Overview
Symptoms such as fever, nosebleeds, bleeding gums, etc. can be treated with antimony, amphotericin B and its lipid-containing preparations, etc. Usually can be cured.
Definition
Leishmaniasis is a parasitic disease caused by the Leishmania parasite [1-4].
Leishmania can be further subdivided into 30 species of Leishmania, of which approximately 20 are pathogenic, with the most common causative species being Leishmania dubliniensis, Leishmania infantum, and Leishmania tropica.
Leishmania infection is characterized by significant clinical heterogeneity and there are no universally appropriate treatment options.
An effective vaccine against leishmaniasis is not yet available. Indoor spraying with insect repellents and the use of mosquito nets with long-lasting insect repellents can reduce the incidence of leishmaniasis.
Classification
The disease can be categorized into cutaneous leishmaniasis, visceral leishmaniasis (also known as black fever) and mucosal leishmaniasis. Visceral leishmaniasis predominates in our country [1].
Cutaneous leishmaniasis (CL)
Cutaneous leishmaniasis has been traced in the western edge of the Junggar Basin in Xinjiang.
According to the survey in Kelamayi, the prevalence of this disease is 1 to 1.6%, and it is a common disease in the area.
As a health hazard for travelers, it is often overlooked because it rarely leads to serious consequences.
Post black fever cutaneous leishmaniasis (PKDL)
Two to seven years after successful treatment of visceral leishmaniasis due to Leishmania donovani, PKDL occurs in 5% to 10% of patients, and rates as high as 50% have been reported, even during treatment of leishmaniasis.
The clinical presentation is a pigment-deficient rash or red macules, followed by the formation of papular or nodular infiltrates.
PKDL may involve the oral and genital mucosa and conjunctiva, and may be associated with cutaneous immune damage triggered by Leishmania protozoa.
Visceral leishmaniasis (VL)
Visceral leishmaniasis (VL) is categorized into anthropogenic visceral leishmaniasis (AVL), mountainous visceral leishmaniasis (MST-ZVL), and desert visceral leishmaniasis (DST-ZVL) based on the species of leishmanial protozoa infecting them, the source of the infection, and the vector of transmission [1].
AVL is caused by Leishmania dubliniensis protozoa, which is mainly distributed in Xinjiang Uygur Autonomous Region, with patients as preserved hosts and long-tubed lacewings and Chinese lacewings as the main vectors.
MST-ZVL is caused by Leishmania infantum, with dogs as the main host and Chinese lacewings as vectors.
DST-ZVL is prevalent in the northwestern desert region and is caused mainly by Alexandrine lacewing and Wu’s lacewing, with an unknown preservation host.
Mucosal Leishmaniasis
Mucosal leishmaniasis mainly occurs in some countries in South America, which can cause swelling and ulceration of the nasopharyngeal mucosa, caused by the Brazilian Leishmania protozoa, there is no such disease in China, and it will not be introduced later.
Incidence
Incidence
Leishmaniasis is one of the most neglected infectious diseases in the world, with 1.5 to 2 million new cases each year.
In China, there were 507 new cases of visceral leishmaniasis in 2015, which is a higher level in the last 10 years. However, the incidence rate remained at a low level of 0.0372/100,000 [3].
Cutaneous leishmaniasis has been found in the western edge of the Junggar Basin in Xinjiang, and according to a survey in Karamay, the prevalence of this disease is 1-1.6%, which is a common disease in the area [4].
Domestic distribution of the incidence of regional
In recent years, visceral leishmaniasis is mainly distributed in the northwestern part of China, and more cases have been reported in the southwestern part of the region, of which the three regions with the highest incidence rates are Xinjiang Uygur Autonomous Region, Gansu Province, and Sichuan Province.
Inner Mongolia Autonomous Region, Shaanxi Province, and Shanxi Province are endemic areas.
Cases in non-endemic areas are mainly adults who go to the endemic areas to work and are mainly male manual workers, while infants and young children predominate in endemic areas.
