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Visceral leishmaniasis

Updated : January 4, 2024





Background

The protozoan Leishmania causes the disease leishmaniasis, which is most frequently spread by infected sandflies. In the past, it was common in tropical regions of several continents, including Africa, Europe, Asia, & America. These parasites multiply intracellularly in humans & typically manifest as a cutaneous or visceral illness. Leishmaniasis has a vast historical impact because it was known thousands of years before the common era (BCE).

Due to the absence of DNA-positive samples before the Middle Kingdom, it is believed that Egyptian trade and military expeditions to Nubia (present Sudan) are to blame for the entry of leishmaniasis throughout Egypt. Moreover, some authorities contend that the primary foci of VL (visceral leishmaniasis) were in Sudan. Moreover, a skin ailment known as the “Nile Pimple,” considered cutaneous leishmaniasis, was documented in the 1500 BC Ebers Papyrus medical texts.

A primitive type of vaccination was conducted in the Middle East & Central Asia using this prehistoric understanding of the disease. This was accomplished by injecting children’s buttocks with exudates from active lesions. Over the subsequent thousand years, leishmaniasis-like cutaneous sores were documented. Nowadays, it is believed that L. tropica was responsible for the “Balkh sore,” a condition that was once prevalent in medieval northern Afghanistan.

Leishmaniasis was first recognized as infectious by a Scottish doctor who found the parasites in a Delhi boil, but it wasn’t until similar observations were made by a Russian doctor, Piotr Fokich Borovsky, that it was thought that these bodies in Asian sores were actually protozoa, as reported in 1898. Ovoid entities were observed in 1900, and a British pathologist hypothesized that they were trypanosomes that had deteriorated. He later called this condition “dum-dum fever.” At about the same period, an article about identical ovoid structures found in native Asian Indians’ spleens was published by Irish physician Charles Donovan.

According to research on the Indian illness kala-azar or the splenic ovoid objects identified by the pathologist Leishman as well as the physician Donavan, these ovoid bodies were not trypanosomes in degeneration but rather a novel protozoan species that was later named Leishmania donovani. Subspecies like L. tropica & L. aethiopica would be discovered during the ensuing decades, among many others. Based on these organisms and their geographic distribution, the illness would be divided into new world & old-world leishmaniasis.

Epidemiology

Asia, Northern Africa, the Middle East, the Mediterranean region, & Central and South America are all home to leishmaniasis. There are between 1.5 and 2 million new infections worldwide each year, and it is present in 89 different countries.

Leishmaniasis is thought to be responsible for 70,000 fatalities annually and can lead to visceral or mucocutaneous illness. According to data from the World Health Organization from 2012, a small number of nations are home to the majority of cutaneous and visceral disorders.

Anatomy

Pathophysiology

Sandflies of the genera Lutzomyia & Phlebotomus are the most frequent carriers of the illness in the Old World & the New World, respectively. Sandflies are the primary vectors of Leishmania pathogens. As previously stated, mainly female sandflies take blood meals, and while eating these meals, the fly acquires and transmits Leishmania spp. to the host.

A disorder sand fly may puncture the skin of an affected host with its saw-like mouthparts to produce a small incision where bleeding from damaged capillaries will collect. The contagious promastigote enters the foregut of the sandfly and multiplies there. The disease subsequently spreads to the next host when the fly feeds on dogs, humans, rodents, or marsupials.

Protozoa penetrate the phagolysosomes after gaining entry to the host. Cutaneous leishmaniasis and visceral leishmaniasis can occur depending on which subgroup of phagocytic cells is infected. In CL, the protozoa attack the skin’s indigenous macrophages. As each damaged cell is loaded with amastigotes, it bursts, allowing the infection of nearby macrophages to spread quickly. Amastigotes are disseminated hematogenously to the spleen, liver, bone marrow, & intestine lymph nodes in VL, which is different from that.

Etiology

A protozoan in the family Trypanosomatidae, class Kinetoplastida, & genera Leishmania causes the illness known as leishmaniasis. Amastigote & promastigote are the two developmental phases, with the former affecting lysosomal vesicles in phagocytes. The extracellular form known as a promastigote adheres to the fly microvilli. The sandfly, an insect vector, has numerous species but different subgroups.

Phlebotomus & Sergentomyia are the organisms that spread Old World illnesses the most frequently. Lutzomyia is a species of sandfly renowned for dispersing New World illness. The length of an adult sandfly is just approximately 3.5 mm, or roughly one-third that of a tiny mosquito. They are prone to dehydration and consequently like humid settings, which contributes to the spread of disease.

