Background

Plasmodium vivax (P. vivax) is the most widely distributed species of Plasmodium outside of Africa. In 2017, malaria caused an estimated 216 million cases globally and P. vivax accounted for more than half of all malaria cases in Asia and Latin America [1]. Autochthonous cases of P. Vivax malaria have been reported also in Europe [2]. In endemic countries, P. vivax can be associated with severe disease and death, especially in areas with high grade of chloroquine resistance where partially effective therapy and recurrent infections lead to severe anaemia and fatal malaria mostly in young children [3,4,5,6,7,8].

In some countries as the New Guinea Islands, Indonesia, Myanmar, India, Ethiopia, and South America, chloroquine (CQ) resistance against P. vivax is an emerging problem also due to the absence of reliable and sensitive methods for the detection and monitoring of antimalarial drug’s efficacy [9]. In these areas, several comparison trials have been conducted to compare the efficacy of chloroquine and artemisinin combination therapy (ACT) [10,11,12].

Artemisinin combination therapy demonstrated a faster clinical response and clearance of P. vivax parasitaemia than chloroquine with a reduction and delay in recurrence due to recrudescence or reinfection [13, 14]. In particular, the association dihydroartemisinin–piperaquine (DP) showed greater efficacy than other associations, leading to a rapid reduction of parasite biomass and to a post-treatment prophylactic effect decreasing the rate of reinfection and relapse due to the long half-life of piperaquine [15,16,17]. Furthermore, in endemic areas for P. falciparum also, misdiagnosis by routine microscopy of coinfection is frequent leading to severe consequence due to already widespread of chloroquine resistant P. falciparum [18]. For these reasons, in endemic countries, the treatment and elimination strategies had been reviewed and a unified ACT-based treatment policy has been adopted.

In Europe, the current strategy for P. vivax malaria treatment still includes the use of chloroquine for patients coming from chloroquine sensitive areas, for its wide availability and the low cost [19, 20].

In relation to the elimination program, we think that a unified treatment with ACT for all cases of imported malaria can support the goal of elimination, given effectiveness, and safety of the treatment.

To support the feasibility and efficacy of ACT use in P. vivax imported malaria, we describe five cases of imported P. vivax malaria treated with the association of dihydroartemisinin–piperaquine (Eurartesim®, Sigma-Tau, Italy) at “Lazzaro Spallanzani” National Institute for Infectious Diseases (INMI), Rome.

Case presentation

Five patients presented at the Infectious Diseases ward at INMI because of fever in returning travelers. Patients’ age ranged from 23 to 53 years old: three were female, four were not Italian. Two patients had recently traveled for touristic purposes, while other two, living in Italy since many years, recently had visited friends and relatives in their country of origin; one patient was a migrant recently arrived in Italy. No patients had taken antimalarial prophylaxis during their travel. Demographic details are summarized in Table 1.

Table 1 Demographic and clinical data
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Presenting symptoms and main results from hemato-chemical tests are reported in Table 1. Malaria rapid antigen test (RDT-Carestart malaria HRP2/pLDH Combo test) resulted positive in all except in patient 3 probably due to a false-negative result. Blood smears resulted positive for P. vivax trophozoites in all cases; in one patient, schizonts were also identified. Diagnosis of P. vivax infection was subsequently confirmed by Polymerase Chain Reaction (PCR) assay in all the cases. The sensitivity to chloroquine was not performed.

These five patients have been enrolled in a multicentre study promoted by Sigma-Tau: “Eurartesim® in patients with imported uncomplicated Plasmodium vivax malaria”. All the following inclusion criteria were satisfied: signature of informed consent, age > 18 years, uncomplicated malaria with microscopically confirmed monoinfection by Plasmodium vivax or mixed infection, ability to swallow oral medication, body weight between 24 and 100 kg for males and females, willingness to comply with the study protocol, and the study visit schedule.

All patients were shortly hospitalized for a careful clinical monitoring of possible and sudden complications, and for the surveillance of possible cardiological side effects of the treatment.

They started therapy with dihydroartemisinin–piperaquine 320/40 mg 3 cpr for 3 days, without clinical side effects and electrocardiogram alterations. In one case only, a mild increase of liver enzymes was evidenced at day 7 after the start of the therapy, with AST 66 U/L (normal range 15–40 U/L) and ALT 209 U/L (normal range 15–40 U/L), and then spontaneously regressed at follow-up. Parasite clearance time is summarized in Table 2.