Population Distribution
The disease occurs in all months of the year, with the majority of cases occurring from February to June.
The male predominates, with a male to female ratio of about 3.4:1.
The disease occurs in all age groups, with a predominance in the age group of 6 to 55 years [5].
Causes
Causes
Leishmaniasis is caused by infection with Leishmania protozoa and there are three basic conditions that lead to epidemics [5].
Source of infection
As a zoonotic disease, animals act as the source of infection in most cases (mainly canines), but it is also seen that humans act as the source of infection.
Leishmania can infect a wide range of mammals, including rodents, canids, anurans, marsupials, primitive hoofed animals, and primates. All of these mammals could theoretically exist as storage hosts.
It is generally accepted that whiteflies have less chance of biting humans, so humans do not serve as the primary reservoir host.
It has been found that patients and subclinically infected individuals may be the most important source of infection for visceral leishmaniasis in South Asia.
Route of transmission
Transmission is mainly through the bite of a female whitefly.
Small insects of the subfamily Cylindroidea of the family Diptera are collectively known as whiteflies. There are more than 500 species of whiteflies in the world, but only 31 of them have been definitively shown to transmit leishmaniasis.
Infections caused by blood transfusions and sharing of drug injection supplies, or even vertical transmission, have also been reported.
Susceptible Population
The population is generally susceptible, with more men being infected.
The human body has no innate immunity to Leishmania, so Leishmaniasis is most common in infants and children.
Pathogenesis
Leishmania parasites are found in the bodies of lacewings. When the lacewing bites again, the protozoan enters the body and multiplies in macrophages, which can inhibit apoptosis and spread throughout the body with the bloodstream, leading to enlargement of the liver, spleen and lymph nodes, with hepatomegaly being the most common.
Visceral Leishmania protozoa are stored in domestic dogs and then transmitted from dogs to humans.
Human-to-human transmission is also possible through the use of contaminated syringes and needles.
Symptoms
Clinical manifestations of Leishmania infection in humans vary from asymptomatic carriers to cutaneous leishmaniasis and even visceral leishmaniasis.
Cutaneous Leishmaniasis
Typical symptoms
The majority of patients are asymptomatic after infection, with an incubation period ranging from 2 weeks to 3 months.
A small pruritic erythema forms on the skin at the site of the lacewing bite, followed by a papule that breaks down to form a typical skin lesion over a period of 2 weeks to 6 months.
The lesion usually heals spontaneously within 2 to 15 months, but scarring of varying size may remain. After spontaneous healing, patients have lifelong immunity to Leishmania protozoa (which may not be limited to the species of protozoa originally infected).
Recurrent cutaneous leishmaniasis
Recurrent cutaneous leishmaniasis is a more severe form of leishmaniasis that is prolonged, causes severe skin damage and even disfigurement, and is extremely difficult to cure.
It usually presents as a slowly developing scarred lesion on an exposed part of the body surrounded by disease activity. The scarcity of protozoa within the lesions makes it very easy to misdiagnose the disease.
Diffuse cutaneous leishmaniasis
Diffuse cutaneous leishmaniasis is seen in patients with cellular immunodeficiency and is characterized by polymorphic lesions, mainly acneiform or papular in form, on at least two non-contiguous areas of skin throughout the body, with rare intralesional protozoa.
Scattered macules, papules, and nodules throughout the body, or diffuse infiltrative lesions of the skin, with a clinical picture resembling tuberculoid leprosy when the skin of the head and face is involved.
Mucosal damage is present in 29% of patients. Mucosal lesions were confined to the borders of the oral and nasal mucosa. The lesions are rich in protozoa and do not ulcerate.
Visceral leishmaniasis
The incubation period tends to be 2 to 6 months, ranging from less than 10 days in the shortest cases to 34 months in the longest [6].
After being bitten by a whitefly, a localized reddish or dark red maculopapular rash containing protozoa appears. The lesions are often overlooked because they are asymptomatic.