As they are nocturnal, you can find these flies during the day in caves, under rocks, and in other hiding places. While at repose, they have a distinctive thoracic hump that forces the head downward or a distinctive “V” form over their backs. Females need a blood meal; males & females both get their carbs via plant juices. The carrier fly delivers the parasites to the host body during this feed.

Genetics

Prognostic Factors

Depending on the host’s innate defenses, a limited cutaneous illness frequently resolves spontaneously. When comparing hospital-based groups to community-based mortality data, there are differences in the mortality rates among individuals with the visceral disorder. The WHO estimated a case-fatality rate of 10% overall.

If medicated, a cure is generally obtained; rates are covered in the corresponding sections above. Nonetheless, mortality is much higher among HIV patients, as evidenced by the 33.6% death rate for Ethiopians who are HIV positive compared to the 3.6% for Ethiopians who are HIV negative. Despite effective therapy, side effects from drugs are frequent and usually severe.

Clinical History

Clinical History

The clinical history of visceral leishmaniasis typically involves the following stages:

  • Incubation period: The incubation period of VL can range from a few weeks to several months, depending on the individual’s immune status and the virulence of the parasite. During this period, the infected individual may not exhibit any symptoms.
  • The onset of symptoms: The first symptoms of VL usually appear gradually and include fever, chills, and malaise. Other common symptoms include weight loss, loss of appetite, and abdominal discomfort.
  • Progressive disease: If left untreated, the disease can progress rapidly, leading to severe symptoms such as anemia, enlarged spleen and liver, and edema. The skin may become pale, and the eyes may appear sunken. In severe cases, the individual may experience difficulty breathing and eventually lapse into a coma.
  • Recovery or chronic disease: With prompt and appropriate treatment, most individuals with VL can recover fully. However, some individuals may develop a chronic form of the disease, which can last for years and cause long-term health problems such as liver and spleen damage, skin lesions, and recurrent infections.

Physical Examination

Physical examination

During a physical examination of an individual suspected of having visceral leishmaniasis (VL), the healthcare provider will typically look for a combination of symptoms and signs that suggest the presence of the disease. The following are some of the key findings that may be observed during a physical exam:

  • Enlarged spleen and liver: The spleen and liver are often enlarged in individuals with VL, which can be detected by palpation of the abdomen. The spleen may be particularly enlarged and may extend beyond the rib cage.
  • Lymph node enlargement: Enlargement of lymph nodes, particularly those in the neck, may be observed in some individuals with VL.
  • Fever: Individuals with VL may have a low-grade fever that persists for an extended period.
  • Pallor: Due to anemia, individuals with VL may have pale skin and mucous membranes.
  • Weight loss: Significant weight loss may be observed in individuals with VL due to loss of appetite and other disease-related factors.
  • Skin abnormalities: Some individuals with VL may develop skin rashes, nodules, or ulcers, particularly in areas where the skin has been injured.
  • Respiratory symptoms: In severe cases of VL, individuals may experience difficulty breathing or may develop a cough.

In addition to a physical exam, healthcare providers may order additional diagnostic tests to confirm the diagnosis of VL, such as blood tests, bone marrow biopsy, or serological tests.

It is important to note that the symptoms and physical findings of VL can vary depending on the severity of the disease and the individual’s immune status. Therefore, a thorough medical history and examination are necessary to make an accurate diagnosis.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential diagnosis

  • In tropical areas, cutaneous ulcers include:
  • Yaws
  • Tuberculoid leprosy
  • Lepromatous leprosy
  • Staphylococcus infection
  • Furuncular myiasis

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

The first steps in treating infectious diseases are frequently focused on prevention. The importance of exposure to animals in regions that contain the disease, information on endemic locations, and awareness of night-time sandfly activity cannot be overstated. Permethrin-based further immunization may also reduce danger. It has also been demonstrated that efforts to vaccinate dogs and the use of pesticide dog collars reduce illness load.

The disease frequently resolves spontaneously for limited CL. Dermatological conditions, however, can be harmful, worsen secondary infections, or leave behind scars that are permanently disabled. Intralesional pentavalent antimonials, such as sodium stibogluconate & meglumine antimoniate, are first-line therapies for limited cutaneous illness. Systemic miltefosine, pentamidine isethionate, amphotericin B, granulocyte-macrophage colony-stimulating factor, or paromomycine are some alternate regimens.

Significant side effects severely restrict the use of several of these systemic medicines. Effective treatments include heat or cryotherapy in instances with fewer than five cutaneous lesions. Most of the time, systemic therapy is needed for patients with mucocutaneous leishmaniasis. First-line treatments for mucocutaneous diseases have included stibogluconate or meglumine, while the World Health Organization also suggests antimonial pentavalent.

