Reply to Lin et al.

To the Editor—We thank Lin and colleagues [1] for their interest in our work and welcome the opportunity to exchange further thoughts about this interesting topic. Indeed, in light of the data published so far characterizing latency periods of Plasmodium ovale spp. in returning travelers [2-4], our findings give rise to questions.

We wholeheartedly agree that the absence of P. ovale wallikeri relapse in our study is surprising, given the documentation of reappearing P. ovale wallikeri parasitemia in returning travelers. The possible explanations for this finding include differences in populations and treatment observation. Although data in our study [5] are from participants residing and being followed up in a highly malaria-endemic country, data in the literature come mostly from individuals residing in a malaria-nonendemic country with a travel history to a malaria-endemic country [2-4].

Thus, though our study reliably captured baseline and recurring infections, and treatment was administered under supervision, the diagnosis of precedent or so called primary infections of travel returnees, as reported in the above-mentioned studies, was neither well defined nor supported by polymerase chain reaction results. Furthermore, travelers may not have adhered to unsupervised treatment regimens. Some cases could thus reflect prolonged latency or recrudescence of the baseline infection rather than true relapse. However, we need to consider the possibility that the absence of detected homologous relapses of P. ovale wallikeri was a chance finding in an overall limited number of patients—a fact we tried to convey in our publication.

Lin et al [1] also rightly question whether our conservative definition of relapse may underestimate the true incidence of relapse events because of the exclusion of heterologous relapses, which may play a particularly important role owing to preferential suppression of homologous relapses by acquired immunity. Although we can only agree with this thoughtful comment, a conservative approach is the only way to exclude the possibility of classifying recrudescences and reinfections as relapse in a long-term follow-up study performed in a region with active transmission. Ultimately, a placebo-controlled randomized clinical trial with a hypnozoitocidal drug is required to adequately address this question.