Version May 2024
INTRODUCTION — Visceral leishmaniasis (VL), also known as kala-azar (black fever in Hindi), is a disease primarily caused by Leishmania donovani and L. infantum (synonym L. chagasi) that is transmitted by phlebotomine sandflies (table 1) [1]. Rarely, visceral disease has been reported in patients infected with leishmanial species usually associated with cutaneous disease, in particular, L. mexicana and L. tropica [2-5]. The major clinical manifestations caused by L. donovani and L. infantum are not generally distinguishable, and specialized techniques are needed to identify the species. However, treatment decisions for VL usually do not require species identification since they are based on disease severity, geographic origin, and the presence of HIV and other coinfections.
Issues related to clinical manifestations and diagnosis of VL will be reviewed here. Issues related to epidemiology and treatment of VL are discussed separately. (See "Visceral leishmaniasis: Treatment" and "Visceral leishmaniasis: Epidemiology and control".)
PATHOPHYSIOLOGY — Leishmania invade and replicate within host macrophages, evading innate and cell-mediated immune responses. Infection generally appears to persist after clinical cure of the primary infection [6,7]. Evasion and persistence are achieved through a combination of strategies including neutralization of complement components, preventing release of macrophage superoxide and nitric oxide, and suppressing induction of antigen-specific CD4+ T helper lymphocytes [7,8]. Spontaneous recovery is rare, although some relatively mild, self-limited cases of VL have been reported in a cohort of Brazilian children [9].
CLINICAL MANIFESTATIONS
Asymptomatic infection — Many leishmaniasis infections are asymptomatic, reflecting the ability of the host immune system to control the parasite [10,11]. The ratio of asymptomatic infection to clinically manifest disease varies widely, from >30:1 in Europe to 6:1 in Brazilian children and 4:1 in Bangladesh. This may reflect differences in parasite virulence, human genetic predisposition, nutritional status, the sensitivity and durability of positive results by the assay used to detect infection, and other factors [11-18].
Subclinical infections can be detected early in their course with serologic testing. The later development of a protective cell-mediated immune response can be detected via leishmanin skin testing; interferon-gamma release assays have been proposed as an alternative assay for detection of asymptomatic infection. (See 'Other assays' below.)
Most patients with subclinical infection harbor viable parasites lifelong and can develop reactivation disease in the setting of immunosuppression [6,19]. Data from United States soldiers deployed to Iraq suggest that as many of 19 percent may have asymptomatic leishmanial infection [20].
Visceral leishmaniasis — The most important clinical manifestation of VL is the syndrome known as kala-azar (Hindi for "black fever"). The incubation period is usually two to six months but can range from a few weeks to several years. Onset of symptoms is usually insidious or subacute, with slow progression of malaise, fever, weight loss, and splenomegaly (with or without hepatomegaly) over a period of weeks to months [10]. In rare cases, acute febrile illness can occur with rapidly progressive symptoms.
Patients may complain of abdominal discomfort and fullness that may be localized to the left upper quadrant. The spleen is usually firm and minimally tender, but in some patients palpation is quite painful, presumably due to capsular pressure from rapid enlargement [21]. Hepatomegaly is usually less marked than splenomegaly. Lymphadenopathy may be observed in East African VL but is rare outside this region.
Since parasites replicate in the reticuloendothelial system, very high parasite loads accumulate in the spleen, liver, and bone marrow. Severe anemia can occur due to bone marrow suppression, hemolysis, and splenic sequestration. Advanced kala-azar is associated with marked cachexia, hypoalbuminemia, and edema. Late in the course of disease, hepatic dysfunction, jaundice, and ascites can occur. Thrombocytopenia and hepatic dysfunction contribute to hemorrhagic complications. Patients may have spontaneous bleeding from the gingiva, nasal mucosa, or other sites. Rarely, chronic diarrhea and malabsorption can occur as a result of parasitic invasion of the intestine [22].
Disseminated intravascular coagulation is a rare but potentially lethal complication of VL [23,24]. The condition may occur with or without hemophagocytic lymphohistiocytosis [25]. Management includes prompt antileishmanial treatment as well as management of the coagulopathy. (See 'Hemophagocytic lymphohistiocytosis' below and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
Kala-azar ("black fever") refers to darkening of the skin, which is a common symptom in South Asia but not elsewhere [26]. This appears to have been more common in classic descriptions of the disease from the early 20th century but has also been reported in more recent case series [21].