High-dose tactics have resulted in patient survival rates as high as 95%; however, moderate dosing strategies are frequently employed to lessen side effects. Ketoconazole, Fluconazole, & itraconazole therapies have been used alone and in conjunction with amphotericin B. Regional variations in the illness, resistance, and the minor advantage they give to amphotericin’s already potent effectiveness limit their usage. Amphotericin B deoxicholate, amphotericin B (colloidal or liposomal dispersion), & pentamidine have been proven to have high cure rates (>90%). Other less successful treatments include itraconazole and antimonial pentavalent.

Treatment options for visceral leishmaniasis include amphotericin, oral miltefosine, paromomycin, & antimony disodium stibogluconate. Due to the wide range of resistances, native species frequently dictate the treatment of choice. In conclusion, although sodium stibogluconate has been utilized in East Africa, it frequently fails in India.

Liposomal amphotericin B is mostly accessible in nations with abundant natural resources, and India uses different amphotericin B formulations. In India, paromomycin has a high rate of cure, whereas it is less effective in Africa. In Africa, it is used with sodium stibogluconate as a form of therapy. Pentamidine is prescribed to AIDS patients in Europe as a secondary preventative measure in addition to primary treatment in South America.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

miltefosine 

<45 kg: 50 mg orally twice a day for 28 days
≥45 kg: 50 mg orally thrice a day for 28 days



amphotericin B liposomal 

Recommended for the treatment of visceral leishmaniasis :


Immunocompetent patients:

On days 1 to 4, 14, and 21: 3 mg/kg intravenous every day

If parasite clearance is not completed, the patient may repeat the course of treatment

Immunocompromised patients:

On days 1 to 5, 10, 17, 24, 31, and 38: 4 mg/kg intravenous every day



sodium antimony gluconate 

10 to 20mg/kg daily given through intravenous or intramuscular infusion over 5 minutes for 20 to 30 days. should not exceed a maximum dose of 850mg/day



 

miltefosine 

<12 years(<30 kgs): Safety and efficacy not established
≥12 years (30 to 44kg): 50 mg orally twice a day for 28 days
≥12 years (≥44kg): 50 mg orally thrice a day for 28 days



 

Media Gallary

References

https://www.ncbi.nlm.nih.gov/books/NBK531456/

Visceral leishmaniasis

Updated : January 4, 2024




The protozoan Leishmania causes the disease leishmaniasis, which is most frequently spread by infected sandflies. In the past, it was common in tropical regions of several continents, including Africa, Europe, Asia, & America. These parasites multiply intracellularly in humans & typically manifest as a cutaneous or visceral illness. Leishmaniasis has a vast historical impact because it was known thousands of years before the common era (BCE).

Due to the absence of DNA-positive samples before the Middle Kingdom, it is believed that Egyptian trade and military expeditions to Nubia (present Sudan) are to blame for the entry of leishmaniasis throughout Egypt. Moreover, some authorities contend that the primary foci of VL (visceral leishmaniasis) were in Sudan. Moreover, a skin ailment known as the “Nile Pimple,” considered cutaneous leishmaniasis, was documented in the 1500 BC Ebers Papyrus medical texts.

A primitive type of vaccination was conducted in the Middle East & Central Asia using this prehistoric understanding of the disease. This was accomplished by injecting children’s buttocks with exudates from active lesions. Over the subsequent thousand years, leishmaniasis-like cutaneous sores were documented. Nowadays, it is believed that L. tropica was responsible for the “Balkh sore,” a condition that was once prevalent in medieval northern Afghanistan.

Leishmaniasis was first recognized as infectious by a Scottish doctor who found the parasites in a Delhi boil, but it wasn’t until similar observations were made by a Russian doctor, Piotr Fokich Borovsky, that it was thought that these bodies in Asian sores were actually protozoa, as reported in 1898. Ovoid entities were observed in 1900, and a British pathologist hypothesized that they were trypanosomes that had deteriorated. He later called this condition “dum-dum fever.” At about the same period, an article about identical ovoid structures found in native Asian Indians’ spleens was published by Irish physician Charles Donovan.

According to research on the Indian illness kala-azar or the splenic ovoid objects identified by the pathologist Leishman as well as the physician Donavan, these ovoid bodies were not trypanosomes in degeneration but rather a novel protozoan species that was later named Leishmania donovani. Subspecies like L. tropica & L. aethiopica would be discovered during the ensuing decades, among many others. Based on these organisms and their geographic distribution, the illness would be divided into new world & old-world leishmaniasis.

