 1940s. It is less effective in parts of south-east Asia. It is given parenterally, either intravenously or intramuscularly.

  • Cutaneous: 20 mg SbV / kg for 10-20 days
  • Mucosal/Visceral: 20 mg SbV / kg for 28 days

Others medications:

  • Amphotericin B deoxycholate
    • rescue therapy for cutaneous (and mucosal) leishmaniasis
    • visceral leishmaniasis, but generally more toxic than liposomal preparation 
      • 0.5 – 1.0 mg/kg daily or every other day IV infusion to a total dose of 15-20 mg/kg (occasionally longer)
  • Pentamidine isethionate
    • irreversible toxicity, variable efficacy (mostly in parts of south Asia)
  • Oral azoles:
    • Ketoconazole: 600 mg OD x 28 days
    • Itraconazole: 200 mg BD x 28 days
    • Fluconazole: 200-400 mg OD x 6 weeks (L. major); 8 mg/kg x 4-6 weeks (L. braziliensis)
  • Paramomycin sulfate:
    • parenteral or topical
  • Scarification works because infection is protective, with lifelong, although not cross-species, protection:
    • Liquid nitrogen
    • Thermotherapy
    • Intralesional SbV
    • Topical Paramomycin: 15% paromomycin/12% methylbenzethonium chloride in soft white paraffin

Cutaneous leishmaniasis can be treated to reduce risk of mucosal dissemination, accelerate healing of facial lesions, decrease risk of relapse, and decrease the reservoir of infection. Treated lesions flatten and soften before gradually resolving.

Prevention

Immunity

Protective mechanisms against leishmania include both innate and adaptive immune responses. Traditionally, resolving cutaneous leishmaniasis was used to inoculate the non-immune with an attenuated organism, creating a herd immunity. Occasionally recurrent infection is seen with cutaneous leishmaniasis.

Prophylaxis

There are no vaccines or drugs to prevent infection. In some parts of the world, infection in people is needed (anthroponotic) to maintain the cycle (human—sandfly—human), such as L. donovani in the Indian subcontinent. In others the transmission cycle can be sustained through reservoirs such as rodents and dogs alone (L. infantum/chagasi).

CDC recommendations:

  1. Avoid outdoor activities, especially from dusk to dawn, when sand flies generally are the most active.
  2. Wear long-sleeved shirts, long pants, and socks; and tuck your shirt into your pants.
  3. Apply DEET-based insect repellent to exposed skin and under the ends of sleeves and pant legs.
  4. Stay in well-screened air-conditioned areas … spraying living/sleeping areas with insecticide … otherwise, use a bed net [ideally, one that has been soaked in /sprayed with pyrethroid-based insecticide] and tuck it under your mattress. [Treat] screens, curtains, sheets, and clothing (clothing should be retreated after five washings).
FUTURE

Kala-azar elimination programmes (South-East Asia) have seen declining cases in the three major endemic countries of Bangladesh, India, and Nepal. Genetically engineered hematophagous (blood-feeding) insects have been used experimentally as the vector of immunisation—the ‘flying vaccinator’. Such transgenic anopheline mosquitos, expressing Leishmania Sp15 antigen, have rendered an antibody response in mice, although ethical and feasibility issues may preclude use.

SUMMARY

Leishmaniasis_summ

Synonyms
  • Kala-azar or “Black fever” (visceral leishmaniasis, India) is generally reserved for advanced visceral disease
  • Oriental sore or Button d’orient (cutaneous leishmaniasis in
  • Delhi boil (cutaneous leishmaniasis, India)
  • Baghdad boil (cutaneous leishmaniasis, Iraq)
  • Balkan sore (cutaneous leishmaniasis, Balkans)
  • Saldana (cutaneous leishmaniasis, Afghanistan)
  • Dumdum fever (visceral leishmaniasis, India)
  • Aleppo Evil (leishmaniasis, Syria)
  • Jericho Buttons (cutaneous leishmaniasis, Jordan)
  • Chiclero’s ulcer
  • White leprosy
  • Andean sickness
  • Valley sickness
Glossary
  • Definitive Host: site of parasite sexual reproduction
  • Intermediate Host: part of the life-cycle, by definition, must occur here
  • Reservoir Host: has the same stage of infection as that of humans
  • Mastigote refers to the flagellum: a promastigote is the flagellated (motile) stage; an amastigote is the stage without a flagellum (non-motile, replicative).
  • Neglected Tropical Disease (NTD): a range of tropical and subtropical infections affecting over a billion people and costing developing economies billions of dollars every year. Of some 13 NTDs, Leishmaniasis, Chagas Disease and Sleeping Sickness are the most dangerous.
References
Further Reading

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Published by Son of Pilgrim

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