The clinical presentation of visceral leishmaniasis possesses a long incubation period (ranging from a few weeks to even years), a nonspecific symptomatology, and a variable clinical course, and may pose a diagnostic challenge [1] [2] [3] [4]. The two main signs of visceral leishmaniasis are fever and pancytopenia, both being almost universally present in all patients who suffer from this type of leishmaniasis [1] [2]. Fever can range anywhere between 37-40°C and often has an irregular pattern of occurrence [5]. On the other hand, pancytopenia (including thrombocytopenia, anemia, and leukopenia) causes weakness and severe immunosuppression, thus promoting various superinfections of bacterial, viral, or parasitic origin [1] [2] [5]. Opportunistic infections are, in fact, the leading cause of death from visceral leishmaniasis, with mortality rates being as high as 75%-95% in the absence of an early diagnosis and appropriate therapy [1]. The term "kala-azar" (meaning black death) is used to describe visceral leishmaniasis that is restricted to the Old World and caused by Leishmania donovani [1]. Wasting and poor general condition induced by pancytopenia are seen in advanced stages of the disease [6]. In addition to fever and bone marrow suppression, hepatosplenomegaly is another important sign in visceral leishmaniasis, seen in up to 85-100% of patients in some studies [5]. Lymphadenitis is a less frequent manifestation [2] [5].

• Splenomegaly

  Infantile VL may begin suddenly, with high fever and vomiting, or insidiously, with irregular daily fever, anorexia, and marked splenomegaly. [ncbi.nlm.nih.gov]

  It can be difficult to diagnose this disease in endemic settings as several causes of febrile splenomegaly exist, notably malaria. [doi.org]

• Massive Splenomegaly

  Visceral leishmaniasis (VL), i.e., infection with Leishmania sp. associated with high fever, weight loss, massive splenomegaly and markedly altered laboratory parameters, is generally fatal if untreated. [ncbi.nlm.nih.gov]

  splenomegaly Laboratory tests may show pancytopenia and hypergammaglobulinaemia Complications include gastrointestinal bleeding, peripheral oedema, acute renal failure and secondary bacterial infections Generalised hyperpigmentation is a late feature [dermnetnz.org]

  There are very few pediatric conditions that can stimulate massive splenomegaly, as observed in our patient and reported in VL [ 20 ]. [ispub.com]

  VL caused by all species has five characteristic hallmark features that include organomegaly (e.g., massive splenomegaly and moderate hepatomegaly), fever, cachexia and weight loss, pancytopenia and hypergammaglobulinemia. [pedinfect.com]

• Generalized Lymphadenopathy

  lymphadenopathy, profound weakness and a wasting syndrome [11▪▪,13,14]. [journals.lww.com]

  Clinical manifestations of VL include recurrent fever, hepatosplenomegaly, generalized lymphadenopathy, pancytopenia, and anemia. Death occurs in the absence of appropriate chemotherapy ( 4 ). [jimmunol.org]

• Fever

  Herein we report an 11 month-old male infant with diagnosis of kala-azar who presented with pallor, hepatosplenomegaly, failure to gain weight, and no history of fever. [ncbi.nlm.nih.gov]

  A type of leishmaniasis occurring chiefly in India, caused by the protozoan parasite Leishmania donovani and characterized by fever, enlargement of the spleen and liver, progressive anemia and leukopenia, and weight loss. [medical-dictionary.thefreedictionary.com]

  […] ka·la-azar | \ ˌkä-lə-ə-ˈzär, ˌka- \ : a severe parasitic disease chiefly of tropical areas that is marked by fever, progressive anemia, leukopenia, and enlargement of the spleen and liver and caused by a leishmania ( Leishmania donovani ) transmitted [merriam-webster.com]

  Fever can range anywhere between 37-40°C and often has an irregular pattern of occurrence. [symptoma.com]

• Anemia

  A type of leishmaniasis occurring chiefly in India, caused by the protozoan parasite Leishmania donovani and characterized by fever, enlargement of the spleen and liver, progressive anemia and leukopenia, and weight loss. [medical-dictionary.thefreedictionary.com]

  […] ka·la-azar | \ ˌkä-lə-ə-ˈzär, ˌka- \ : a severe parasitic disease chiefly of tropical areas that is marked by fever, progressive anemia, leukopenia, and enlargement of the spleen and liver and caused by a leishmania ( Leishmania donovani ) transmitted [merriam-webster.com]

  Adverse events in the liposomal-therapy group were infusion-related fever or rigors (in 40%) and increased anemia or thrombocytopenia (in 2%); such events in the conventional-therapy group were fever or rigors (in 64%), increased anemia (in 19%), and [ncbi.nlm.nih.gov]

  Infection is characterized by pancytopenia (anemia, thrombocytopenia, neutropenia), hepatosplenomegaly, fever, and severe immunosuppression that can lead to fatal opportunistic diseases without early recognition. [symptoma.com]