Asia, Northern Africa, the Middle East, the Mediterranean region, & Central and South America are all home to leishmaniasis. There are between 1.5 and 2 million new infections worldwide each year, and it is present in 89 different countries.

Leishmaniasis is thought to be responsible for 70,000 fatalities annually and can lead to visceral or mucocutaneous illness. According to data from the World Health Organization from 2012, a small number of nations are home to the majority of cutaneous and visceral disorders.

Sandflies of the genera Lutzomyia & Phlebotomus are the most frequent carriers of the illness in the Old World & the New World, respectively. Sandflies are the primary vectors of Leishmania pathogens. As previously stated, mainly female sandflies take blood meals, and while eating these meals, the fly acquires and transmits Leishmania spp. to the host.

A disorder sand fly may puncture the skin of an affected host with its saw-like mouthparts to produce a small incision where bleeding from damaged capillaries will collect. The contagious promastigote enters the foregut of the sandfly and multiplies there. The disease subsequently spreads to the next host when the fly feeds on dogs, humans, rodents, or marsupials.

Protozoa penetrate the phagolysosomes after gaining entry to the host. Cutaneous leishmaniasis and visceral leishmaniasis can occur depending on which subgroup of phagocytic cells is infected. In CL, the protozoa attack the skin’s indigenous macrophages. As each damaged cell is loaded with amastigotes, it bursts, allowing the infection of nearby macrophages to spread quickly. Amastigotes are disseminated hematogenously to the spleen, liver, bone marrow, & intestine lymph nodes in VL, which is different from that.

A protozoan in the family Trypanosomatidae, class Kinetoplastida, & genera Leishmania causes the illness known as leishmaniasis. Amastigote & promastigote are the two developmental phases, with the former affecting lysosomal vesicles in phagocytes. The extracellular form known as a promastigote adheres to the fly microvilli. The sandfly, an insect vector, has numerous species but different subgroups.

Phlebotomus & Sergentomyia are the organisms that spread Old World illnesses the most frequently. Lutzomyia is a species of sandfly renowned for dispersing New World illness. The length of an adult sandfly is just approximately 3.5 mm, or roughly one-third that of a tiny mosquito. They are prone to dehydration and consequently like humid settings, which contributes to the spread of disease.

As they are nocturnal, you can find these flies during the day in caves, under rocks, and in other hiding places. While at repose, they have a distinctive thoracic hump that forces the head downward or a distinctive “V” form over their backs. Females need a blood meal; males & females both get their carbs via plant juices. The carrier fly delivers the parasites to the host body during this feed.

Depending on the host’s innate defenses, a limited cutaneous illness frequently resolves spontaneously. When comparing hospital-based groups to community-based mortality data, there are differences in the mortality rates among individuals with the visceral disorder. The WHO estimated a case-fatality rate of 10% overall.

If medicated, a cure is generally obtained; rates are covered in the corresponding sections above. Nonetheless, mortality is much higher among HIV patients, as evidenced by the 33.6% death rate for Ethiopians who are HIV positive compared to the 3.6% for Ethiopians who are HIV negative. Despite effective therapy, side effects from drugs are frequent and usually severe.

Clinical History

The clinical history of visceral leishmaniasis typically involves the following stages:

  • Incubation period: The incubation period of VL can range from a few weeks to several months, depending on the individual’s immune status and the virulence of the parasite. During this period, the infected individual may not exhibit any symptoms.
  • The onset of symptoms: The first symptoms of VL usually appear gradually and include fever, chills, and malaise. Other common symptoms include weight loss, loss of appetite, and abdominal discomfort.
  • Progressive disease: If left untreated, the disease can progress rapidly, leading to severe symptoms such as anemia, enlarged spleen and liver, and edema. The skin may become pale, and the eyes may appear sunken. In severe cases, the individual may experience difficulty breathing and eventually lapse into a coma.
  • Recovery or chronic disease: With prompt and appropriate treatment, most individuals with VL can recover fully. However, some individuals may develop a chronic form of the disease, which can last for years and cause long-term health problems such as liver and spleen damage, skin lesions, and recurrent infections.