The proportion between asymptomatically infected and clinically manifested patients varies among endemic areas.
Early symptoms
The disease tends to have a slow onset, and early symptoms are mainly nonspecific, such as irregular fever, poor appetite, and abdominal discomfort.
Fever is seen in more than 90% of patients. The fever is irregular, about 1/3 to 1/2 of the patients are bimodal fever, fever in the afternoon and evening, which can be accompanied by mild chills, and the temperature can be up to 41℃.
At this time, although there is a high fever, but the systemic toxic symptoms are not obvious, most can live a normal life.
Fever often lasts for 3 to 5 weeks and then relieves itself, and the temperature rises again after an interval of 2 to 3 weeks, and so on for several months. Children often have obvious gastrointestinal symptoms, early splenomegaly and superficial lymph node enlargement.
Intermediate symptoms
Three months after the onset of the disease, the fever becomes prolonged and irregular, and the disease becomes more and more serious.
There may be gastrointestinal symptoms such as emaciation, lack of appetite and abdominal distension.
There may also be fatigue, palpitations, dizziness, and bleeding (e.g., nosebleeds and gum bleeds).
Late-stage symptoms
In the advanced stage, patients tend to be malnourished, emaciated, depressed, with rough and dry skin, scanty hair, and dark skin on the hands, feet, face, and abdomen due to hyperpigmentation, from which black fever gets its name.
Normal development may be affected in pediatric patients.
Severe anemia may be accompanied by swelling.
Those with concurrent cirrhosis may have ascites and jaundice.
Common Signs
The most common signs in patients with visceral leishmaniasis are splenomegaly and hepatomegaly.
Spleen
An enlarged spleen can be palpated 2 weeks after the onset of fever, and the younger the patient, the earlier the enlargement of the spleen.
Early on, it is smooth, soft, and nontender, and after 4 to 6 months, it is often flat to the umbilicus or below the umbilicus, and may eventually enter the pelvic cavity.
In advanced stages, the spleen often becomes hard. There is usually no tenderness in the spleen, but if there is infarction, hemorrhage, or perisplenic inflammation in the spleen, there may be pain and tenderness in the left upper abdominal splenic region.
Liver
The liver may be mildly or moderately enlarged, often following splenomegaly.
The liver may be enlarged to 1-2 cm below the rib margin without tenderness, and more than 5 cm below the rib margin is rare.
About 93.2% of patients with long duration of illness and malnutrition may have both liver and spleen enlargement.
Consultation
Department of Medicine
Department of Infectious Diseases
If you have been bitten by an unidentified insect recently and have developed red spots or pimples on the skin at the site of the bite, as well as fever, weight loss, lack of appetite, and abdominal distension, it is recommended that you consult the Department of Infectious Diseases.
Dermatology
Dermatology may also be consulted if the above symptoms are present.
Preparation for medical treatment
Preparation for consultation: registration, preparation of documents, FAQs
Tips for the doctor
A full body checkup may be required, so wear loose-fitting clothing and avoid clothing made of metal.
If you have a fever, you may apply warm towels to your forehead or armpits to lower the temperature.
Preparation Checklist
Symptom checklist
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Are there any red spots or papules on the skin?
Is there fever and what are the changes?
Is there any lethargy, lack of appetite, bloating?
Any weakness, palpitations, dizziness?
Any nosebleeds and bleeding gums?
Medical History Checklist
Any recent bites from unknown bugs (whitefly)?
Have you recently traveled to or through an infected area with Leishmania protozoa?
Checklist.
Test results for the last 6 months to bring to the doctor’s office
Laboratory tests: blood count, liver function, etc.
Imaging tests: chest CT, abdominal ultrasound, etc.
Medication list
Medication in the last 1 week, if there is a medicine box or package, you can bring it to the doctor
Antipyretics: ibuprofen, acetaminophen, etc.
Diagnosis
Patient resides in or has traveled to an infected area, presents with prolonged irregular fever with chills, hepatosplenomegaly and signs of wasting or with corresponding cutaneous mucosal manifestations, diagnosis is confirmed on the basis of laboratory findings.