• Malaise

  […] funkcionalno nepismene, kot potrebe po izogibanju morebitnim stereotipom v zvezi s tem profilom ugotavljajo naslednje en Leishmaniasis sl Stari se bo zlomil, pa če bo tekla kri en Visceral leishmaniasis causes systemic disease, presenting with fever, malaise [sl.glosbe.com]

  Common symptoms are fever, malaise, weight loss and anaemia, with swelling of the spleen, liver and lymph nodes in visceral human leishmaniasis. [ecdc.europa.eu]

  English Visceral leishmaniasis causes systemic disease, presenting with fever, malaise, weight loss and anaemia, swelling of the spleen, liver and lymph nodes; most of the cases reported worldwide occur in Bangladesh, Brazil, India, Nepal and Sudan. [mymemory.translated.net]

  […] systemic disease characterized by darkening of the skin as well as the pentad of fever, weight loss, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia Viscerotropic leishmaniasis: Nonspecific abdominal tenderness; fever, rigors, fatigue, malaise [medscape.com]

• Chills

  We report the case of a 73-year-old American traveler who presented with 3 weeks of fatigue, fevers, chills, and pancytopenia. [ncbi.nlm.nih.gov]

  It is commonly characterized by fever, chills, vomiting, anemia, hepatosplenomegaly, leukopenia, hypergammaglobulinemia, emaciation, and an earth-gray color of the skin. [icd10data.com]

• Cough

  An 18-year-old immunocompetent patient was referred to a local hospital with submandibular lymphadenopathy, nonproductive cough, and occasional fever. [intjinfection.com]

  We present a case of a 12-year-old girl with a history of recurrent fever, anorexia, cachexia, chronic fatigue, weight loss, left palpebral unilateral edema, persistent cough and pancytopenia. [ncbi.nlm.nih.gov]

  Side-effects include abdominal pain, vomiting, nausea, fatigue, headache, increase of liver enzymes, nephrotoxicity, arthralgia, fever, rash, cough, pneumonia, pancytopenia and reversible peripheral neuropathy. [clinicalmicrobiologyandinfection.com]

• Abdominal Distension

  On general physical examination, the patient was found to be thin built, pale, and afebrile with abdominal distension. Left submandibular and left axillary lymph nodes were enlarged and measured 1.5 cm in diameter. [cytojournal.com]

  Fifty-seven percent of the patients had abdominal distension, and 49% had anorexia. Fever and splenomegaly were present in more than 95% of the patients. [pedinfect.com]

  distension, abdominal pain, vomiting, nausea, bleeding tendency, paleness, jaundice, lymph node enlargement, palpable spleen and palpable liver, only a few weakly significant differences appeared. [jimmunol.org]

• Hepatosplenomegaly

  VL should be considered in the differential diagnosis in returning travellers presenting with prolonged fever, hepatosplenomegaly and/or pancytopenia. [ncbi.nlm.nih.gov]

  Infection is characterized by pancytopenia (anemia, thrombocytopenia, neutropenia), hepatosplenomegaly, fever, and severe immunosuppression that can lead to fatal opportunistic diseases without early recognition. [symptoma.com]

• Hepatomegaly

  The features of VL may be different in immunosuppressed patients, with more fever and less hepatomegaly and leukopenia than in HIV-infected patients. [ncbi.nlm.nih.gov]

• Liver Fibrosis

  The differential diagnosis includes liver fibrosis, abnormal blood flow due to splenic vein thrombosis or portal vein obstruction, and liver cirrhosis due to chronic viral hepatitis B or C, fatty liver, and alcohol use. [acgcasereports.gi.org]

A detailed patient history and a thorough physical examination are the first and perhaps crucial steps for making an initial diagnosis of visceral leishmaniasis. The vast majority of patients (> 90%) who suffer from visceral leishmaniasis come from six countries of the world: India, Bangladesh, Sudan, South Sudan, Ethiopia, and Brazil [6] [7] [8]. For this reason, the physician should conduct a detailed patient history that will cover recent travel to endemic countries, as well as possible exposure to sand flies in the last few years. After assessing the course of symptoms and their progression during the interview, a meticulous physical examination, particularly abdominal palpation, will reveal either hepatomegaly, splenomegaly, or both. In order to solidify the diagnosis, laboratory and microbiological tests need to be conducted. A basic complete blood count (CBC) is sufficient to detect pancytopenia, while directed diagnostic testing for Leishmania is broadly divided into indirect and direct methods. Serological testing (specifically enzyme-linked immunosorbent assay, or ELISA, and fluorescence antibody testing) is widely used as the main indirect test that has good sensitivity/specificity [1] [2] [3] [4]. Detection of antigen rk39 through ELISA is a very reliable procedure and is used by many laboratories over the world [3] Conversely, identification of the parasite by light microscopy and Giemsa staining from blood samples is a relatively easy and effective procedure, while lymph node, liver, spleen, or even bone marrow samples might be used for evaluation, but the risks of bleeding (particularly in the case of spleen and bone marrow) often outweigh the benefit of confirming the diagnosis histologically [1] [2] [3] [4].