Immunosuppression increases risk for secondary bacterial infections. Among 30 Brazilian children with VL, 60 percent developed bacterial infections (eg, cutaneous and oral mucosal infections, pneumonia, otitis media, gastrointestinal infections, and sepsis) [27]. (See 'Pathophysiology' above.)
Kala-azar during pregnancy can lead to spontaneous abortion or congenital leishmaniasis [28].
Kala-azar is nearly always lethal without treatment [29-31]. Even with treatment, fatality rates can be 10 percent or higher. Jaundice, wasting, severe anemia, and HIV coinfection are associated with increased mortality [32-34]. The triad of HIV, VL, and tuberculosis is increasingly reported in India and Ethiopia [35]. Tuberculosis coinfection also increases VL mortality, even in the absence of HIV [36,37]. (See 'HIV-VL coinfection' below.)
Viscerotropic disease — Viscerotropic leishmaniasis is a term used for a systemic illness similar to but substantially milder than kala-azar. The syndrome was described among eight United States military veterans of the 1991 Gulf War and was attributed to L. tropica infection (a species that usually causes cutaneous disease) [5].
Symptoms included fever, malaise, cough, intermittent diarrhea, abdominal pain, adenopathy, and mild hepatosplenomegaly. Treatment with sodium stibogluconate was administered to six patients; the remaining two had spontaneous recovery without antileishmanial treatment.
Renal impairment — Mild renal impairment appears to occur in a significant proportion of adults and children with VL [38-41]. Most published data come from areas where VL is due to L. infantum, but a study of children with VL in India suggests that both parasite species affect the kidney [42].
One study of 49 adults in Brazil demonstrated abnormal urinalysis (proteinuria, hematuria, and/or white blood cells) in 32 percent, elevated creatinine in 16 percent, elevated blood urea nitrogen in 8 percent, elevated quantitative proteinuria in 57 percent, and creatinine clearance <80 mL/minute/1.7 m2 in 37 percent of patients [39]. Of seven patients who underwent renal biopsy, all had interstitial nephritis and three also had glomerulonephritis (considered minimal in two cases). The renal injury was reversible with effective treatment of VL. Within one month of treatment, all patients had normal serum creatinine and blood urea nitrogen concentration; the glomerular filtration rate improved but remained mildly diminished in 32 percent of cases.
Another study including 146 Brazilian children noted renal impairment in 45 percent of cases [40]. The estimated glomerular filtration rate was reduced by 25, 50, and 100 percent in 67, 31, and 1 percent of cases, respectively. The risk of renal impairment was increased among younger children and those with secondary bacterial infection. Patients treated with amphotericin had a lower rate of renal impairment compared with those treated with meglumine antimoniate. No patients required dialysis.
In a study of 40 Indian children between 2 and 14 years old with VL, 10 percent had albuminuria, 20 percent had white blood cells in urine, 10 percent had hematuria, 37 percent had microalbuminuria, and 27 percent had decreased estimated glomerular filtration rate (values of 60 to 89 mL/minute/1.73 m2) [42]. Renal injury in VL is generally attributed to immune-complex interstitial nephritis, but animal studies suggest that the etiology may also involve cellular inflammatory responses [41,43]. Based on these data, renal function should be monitored routinely in VL, but the only treatment needed in most cases is effective antileishmanial therapy.
Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is a systemic disorder of excess immune activation that can be triggered by certain infections; it is an uncommon complication of VL [44,45]. However, the incidence may be greater in VL-endemic areas than previously thought. As an example, in one series of 127 children with VL severe enough to warrant admission to a tertiary care hospital in Brazil, HLH was observed in 28 percent of cases [46]. HLH and VL share clinical features including fever, hepatosplenomegaly, and pancytopenia; the diagnostic criteria for HLH are discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
Timely diagnosis is important; while 60 to 70 percent of patients with HLH secondary to VL respond to antileishmanial treatment alone, a delay in diagnosis of HLH may increase the need for adjunctive therapy [45]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
Laboratory findings — Nonspecific laboratory findings of VL include anemia, neutropenia, eosinopenia, and thrombocytopenia [10]. The anemia is normocytic and normochromic, unless iron deficiency is also present. The etiology of anemia is thought to be multifactorial, including bone marrow suppression, hemolysis, and hypersplenism [47]. An elevated neutrophil count is uncharacteristic of VL and should prompt a search for secondary bacterial infection. Elevated liver enzymes and bilirubin are also seen. Hypergammaglobulinemia results from polyclonal B cell activation. Severe anemia and frank jaundice are associated with a poor prognosis [32,36,48].
