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

Abstract

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.

Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

“…The importance of restoring the host immunity in VL is particularly demonstrated in immunosuppressed patients, such as those who are coinfected with human immunodeficiency virus (HIV), where VL is even more challenging to treat and results in more episodes of relapse and even death (58). Furthermore, neopterin, a Th1 immune marker, has been recently evaluated in VL patients after treatment with miltefosine alone or in combination with amphotericin B (59). Neopterin is exclusively produced by macrophages, which are activated by IFN-ɣ upon treatment (60, 61).…”

Serum Levels of Soluble CD40 Ligand and Neopterin in HIV Coinfected Asymptomatic and Symptomatic Visceral Leishmaniasis Patients

“…These results confirmed the findings in 20 VL patients by Schriefer and coworkers (Schriefer et al, 1995). Likewise, Kip and coworkers recently confirmed the pharmacodynamic potential of neopterin to identify Sudanese and Kenyan VL patients at risk for VL relapse (Kip et al, 2018). Unfortunately, the longitudinal evaluation of neopterin in coinfected patients has not yet been reported.…”

Biomarkers of the early response to treatment of visceral leishmaniasis: A prospective cohort study

“…This study showed a dramatic change in the inflammatory cytokines during the 7 days after the start of therapy. Few studies have evaluated the biomarkers of response as early as this time 12 . At seven days, the concentrations of IL‐6, IL‐10 and IL‐8 were the best biomarkers of the early response, followed by the platelet and white blood cells counts.…”

“…In their systematic review, Kip et al 12 revealed few studies for the biomarkers of response as early as seven days or less. Wasunna et al 13 evaluated CRP and other acute‐phase reactants as early markers, even before seven days.…”

“…The disappearance of fever and hepatosplenomegaly and improvement of anaemia, leucopenia and thrombocytopenia, as well as liver function tests, are useful to assess the response to specific therapy. Because an exaggerated plasma pro‐ and anti‐inflammatory cytokine profile has been shown in patients with VL, particularly the inflammatory interferon gamma (IFN‐γ), interleukin 1 beta (IL‐1β), interleukin 6 (IL‐6), interleukin 8 (IL‐8), tumour necrosis factor alpha (TNF‐α) and the anti‐inflammatory interleukin 10 (IL‐10) concentration, 5 their decline also signals clinical improvement 10‐12 …”