Diagnosis is based on
Disease history
Patients with this disease may have the following epidemiologic history.
A recent bite from an unknown bug (whitefly).
History of travel to an infected area with Leishmania protozoa infection.
Clinical manifestations
Symptoms.
Erythema or papules on the skin.
Fever with chills.
Wasting, lack of appetite, abdominal distension.
Weakness, palpitations, dizziness.
Nosebleeds and bleeding gums.
Physical signs
Enlargement of superficial lymph nodes.
Splenomegaly and hepatomegaly.
Laboratory Tests
General Examination
Most patients with visceral leishmaniasis have varying degrees of decreased leukocytes, erythrocytes, and platelets in their blood counts, with anemia being the most common.
Bone marrow imaging suggests leukocytotoxic changes, megakaryocyte maturation disorders, and iron-deficiency anemia, while significant elevation of polyclonal gammaglobulin in peripheral blood is one of the characteristic laboratory features.
Not every patient will have the characteristic blood changes.
Pathogenetic examination
Microscopic examination of bone marrow, lymph node and spleen aspirates remains the most reliable confirmatory test for visceral leishmaniasis.
On stained smears, scattered extracellular worms due to rupture of macrophages are still seen.
Splenic puncture fluid has the highest diagnostic value (specificity and sensitivity >90%), followed by bone marrow and lymph nodes.
Microscopic examination or culture of skin lesions is less sensitive (15% to 70%), and the detection rate can be improved by combining it with immunofluorescence techniques.
Specific antibody tests
Serologic examination is currently an important method for the diagnosis of leishmaniasis, especially visceral leishmaniasis, among which the rapid test based on rK39 antigen is the most widely used, and is also widely used in China.
ELISA or immunochromatography are both reliable means of detecting circulating IgG antibodies against rK39.
Currently, rK39-based antibody tests are used in China with high sensitivity (97%-100%) and specificity (83%-85%) for the diagnosis of visceral leishmaniasis [7].
The disadvantages of the antibody test are that it does not identify disease recurrence after treatment and, in highly endemic areas, it does not differentiate between those with presenting symptoms and those with asymptomatic infection [8]. Therefore, rK39 positivity alone without clinical symptoms cannot be used as a basis for diagnosis in endemic areas.
In HIV-infected patients, due to their immunodeficiency, Leishmania protozoa infection cannot be excluded when the antibody test is negative, and other tests should be performed.
Antigen detection and molecular biology testing
Latex agglutination test detects protozoan antigens in urine with good specificity, but the sensitivity varies widely (35.8%-100.0%), which is suitable for application in HIV-infected patients.
Molecular biology testing can choose PCR, but there are fewer mature technologies to choose from. There are reports in the literature on the use of second-generation sequencing and other methods to successfully diagnose cases that cannot be detected by bone marrow aspiration and biopsy, which may be applied to the clinic in the future.
Differential diagnosis
Malaria
Similarities: Both malaria and visceral leishmaniasis may present with fever, malaise and splenomegaly.
Differences: Malaria is usually acute in onset, whereas visceral leishmaniasis tends to be chronic. Fever and splenomegaly may also occur in patients with chronic malaria. Blood smears or rapid diagnostic tests can confirm the diagnosis of malaria [9].
Histoplasmosis
Similarities: Patients with acute histoplasmosis present with fever, malaise, hepatosplenomegaly and pancytopenia, which usually occur in an immunosuppressed state.
Differences: Diagnosis is confirmed by antigen detection, culture or histopathologic examination.
Schistosomiasis
Similarities: Hepatosplenic schistosomiasis consists of granulomatous inflammation and subsequent periportal fibrosis of the liver, followed by portal hypertension and splenomegaly.
Differences: microscopic findings of eggs and/or serologic testing confirm the diagnosis [10].
Lymphoma
Similarities: patients with lymphoma may present with enlarged lymph nodes, hepatomegaly, splenomegaly, hematopenia, fever, night sweats and weight loss [11].