DIAGNOSIS
Clinical approach — Diagnostic methods to establish the diagnosis of VL include visualization of the characteristic amastigote in smears or tissue (histopathology), parasite isolation by in vitro culture, molecular detection of parasite DNA, and serologic testing [1]. It is reasonable to pursue multiple diagnostic approaches to maximize the likelihood of a positive result in conjunction with the expertise of a reference laboratory. Serologic testing is warranted for patients with suspected VL who have negative or inconclusive results for histopathology, culture, and molecular testing [1].
Definitive diagnosis of VL requires the demonstration of parasite by smear or culture in tissue (usually bone marrow or spleen). The utility of less invasive diagnostic tools (such as demonstration of specific antibodies, antigens, or parasite DNA in peripheral blood specimens) depends on the clinical status of the patient, the geographic origin of the parasite, the methods employed, and laboratory experience [49]. In patients with HIV infection, the sensitivity of serologic tests is diminished; in these patients, parasite loads are very high, raising the sensitivity of culture and molecular assays in peripheral blood [1,50,51].
An expert review recommends against routine diagnostic testing for asymptomatic leishmanial infection, including in those who may undergo immunosuppressive therapy [1].
Clinical and laboratory consultation for VL diagnosis, including access to serologic and molecular testing, culture medium, and slide review, are available by contacting the United States Centers for Disease Control and Prevention (CDC) Parasitic Diseases Public Inquiries line (404-718-4745; email [email protected]) or, for emergencies outside business hours, the CDC Emergency Operations Center (770-488-7100). Diagnostic information, an image library, and consultations are also available through the CDC DPDx website. The Walter Reed Army Institute of Research (email [email protected]) also provides diagnostic services (240-595-7353) for active duty military personnel.
Specimen collection — Bone marrow aspiration (for histopathology, culture, and molecular testing) is the preferred diagnostic specimen. Other potential tissue specimens (for histopathology, culture, and molecular testing) include spleen, enlarged lymph nodes, and whole blood (buffy coat). Serum should be collected for detection of antileishmanial antibodies for patients with suspected VL who have negative or inconclusive results for histopathology, culture, and molecular testing [1].
In immunocompromised individuals, blood is a useful diagnostic specimen for buffy coat histopathology examination, culture, and molecular testing.
Diagnostic tools
Histopathology — Histopathologic demonstration of parasite requires needle aspiration or biopsy of affected organs [1]. Usually, bone marrow or spleen aspirations are performed (sensitivity 70 and 96 percent in one comparative analysis); in Sudanese VL, lymph node aspiration can also be performed, although sensitivity is lower than at the other sites (sensitivity 58 percent) [52].
Splenic aspiration is associated with risk of splenic hemorrhage or bowel perforation. These risks are reported to be low in experienced hands, but the complications can be lethal [49,53,54]. Splenic aspiration should be performed only if the platelet count and prothrombin times are adequate.
Bone marrow aspirates are generally safer than splenic aspirates and in one study the sensitivity of bone marrow examination was found to be proportional to the amount of time spent examining the smear (66 and 92 percent at five minutes and one hour, respectively) [53].
Aspirated material should be inoculated into culture and used to prepare a Giemsa-stained smear [55]. Biopsy specimens should be prepared with tissue sections as well as touch preparation, which facilitates visualization of intracellular amastigotes in a cell monolayer [49].
Histopathologic diagnosis requires visualization of amastigotes; these are spherical or ovoid bodies that measure 1 to 5 microns long by 1 to 2 microns wide. Amastigotes are usually found within macrophages but may be seen outside of cells, especially in touch preparations. Amastigotes possess a large nucleus and a prominent deeply stained rod-like organelle called the kinetoplast, made up of tightly concatenated extranuclear DNA. The presence of the kinetoplast is the characteristic that most clearly distinguishes Leishmania amastigotes from Histoplasma, whose size is similar. The parasite load can be quantified based on a scale from 0 (no parasites in 1000 microscopic fields) to 6+ (>100 parasites per microscopic field) [55]. Because the number of parasites can vary widely from field to field, quantification requires careful, prolonged examination of the slide (picture 1).