Physical examination

During a physical examination of an individual suspected of having visceral leishmaniasis (VL), the healthcare provider will typically look for a combination of symptoms and signs that suggest the presence of the disease. The following are some of the key findings that may be observed during a physical exam:

  • Enlarged spleen and liver: The spleen and liver are often enlarged in individuals with VL, which can be detected by palpation of the abdomen. The spleen may be particularly enlarged and may extend beyond the rib cage.
  • Lymph node enlargement: Enlargement of lymph nodes, particularly those in the neck, may be observed in some individuals with VL.
  • Fever: Individuals with VL may have a low-grade fever that persists for an extended period.
  • Pallor: Due to anemia, individuals with VL may have pale skin and mucous membranes.
  • Weight loss: Significant weight loss may be observed in individuals with VL due to loss of appetite and other disease-related factors.
  • Skin abnormalities: Some individuals with VL may develop skin rashes, nodules, or ulcers, particularly in areas where the skin has been injured.
  • Respiratory symptoms: In severe cases of VL, individuals may experience difficulty breathing or may develop a cough.

In addition to a physical exam, healthcare providers may order additional diagnostic tests to confirm the diagnosis of VL, such as blood tests, bone marrow biopsy, or serological tests.

It is important to note that the symptoms and physical findings of VL can vary depending on the severity of the disease and the individual’s immune status. Therefore, a thorough medical history and examination are necessary to make an accurate diagnosis.

Differential diagnosis

  • In tropical areas, cutaneous ulcers include:
  • Yaws
  • Tuberculoid leprosy
  • Lepromatous leprosy
  • Staphylococcus infection
  • Furuncular myiasis

The first steps in treating infectious diseases are frequently focused on prevention. The importance of exposure to animals in regions that contain the disease, information on endemic locations, and awareness of night-time sandfly activity cannot be overstated. Permethrin-based further immunization may also reduce danger. It has also been demonstrated that efforts to vaccinate dogs and the use of pesticide dog collars reduce illness load.

The disease frequently resolves spontaneously for limited CL. Dermatological conditions, however, can be harmful, worsen secondary infections, or leave behind scars that are permanently disabled. Intralesional pentavalent antimonials, such as sodium stibogluconate & meglumine antimoniate, are first-line therapies for limited cutaneous illness. Systemic miltefosine, pentamidine isethionate, amphotericin B, granulocyte-macrophage colony-stimulating factor, or paromomycine are some alternate regimens.

Significant side effects severely restrict the use of several of these systemic medicines. Effective treatments include heat or cryotherapy in instances with fewer than five cutaneous lesions. Most of the time, systemic therapy is needed for patients with mucocutaneous leishmaniasis. First-line treatments for mucocutaneous diseases have included stibogluconate or meglumine, while the World Health Organization also suggests antimonial pentavalent.

High-dose tactics have resulted in patient survival rates as high as 95%; however, moderate dosing strategies are frequently employed to lessen side effects. Ketoconazole, Fluconazole, & itraconazole therapies have been used alone and in conjunction with amphotericin B. Regional variations in the illness, resistance, and the minor advantage they give to amphotericin’s already potent effectiveness limit their usage. Amphotericin B deoxicholate, amphotericin B (colloidal or liposomal dispersion), & pentamidine have been proven to have high cure rates (>90%). Other less successful treatments include itraconazole and antimonial pentavalent.

Treatment options for visceral leishmaniasis include amphotericin, oral miltefosine, paromomycin, & antimony disodium stibogluconate. Due to the wide range of resistances, native species frequently dictate the treatment of choice. In conclusion, although sodium stibogluconate has been utilized in East Africa, it frequently fails in India.

Liposomal amphotericin B is mostly accessible in nations with abundant natural resources, and India uses different amphotericin B formulations. In India, paromomycin has a high rate of cure, whereas it is less effective in Africa. In Africa, it is used with sodium stibogluconate as a form of therapy. Pentamidine is prescribed to AIDS patients in Europe as a secondary preventative measure in addition to primary treatment in South America.

miltefosine 

<45 kg: 50 mg orally twice a day for 28 days
≥45 kg: 50 mg orally thrice a day for 28 days



amphotericin B liposomal 

Recommended for the treatment of visceral leishmaniasis :


Immunocompetent patients:

On days 1 to 4, 14, and 21: 3 mg/kg intravenous every day

If parasite clearance is not completed, the patient may repeat the course of treatment

Immunocompromised patients:

On days 1 to 5, 10, 17, 24, 31, and 38: 4 mg/kg intravenous every day



sodium antimony gluconate 

10 to 20mg/kg daily given through intravenous or intramuscular infusion over 5 minutes for 20 to 30 days. should not exceed a maximum dose of 850mg/day



miltefosine 

<12 years(<30 kgs): Safety and efficacy not established
≥12 years (30 to 44kg): 50 mg orally twice a day for 28 days
≥12 years (≥44kg): 50 mg orally thrice a day for 28 days



https://www.ncbi.nlm.nih.gov/books/NBK531456/