title: IgG1 as a potential biomarker of post-chemotherapeutic relapse in visceral leishmaniasis, and adaptation to a rapid diagnostic test.
abstract: BACKGROUND
  Visceral leishmaniasis (VL), caused by protozoa of the Leishmania donovani complex, is a widespread parasitic disease of great public health importance; without effective chemotherapy symptomatic VL is usually fatal. Distinction of asymptomatic carriage from progressive disease and the prediction of relapse following treatment are hampered by the lack of prognostic biomarkers for use at point of care.
  
  
  RESULTS
  All IgG subclass and IgG isotype antibody levels were determined using unpaired serum samples from Indian and Sudanese patients with differing clinical status of VL, which included pre-treatment active VL, post-treatment cured, post-treatment relapsed, and post kala-azar dermal leishmaniasis (PKDL), as well as seropositive (DAT and/or rK39) endemic healthy controls (EHCs) and seronegative EHCs. L. donovani antigen-specific IgG1 levels were significantly elevated in relapsed versus cured VL patients (p<0.0001). Using paired Indian VL sera, consistent with the known IgG1 half-life, IgG1 levels had not decreased significantly at day 30 after the start of treatment (p = 0.8304), but were dramatically decreased by 6 months compared to day 0 (p = 0.0032) or day 15 (p<0.0001) after start of treatment. Similarly, Sudanese sera taken soon after treatment did not show a significant change in the IgG1 levels (p = 0.3939). Two prototype lateral flow immunochromatographic rapid diagnostic tests (RDTs) were developed to detect IgG1 levels following VL treatment: more than 80% of the relapsed VL patients were IgG1 positive; at least 80% of the cured VL patients were IgG1 negative (p<0.0001).
  
  
  CONCLUSIONS
  Six months after treatment of active VL, elevated levels of specific IgG1 were associated with treatment failure and relapse, whereas no IgG1 or low levels were detected in cured VL patients. A lateral flow RDT was successfully developed to detect anti-Leishmania IgG1 as a potential biomarker of post-chemotherapeutic relapse.
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Tapan
authors.initials: T
authors.lastname: Bhattacharyya
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Armon
authors.initials: A
authors.lastname: Ayandeh
authors.affiliation: Departamento de Medicina, Universidad del Norte, Barranquilla, Colombia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Falconar
authors.affiliation: Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
authors.forename: Sayda
authors.initials: S
authors.lastname: El-Safi
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Marissa A
authors.initials: MA
authors.lastname: Gripenberg
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Bowes
authors.affiliation: Coris BioConcept, Gembloux, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Thunissen
authors.affiliation: Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
authors.forename: Om Prakash
authors.initials: OP
authors.lastname: Singh
authors.affiliation: Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India; Immunology and Infection Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Department of Laboratory Medicine, Karolinska Insitutet, Stockholm, Sweden.
authors.forename: Osman
authors.initials: O
authors.lastname: Ahmed
authors.affiliation: Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
authors.forename: Osama
authors.initials: O
authors.lastname: Eisa
authors.affiliation: Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
authors.forename: Alfarazdeg
authors.initials: A
authors.lastname: Saad
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Silva Pereira
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Boelaert
authors.affiliation: Coris BioConcept, Gembloux, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mertens
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miles
mesh_terms: D000913:Antibodies, Protozoan / Q000097:blood*; D015415:Biomarkers; D002846:Chromatography, Affinity; D003955:Diagnostic Tests, Routine; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000175:diagnosis* / Q000188:drug therapy; D012008:Recurrence
chemical_list: D000913:Antibodies, Protozoan; D015415:Biomarkers; D007074:Immunoglobulin G