Culture — Culture can be performed in Novy-McNeal-Nicolle or other parasitic growth media (available upon request from the CDC) [49]. Two to three drops of buffy coat, bone marrow, or splenic aspirate are inoculated into the medium. The culture is checked weekly by microscopy for the presence of promastigotes for up to four weeks after inoculation [56,57]. Growth usually occurs within two weeks but may take longer using material with few parasites. An adaptation using microtiter plates has been successfully applied in India [58]. The sensitivity of culture depends on the parasite load in the sampled material but is generally 60 to 85 percent [56-58].
Molecular techniques — Polymerase chain reaction (PCR) has been used for diagnosis of VL; many different primer sets, protocols, and visualization methods have been evaluated [59-63]. PCR sensitivity is higher than for smear or culture but is variable depending on the tissue used [64,65]. Sensitivity is highest in tissues (eg, spleen or bone marrow); it is more variable in peripheral blood, likely because the circulating parasite load varies with the severity of disease.
Serologic tests — In areas with access to advanced laboratory techniques, serologic testing is used primarily for patients with suspected VL who have negative or inconclusive results for histopathology, culture, and molecular testing [1]. In endemic regions with limited laboratory access, serological tests are used as the primary test to confirm the diagnosis in patients with high clinical suspicion of VL [66]. Indirect fluorescent antibody tests (IFA) and enzyme-linked immunosorbent assays (ELISAs) are useful diagnostic tools since VL infection stimulates intense polyclonal B cell activation, leading to production of a broad array of antibodies [67].
The direct agglutination test (DAT) is a diagnostic tool that can be read by eye and therefore requires less equipment than ELISA so can be useful in developing settings [68]. The sensitivity and specificity of serologic assays vary depending on the antigen and format used [49,69]. In general, the assays that use whole parasite antigens have high sensitivity but relatively low specificity because of cross-reaction with Chagas disease, malaria, and other infections (as well as nonspecific cross-reactivity) [69].
The recombinant kinesin antigen (rK39) is a useful antigen in ELISA assays with high sensitivity and specificity in immunocompetent patients in the Indian subcontinent (92.8 to 100 percent and 96 to 100 percent, respectively) [70-72]. The sensitivity is lower and more variable in East Africa and Brazil (61.5 to 91 percent), although specificity remains high (>95 percent in Brazil, 90.8 to 98 percent in Africa) [73-75]. This antigen has also been adapted for use in immunochromatographic strip format as a rapid test that requires minimal equipment and is easy to use in developing settings [49,73,76,77]. The accuracy of the rK39 tests is comparable to the direct agglutination test.
In regions where VL is endemic, positive antibody test results may be observed among asymptomatic individuals with subclinical infection [12,76]. Patients with clinical recovery after successful treatment of VL continue to have positive serology for months to years, so these assays cannot be used to assess response to treatment [1,12,78]. For these reasons, a positive serological test is not definitive proof of active VL; such results must be interpreted in the context of clinical and epidemiologic information. Serum antibodies may be low or undetectable in immunocompromised individuals.
Prior to the development of the assays described above, one early diagnostic tool was the formol-gel (aldehyde) test; placing a drop of formaldehyde in the serum from a patient with VL would cause the specimen to form a gel. However, this finding is observed only when the disease is quite advanced. In Nepal and Uganda, the sensitivity was noted to be 40 to 66 percent; specificity was also low [79,80]. This test was widely used from the 1920s until more specific immunologic testing became available in the 1980s.
Other assays — Assays that do not play an important role in diagnosis of VL include the leishmanin skin test, interferon-gamma release assays (IGRAs), and the urine leishmanial antigen assays.
The leishmanin skin test (LST) (also called the Montenegro skin test) is almost uniformly negative in active VL and has no role in VL diagnosis [81]. The test is a valuable tool for assessing the degree of exposure and immunity in a population; a positive response usually develops 2 to 24 months after clinical recovery [81-84]. Recovered immunocompetent patients usually have strong leishmanin skin test responses; HIV coinfection is associated with anergy to Leishmania antigens.
IGRAs have been proposed as an alternative to LST for identification of patients with asymptomatic infection. However, limited comparative data suggest that IGRA may be less sensitive than LST [85]. IGRAs can be positive in patients with protective immunity or in the setting of active VL. IGRAs can be conducted in whole blood or in isolated peripheral blood mononuclear cells [20,86-88].
