P. vivax is increasingly recognized as responsible for severe malaria in endemic areas and also in imported malaria [8, 9]. In a recent retrospective study conducted in Sweden, Wangdahl et al. claimed that 7.7% of imported P. vivax cases were severe, which was comparable to the proportion seen with P. falciparum (9.4%) [9]. Those surprising results may reflect an increase or a better diagnosis of severe cases due to P. vivax during the last decades. However, as single nor mixed infections in their series were not systematically confirmed by PCR, it is possible that the number of severe P. vivax cases was over estimated due to unrecognized association with P. falciparum. In the both cases presented here, we confirmed by PCR assays that P. vivax was the unique species involved in the malaria episodes.
Both patients suffered from septic shock, which is a criterion frequently reported for P. vivax severe malaria [6, 9, 10]. Patient 2 showed a marked hyperbilirubinemia (102 mol/L) on his first visit as a clinically uncomplicated malaria episode was diagnosed. The current WHO criteria for severe forms of malaria include hyperbilirubinemia with a threshold > 50 mol/L [11, 12]. We agree with other authors that hyperbilirubinemia, when isolated, does not seem to be a suitable criterion for imported severe malaria [9]. At his third visit, as patient 2 developed a severe episode, the bilirubinemia was slightly above the threshold (52 mol/L). Patient 1 had a value below the threshold (20 mol/L) during his severe episode.
In nonendemic areas, older age is a risk factor for severe malaria for P. falciparum and for other species [9, 13]. It may be underlined that both patients were young and thus were not particularly at risk for this point.
To our knowledge, imported malaria episodes due to other species than P. falciparum usually do not evolve towards the death of travelers [9, 14] but in some instances they may have led to serious complications and important residual damages [15]. As their condition deteriorated, both patients presented here were rapidly admitted in ICU where they received appropriate treatments. Thus, both patients recovered without sequelae.
Both patients had not traveled recently in a malaria endemic area and did not live near an airport. None of the patients had reported an episode of severe malaria when they were still in endemic area. P. vivax is prevalent in Afghanistan and Pakistan and hepatic dormant forms (hypnozoites) may persist several years in the liver of infected subjects [16, 17]. There are different strains of P. vivax according to geographical region/endemicity areas, with relapse patterns that vary by latency (time to first relapse), likelihood of relapse, and frequency of relapses [17]. The temperate strains, including those found in Afghanistan and in the North of Pakistan, relapse much more slowly than other strains (up to two years or more) [17]. They may also exhibit extended incubation period (7–14 months) [16, 18, 19]. Much longer incubations (> three years) are exceptionally reported for P. vivax in the literature [20]. We inferred that Patient 1 presented at his first visit to our hospital during a relapse because he had not traveled in endemic area since at least three years. However, as we did not observe the primary episode by ourselves, we cannot formally exclude an exceptionally long incubation for this case.
The cases presented here are particular in that the severity of the attacks revealed itself not at the primary infection but on relapses. Severe P. vivax episodes have been already reported in endemic areas after 2–3 relapses in the case of strains with long incubation [20]. To our knowledge, such cases have not been reported previously in imported malaria. It is generally admitted that a relapse originates from a single genotype which is dormant in the liver [21, 22]. As infections are often polyclonal [23, 24], the clonal parasite population responsible of the relapse may be different from the one giving the primary infection or other subsequent relapses. Relapses may also result from activation of heterologous latent hypnozoites acquired from previous inoculations [25]. Thus, the parasites responsible for a severe relapse may be more virulent than the parasites observed during other episodes. It is also possible that the patients experienced a degradation of their health during their stay in France due to difficult conditions of living of immigrants or refugees.
In conclusion, clinicians should be aware of the potential severe complications associated with P. vivax in imported malaria, even though the primary infection is uncomplicated. A radical treatment with primaquine or tafenoquine should be implemented whenever possible in order to avoid relapses, severe or not [26, 27].