Table 2 Diagnostic and follow-up data
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All patients were discharged in good clinical conditions after 5–7 days of hospitalization. After excluding G6PD deficiency, all patients received oral primaquine for 14 days to prevent a relapse of P. vivax infection. Follow-up visits, performed in 3 patients until day 42 and in 1 patient at day 21, confirmed clinical cure and clearance of parasitaemia.

Conclusion and discussion

Our preliminary experience supports that DP treatment is safe and effective in the management of patients with P. vivax imported malaria. No side effects were reported in our patients and cure rate was maintained at day 42 of follow-up in three patients, though this follow-up time is not enough to define a complete cure due to possible relapse from hypnozoite stages up to 6 months [10].

Patients described in our brief report came from different geographical areas, as Indonesia and Ethiopia, where chloroquine resistance is described. Particularly, for the management of malaria in immigrants crossing several countries before the final destination, different patterns of chloroquine sensitivity should be considered in relation to the different crossed countries. This uncertainty should support the use of a unified treatment approach.

Among different artemisinin-based combinations, the association of dihydroartemisinin–piperaquine has proved to be superior to artemether–lumefantrine (AL), with higher cure rates proved in different studies conducted in different regions. In a randomized-controlled study from Thailand comparing DP and CQ, fever and parasite clearance times were slower in the CQ group than in the DP group and, by day 28, recurrent infections were more frequent in patient treated with the CQ [15]. Comparable results have emerged from the meta-analysis by Naing et al., showing that DP is more efficacious than CQ and AL in treating uncomplicated P. vivax malaria with a better safety profile. The long half-life of piperaquine, in fact, adds to the efficacy of artemisinin derivative in rapidly reducing the parasite biomass, a prophylactic post-treatment effect decreasing the rate of reinfection and relapse [17].

Despite ACT is more expensive than chloroquine, its use may result more cost-effective, as suggested by the recent experience: indeed, the higher rate of cure and lower rate of recrudescence and reinfections contribute to make ACT a cost-saving approach [21].

All patients took the dose of DP 320 mg/40 mg 3 tablets daily as the manufacturer’s prescriptions. This dosage, according to WHO, is under-dosed in overweighed patients and in less-than 5-year-old children, resulting in a lower cure rate, and higher rate of recrudescence [1]. None of our five patients was at risk of under-dosing.

The issue of drug under-dosing, especially in children younger than 5 years, has been recently discussed in a systematic review by Commons et al. about the effect of chloroquine dose on P. vivax recurrences. The authors point out that, given that parasites rate of P. vivax peak at 2–6 years of age, the chloroquine under-dosing should carefully be considered in view of the implementation of efficacious treatment [22].

Another point to discuss is the possible emergence in the future of resistant plasmodium due to the wider use of ACT as mutations have been already described in P. vivax malaria in Cambodia, though the clinical equivalence of these mutation is still unclear [23]. The clinical impact of ACT resistance is already evident for P. falciparum malaria: recently, a case of DP treatment failure in an uncomplicated case imported from Ethiopia has been described showing recrudescence after the initial recovery [24].

Despite all the criticisms discussed, we believe that, to sustain the efforts for malaria elimination, a more extended unified malaria treatment would have practical and malariometric advantages such as the rapid reduction in parasite and gametocyte biomass, [5, 7, 8], the reduction in recrudescence also in chloroquine-sensible areas [22], the high cure rate, the limitation of further spread of chloroquine resistance, and a better management of misdiagnosed P. falciparum coinfection.

In light of these evidences, we believe that this therapeutic strategy should be adopted for patients with imported non-falciparum malaria also, because a treatment standardization is essential in view of global malaria eradication [25]. Moreover, this approach is important also for the comparison of data between endemic and imported malaria cases, and for the sharing of clinical experiences. For the purpose of treatment standardization, some clinical trials are already in progress to validate this strategy, and our data may represent a support for clinicians of western countries to timely adopt this approach.

The future challenges in treatment of P. vivax malaria are likely to include the emergence of resistance to ACT, stimulating an ongoing research effort in new pharmaceuticals and control strategies.