SPECIAL CIRCUMSTANCES
Post-kala-azar dermal leishmaniasis
Clinical manifestations — Post-kala-azar dermal leishmaniasis (PKDL) is a chronic skin rash observed following clinical response to treatment for VL due to L. donovani [89,90]. PKDL usually presents with erythematous or hypopigmented macules that sometimes progress to plaques or nodules (picture 2 and picture 3 and picture 4) [89]. The lesions resemble (and must be differentiated from) those of leprosy but are not associated with sensorineural changes [91]. Risk factors for progression to PKDL are uncertain but may include immune response to infection, parasite strain, and efficacy of therapy [90,92,93].
PKDL has been described among patients in the Horn of Africa and in South Asia. In Sudan, about 50 to 60 percent of patients with VL develop PKDL within six months of treatment; most cases are mild and resolve without further therapy [89]. In South Asia, the incidence of PKDL after VL is about 5 to 15 percent, with an average interval of about two years [90,94,95].
Diagnosis — PKDL is diagnosed by microscopy (skin biopsies or slit skin specimens), culture, and/or molecular methods [96,97]. In macular lesions, parasites are sparse and may be difficult to detect in smears or histology (microscopy sensitivity 50 percent or lower). However, real-time polymerase chain reaction (PCR) in 3-mm skin biopsies has been shown to have sensitivity of 91 percent in one study including 91 patients with macular PKDL [98]. Serological tests are often positive in patients with PKDL although it is uncertain whether positive serology is an indicator of PKDL or a persistent antibody response to the antecedent infection, since serum antibodies can persist for years after treatment [96,97]. (See 'Serologic tests' above.)
The treatment of PKDL is discussed separately. (See "Visceral leishmaniasis: Treatment", section on 'Post kala-azar dermal leishmaniasis'.)
HIV-VL coinfection — HIV coinfection of VL has been identified as an emerging challenge for VL control [50]. HIV infection increases the risk of VL and, conversely, VL accelerates HIV disease progression. The problem is severe in parts of eastern Africa, particularly Ethiopia, where the prevalence of HIV infection in VL patients was reported to be as high as 40 percent in earlier studies and 18 percent in subsequent publication [51]. In Brazil in 2011, the ministry of health noted a coinfection rate of 6 percent of VL cases. Another study among 2077 patients with VL in Bihar, India, noted 2.4 percent with newly diagnosed HIV infection [99].
Clinical manifestations — In general, patients with HIV-VL coinfection present with the manifestations described in the preceding section. Splenomegaly was observed less frequently observed in the setting of HIV-coinfection (80 versus 97 percent in one series) [100]. (See 'Visceral leishmaniasis' above.)
Among patients with profound immunosuppression (eg, CD4 <50), parasitic infection of atypical sites may occur, including the gastrointestinal tract, peritoneal space, lung, pleural space, and skin [100-103]. Esophageal involvement can lead to dysphagia and odynophagia, which must be distinguished from other causes of esophagitis such as candidiasis [101]. Mucocutaneous manifestations include nonulcerative cutaneous lesions that may mimic Kaposi's sarcoma, nodular diffuse leishmaniasis, mucosal lesions, and PKDL [103-106].
Diagnosis — HIV-VL coinfected patients tend to have relatively low antibody titers [101,107]. In one study, the sensitivity of various serological tests ranged from 25 to 50 percent [108]. Therefore, histopathologic or molecular confirmation is warranted for definitive diagnosis [107]. (See 'Histopathology' above.)
In contrast to serologic tests, molecular techniques tend to have high sensitivity in HIV-VL coinfected patients, since in these individuals the parasite load in peripheral blood specimens is generally high [59]. The parasite load tends to be inversely proportional to the CD4 count; in patients with very low CD4 counts, PCR and hemoculture have high sensitivity, and amastigotes may be visualized in buffy coat smears. (See 'Molecular techniques' above.)
The treatment of HIV-VL coinfection is discussed separately. (See "Visceral leishmaniasis: Treatment", section on 'HIV coinfection'.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of VL includes:
●Malaria – Both malaria and VL may present with fever, malaise, and splenomegaly; symptoms of malaria generally occur acutely whereas symptoms of VL tend to be chronic. Tropical splenomegaly can also occur in the setting of chronic malaria. The diagnosis of malaria is established by blood smear or rapid diagnostic testing. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for diagnosis of malaria".)
●Histoplasmosis – Patients with acute histoplasmosis present with fever, fatigue, hepatosplenomegaly, and pancytopenia; these manifestations usually occur in the setting of immunosuppression. The diagnosis may be established by antigen testing, culture, or histopathology. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV".)
