Macrophage Activation Marker Neopterin: A Candidate Biomarker for Treatment Response and Relapse in Visceral Leishmaniasis

Front Cell Infect Microbiol. 2018 Jun 1;8:181. doi: 10.3389/fcimb.2018.00181. eCollection 2018.


The Leishmania parasite resides and replicates within host macrophages during visceral leishmaniasis (VL). This study aimed to evaluate neopterin, a marker of macrophage activation, as possible pharmacodynamic biomarker to monitor VL treatment response and to predict long-term clinical relapse of VL. Following informed consent, 497 plasma samples were collected from East-African VL patients receiving a 28-day miltefosine monotherapy (48 patients) or 11-day combination therapy of miltefosine and liposomal amphotericin B (L-AMB, 48 patients). Neopterin was quantified with ELISA. Values are reported as median (inter-quartile range). Baseline neopterin concentrations were elevated in all VL patients at 98.8 (63.9-135) nmol/L compared to reported levels for healthy controls (<10 nmol/L). During the first treatment week, concentrations remained stable in monotherapy patients (p = 0.807), but decreased two-fold compared to baseline in the combination therapy patients (p < 0.01). In the combination therapy arm, neopterin concentrations increased significantly 1 day after L-AMB infusion compared to baseline for cured patients [137 (98.5-197) nmol/L, p < 0.01], but not for relapsing patients [84.4 (68.9-106) nmol/L, p = 0.96]. The neopterin parameter with the highest predictive power for VL relapse was a higher than 8% neopterin concentration increase between end of treatment and day 60 follow-up (ROC AUC 0.84), with a 93% sensitivity and 65% specificity. In conclusion, the identified neopterin parameter could be a potentially useful surrogate endpoint to identify patients in clinical trials at risk of relapse earlier during follow-up, possibly in a panel of biomarkers to increase its specificity.

Keywords: biomarker; kala-azar; liposomal amphotericin B; macrophage activation; miltefosine; neopterin; pharmacodynamics; visceral leishmaniasis.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amphotericin B / administration & dosage
  • Amphotericin B / therapeutic use
  • Biomarkers*
  • Child
  • Drug Combinations
  • Female
  • Humans
  • Kenya
  • Kinetics
  • Leishmaniasis, Visceral / drug therapy*
  • Macrophage Activation*
  • Male
  • Middle Aged
  • Multicenter Studies as Topic
  • Neopterin / blood*
  • Neopterin / metabolism*
  • Phosphorylcholine / administration & dosage
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / therapeutic use
  • Recurrence
  • Sensitivity and Specificity
  • Treatment Outcome
  • Young Adult


  • Biomarkers
  • Drug Combinations
  • liposomal amphotericin B
  • Phosphorylcholine
  • miltefosine
  • Neopterin
  • Amphotericin B