Differences: histopathologic examination confirms the diagnosis.
Leprosy
Similarities: the cutaneous manifestations of leprosy may overlap with a range of manifestations of cutaneous leishmaniasis.
Difference: Neuropathy is seen in patients with leprosy but does not occur in patients with cutaneous leishmaniasis.
Skin cancer
Similarities: The appearance of leishmaniasis can resemble squamous cell carcinoma.
Difference: It can be distinguished by histopathologic examination.
Treatment
Aims of treatment: to relieve symptoms, improve prognosis, and minimize sequelae [1].
Treatment principle: for patients with suspected diagnosis of leishmaniasis, serologic and pathogenic evidence specific to leishmaniasis should be actively sought, and treatment should be carried out as soon as possible after clinical confirmation of the diagnosis.
Visceral leishmaniasis
In visceral leishmaniasis, systemic application of antileishmanial agents is the only option, and splenectomy may be considered for palliation if necessary.
For patients with severe hypersplenism and a definite need for splenectomy, splenectomy can be performed after fully assessing the risks and benefits of surgery.
Antimony
In China, antimony is still the first choice of treatment, which has the advantages of cheap and easy to obtain, and experienced application.
However, antimony resistance occurs from time to time, and should be detected in time and changed to other therapeutic options.
Programs
Antimony agents are available in two preparations, sodium antimony gluconate (SSG) and glucosamine antimonate (MA), which are chemically equivalent, with the active ingredient being the 5-valent antimony ion.
In China, SSG has long been used in the first-line treatment of leishmaniasis, and the commonly used regimen is mainly the “six-day regimen”, and the “three-week regimen” can be used for patients with poor health or critical conditions.
Patients who have not been cured after one course of treatment or who have relapsed after being cured may be considered for an increase in dosage and course of treatment.
Adverse effects
The main adverse effects of antimony are cardiotoxicity, characterized by T-wave inversion, prolongation of the Q-T interval, and various types of arrhythmias.
Other adverse reactions include arthromyalgia, elevated liver and pancreatic enzymes.
Adverse drug reactions should be closely monitored during antimony application and ECGs should be tested regularly.
Amphotericin B and its lipid-containing preparations
Amphotericin B and its lipid-containing preparations are effective in the treatment of visceral leishmaniasis, with low relapse rates, and treatment with amphotericin B remains effective after relapse.
General Amphotericin B
General amphotericin B (amphotericin B deoxycholate) is efficacious, but the adverse effects are large, and should be used in experienced hospitals, and the adverse effects should be closely observed during treatment.
Amphotericin B Lipid Preparation
Amphotericin B fat-containing preparations have fewer adverse effects and can be given in single doses greater than regular amphotericin B.
There are three existing lipid-containing formulations of amphotericin B, including L-AmB, amphotericin B liposome complex (ABLC), and amphotericin B colloidal dispersion (ABCD).
Internationally, L-AmB is recommended as the first-line treatment program, and domestic L-AmB is available in China. Overseas studies have shown that the efficacy of L-AmB is similar to that of ordinary amphotericin B.
Adverse reactions
The main adverse reaction of Amphotericin B is nephrotoxicity.
Others include infusion reaction (thrombophlebitis), hypokalemia, myocarditis, leukocyte drop, liver function impairment and so on.
Therefore, the use of amphotericin B and its lipid-containing preparations must be hospitalized in an experienced hospital and the treatment should be closely monitored for adverse reactions.
Cutaneous leishmaniasis
Cutaneous leishmaniasis is often a localized infection of Leishmania. The natural history of leishmaniasis varies greatly with the severity of the disease and the species of the parasite, and the treatment should be varied accordingly.
Treatment of cutaneous leishmaniasis is varied and includes wound management, systemic application of drugs (antimony, amphotericin B, miltefosine), and topical application of drugs (topical application of baloney, intra-lesional injection of antimony).