• Hyperglobulinemia

  In active VL, macrophages host the replicating amastigotes in phagolysosomal compartments leading to splenomegaly, hepatomegaly, hyperglobulinemia, anemia, weight-loss, incessant fever and ultimately death if not treated. [books.google.com]

  The most consistent serum biochemistry findings in dogs with clinical canine leishmaniosis are serum hyperproteinemia with hyperglobulinemia and hypoalbuminemia, frequently expressed by a decreased albumin:globulin ratio. [msdvetmanual.com]

  Serum biochemistry revealed hyperproteinemia 100.0 g/L [54.0 – 82.0 g/L], hyperglobulinemia 83.0 g/L [23.0 – 52.0 g/L] and hypoalbuminemia 18.0 g/L [25.0 – 44.0 g/L]. [parasitesandvectors.biomedcentral.com]

• Brugia Malayi

  Murthy, Cross reactive molecules of human lymphatic filaria Brugia malayi inhibit Leishmania donovani infection in hamsters, Acta Tropica, 10.1016/j.actatropica.2015.08.018, 152, (103-111), (2015). [doi.org]

The estimated cost of treatment with amphotericin B deoxycholate was USD 1,522.70. [ncbi.nlm.nih.gov]

Visceral leishmaniasis, associated with HIV/AIDS coinfection, is becoming a more aggressive disease, complicating an accurate prognosis. [ncbi.nlm.nih.gov]

References:[3][6][7] Leishmaniasis Summary Epidemiology Etiology Cutaneous leishmaniasis Clinical features Diagnostics Treatment Prognosis Visceral leishmaniasis Clinical features Diagnostics Treatment [amboss.com]

Prognosis Prognosis is highly variable and is dependent on many factors. In those with benign, surgically resectable tumors, the reported 5-year survival rate is almost 95%. [orpha.net]

Some researchers have noted that patients with jaundice had worse prognosis [21]. [intechopen.com]

The presentation and prognosis will vary depending on the species involved. [dermnetnz.org]

CONCLUSIONS: VL in HLH patients does not exclude a genetic etiology and requires structured clinical management. [ncbi.nlm.nih.gov]

All the common etiologies were excluded in our patient, but her travel history triggered an extended work-up to investigate parasitic etiologies such as Leishmania, which are otherwise unusual to the United States. [acgcasereports.gi.org]

References:[3][6][7] Leishmaniasis Summary Epidemiology Etiology Cutaneous leishmaniasis Clinical features Diagnostics Treatment Prognosis Visceral leishmaniasis Clinical features Diagnostics Treatment [amboss.com]

It contains all of the latest facts regarding the etiology, prophylaxis, and treatment of this infection, and is of special interest because written by one who has contributed so many basic additions to our knowledge of the subject. [ajtmh.org]

/epidemiology* DNA, Intergenic/genetics DNA, Protozoan/blood DNA, Protozoan/genetics Enzyme-Linked Immunosorbent Assay Female HIV Infections/complications HIV Infections/epidemiology* Humans Iran/epidemiology Leishmania infantum/immunology Leishmania [ncbi.nlm.nih.gov]

Ref: WHO/CTD/LEISH/98.23 Leishmania/HIV co-infection - Epidemiological analysis of 692 retrospective cases. [who.int]

Knowledge gaps were identified in relation to pathophysiology, risk factors, and the role of PKDL patients in transmission. [dndi.org]

This two-page spread overviews the pathophysiology of visceral leishmaniasis—also known as Kala Azar, or black fever. [inessaskaya.com]

Useful For Suggests clinical disorders or settings where the test may be helpful Diagnosis of active visceral leishmaniasis Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Visceral [mayomedicallaboratories.com]

Verner–Morrison syndrome and WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria) (Rom J Morphol Embryol 2017;58:371) ICD coding ICD-10: C7A.8 - other malignant neuroendocrine tumors ICD-10: E16.8 - other specified disorders of pancreatic internal secretion Pathophysiology [pathologyoutlines.com]

Pathophysiology and Etiology VIP has a molecular weight of 3381, consists of 28 amino acids, and belongs to the secretin-glucagon family. The VIP gene is located on chromosome 6. [emedicine.medscape.com]

Key strategies for prevention are listed below: Early diagnosis and effective prompt treatment reduces the prevalence of the disease and prevents disabilities and death. [who.int]

The incubation period may provide an important window of opportunity for a pre-emptive "screen an treat" approach in HIV co-infected patients to prevent progression from infection to the active disease. [clinicaltrials.gov]

PREVENTION No vaccines or drugs to prevent infection are available. [wwwnc.cdc.gov]

Therefore, clinicians especially in endemic areas are highly recommended to include kala-azar among differential diagnosis of unexplained anemia without fever to prevent misdiagnosis of this potentially fatal, but treatable condition. [ncbi.nlm.nih.gov]

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