●Amebic liver abscess – Patients with amebic liver abscess usually present with one to two weeks of right upper quadrant pain and fever; other symptoms may include sweating, malaise, weight loss, and anorexia. The diagnosis is established by radiographic imaging. (See "Extraintestinal Entamoeba histolytica amebiasis".)
●Schistosomiasis – Hepatosplenic schistosomiasis consists of granulomatous inflammation and subsequent fibrosis of the periportal spaces of the liver, with subsequent portal hypertension and splenomegaly. The diagnosis is established by visualization of eggs on microscopy and/or serology. (See "Schistosomiasis: Epidemiology and clinical manifestations" and "Schistosomiasis: Diagnosis".)
●Lymphoma – Lymphoma may present with lymphadenopathy, hepatomegaly, splenomegaly, cytopenia, fever, night sweats, and weight loss. The diagnosis is established by histopathology. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Hodgkin lymphoma: Epidemiology and risk factors".)
●Tuberculosis – Extrapulmonary tuberculosis may present with seeding of nearly any organ of the body, including hepatic and/or splenic disease. The diagnosis is established by culture of acid-fast bacilli from the sputum or other fluid/tissue. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leishmaniasis".)
SUMMARY
●Visceral leishmaniasis (VL) is primarily caused by L. donovani and L. infantum (synonym L. chagasi). Leishmania invade and replicate within host macrophages, evading innate and cell-mediated immune responses. Infection generally appears to persist after clinical cure of the primary infection. (See 'Pathophysiology' above.)
●Many leishmanial infections are asymptomatic, reflecting the ability of the host immune system to control the parasite. The ratio of asymptomatic infection to clinical infection varies widely and may depend on a variety of factors. Most patients with subclinical infection harbor viable parasites lifelong and can develop reactivation disease if immunosuppression occurs. (See 'Asymptomatic infection' above.)
●The most important clinical manifestation of VL is the syndrome known as kala-azar (Hindi for "black fever"). The incubation period is usually two to six months but can range from a few weeks to several years. Onset of symptoms is usually insidious or subacute, with slow progression of malaise, fever, weight loss, and splenomegaly (with or without hepatomegaly) over a period of months. Less frequently, acute febrile illness can occur with rapidly progressive symptoms. (See 'Visceral leishmaniasis' above.)
●Definitive diagnosis requires demonstration of the parasite by either histopathology or culture of material obtained by needle aspiration or biopsy from affected organs (usually bone marrow or spleen). Aspirated material should be inoculated into culture and the remainder used to prepare a Giemsa-stained smear. Biopsy specimens should be prepared with tissue sections as well as touch preparation. Histopathologic diagnosis requires visualization of amastigotes; culture can be performed in Novy-McNeal-Nicolle or other parasitic growth media. Molecular methods (ie, polymerase chain reaction) can also be used to detect parasite in tissue or peripheral blood. (See 'Histopathology' above and 'Culture' above and 'Molecular techniques' above.)
●Serologic tests including indirect fluorescent antibody tests (IFA) and enzyme-linked immunosorbent assays (ELISAs) are useful diagnostic tools. The direct agglutination test (DAT) requires less equipment than ELISA so is useful in developing settings. The recombinant kinesin antigen (rK39) is a useful antigen in ELISA assays as well as in immunochromatographic strip format as a rapid test. A positive serological test is not definitive proof of active VL; such results must be interpreted in the context of clinical and epidemiological information. (See 'Serologic tests' above.)
●Post-kala-azar dermal leishmaniasis (PKDL) is a chronic skin rash typically observed following clinical response to treatment for VL. PKDL occurs in up to 60 percent of VL patients in East Africa and in 5 to 15 percent of VL patients in the Indian subcontinent. PKDL is rare in areas with L. infantum VL. It usually presents with erythematous or hypopigmented macules, which sometimes progress to plaques or nodules. The diagnosis is made by evaluation of skin biopsies or slit skin specimens by microscopy, culture, and/or molecular methods. (See 'Post-kala-azar dermal leishmaniasis' above.)
●Patients with HIV-VL coinfection may have a lower incidence of splenomegaly. Among patients with profound immunosuppression parasitic infection of atypical sites may occur, including the gastrointestinal tract, peritoneal space, lung, pleural space, and skin. HIV-VL coinfected patients tend to have relatively low antibody titers but molecular techniques have good sensitivity given generally high levels of parasitemia in peripheral blood specimens. Histopathologic or molecular confirmation is warranted for definitive diagnosis. (See 'HIV-VL coinfection' above.)
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