When cutaneous and mucocutaneous leishmaniasis is complicated by visceral leishmaniasis, systemic treatment is often required, and the specific protocol can be referred to the treatment protocol for visceral leishmaniasis.
Post black fever cutaneous leishmaniasis (PKDL)
PKDL occurs in approximately 10% of patients months to years after clinical cure of leishmaniasis due to Leishmania donovani.
Conventional regimens
PKDL treatment regimens may be amphotericin B or antimony regimens.
Chemotherapy + immunotherapy
For prolonged refractory PKDL, chemotherapy + immunotherapy, i.e., 5-valent antimony conjugate vaccine (Leishmania major dead vaccine + BCG vaccine) has been reported abroad, but there is no corresponding drug available in China at present.
Prognosis
Cure
Some patients may recover spontaneously, but the vast majority of patients need to seek prompt medical attention and receive anti-Leishmania treatment in order to obtain cure.
Infected patients with different species of infected worms, different sites of involvement, and different underlying diseases have different treatment plans and treatment effects, and the current cure standard has not been standardized [1].
Cure can be categorized into clinical cure, pathogenetic cure and serologic cure.
Clinical cure
Clinical cure is marked by complete remission of clinical symptoms and signs (e.g., the patient’s fever, the remission of splenomegaly and the normalization of blood counts).
Pathogenetic cure
Pathogenetic cure is indicated by the complete disappearance of Leishmania after treatment (puncture smear, culture or PCR).
Serologic cure
Serologic cure is indicated by a significant decrease in blood antibody potency or a change in skin test from positive to negative.
Relapse
Clinical cure is rarely accompanied by pathogenetic cure, and Leishmania protozoa are often still detectable in tissues (e.g., lymph nodes), which may be one of the reasons for relapse after cure of leishmaniasis.
Hazards
The cerebral form of the disease can lead to disability or death from brain herniation.
There may be sequelae if treatment is not timely.
HIV-infected people
Most of our Leishmania protozoa and HIV co-infected patients present with visceral leishmaniasis with or without cutaneous leishmaniasis, which has a low rate of treatment response, a high rate of relapse, and aggravates the condition of AIDS, and is less tolerant to treatment.
Pregnant women
Visceral leishmaniasis during pregnancy is often accompanied by an extremely high risk.
Leishmaniasis during pregnancy can often lead to maternal death, spontaneous abortion or the need for abortion, preterm labor, babies younger than gestational age, vertical transmission of leishmaniasis, and other hazards.
Daily
Daily management
Patients with loss of appetite should eat easy-to-digest soft food, such as noodles, rice porridge, etc. Avoid cold and spicy food, and avoid rough and hard food.
Take rest, moderate exercise, reduce strenuous farm work and housework, and avoid strenuous exercise.
Follow-up review
When the patients end the drug treatment, they should again carry out the pathogenic examination and obtain the basis of cure [1].
It mainly includes negative smear and culture of bone marrow, lymph node and spleen puncture material, negative blood molecular biology diagnosis, and no recurrence 6 months after clinical cure can be used as the basis of pathogenetic cure.
Prevention
Control of the source of infection
Infected dogs are difficult to eradicate Leishmania protozoa by treatment, and inspection and trapping of infected dogs is not actionable, so the use of insecticide-containing collars can be promoted for dogs in endemic areas [1,5].
Indoor residual spraying and the use of mosquito nets containing long-lasting insecticides can reduce the incidence of leishmaniasis.
Changing the wall materials of the living environment also plays a role.
Cutting off the transmission pathway
Since leishmaniasis has a natural source of infection, its transmission pathway and circulation in human and natural environments are quite complex, so it is difficult to completely eradicate it.
Protecting the susceptible
Currently, no effective vaccine has been developed against Leishmania protozoa.
Leishmaniasis is mainly prevalent in poor and backward areas. Improving local economic and sanitary conditions is the most important means to reduce leishmaniasis.
People in infected areas should take the initiative to learn about the prevention and treatment of this disease.