This work provides a long-term review of imported malaria cases in Spain, one of the European countries where more cases are reported. Many aspects of the disease´s epidemiology, clinical presentation, diagnosis and management are analysed for the main types of patients faced in clinical practice according to their travel motivation. In addition, these key issues for malaria are compared between the most (MM) and least (SMM) frequent clinical presentations of malaria.

The main diagnostic method used in the hospital was microscopy, although it was the least sensitive (74.4%), as already demonstrated by other authors [16]. However, microscopy remains an important diagnostic tool, being able to estimate parasitemia and distinguish between the different Plasmodium species when an experienced observer performs it. ICT was the most rapid technique, showing a similar sensitivity to microscopy (78.2%), as was showed in previous studies [11, 17], but being handicapped by the inability to determine parasitemia and, in general, being only able to distinguish P. falciparum and not the other Plasmodium species for the lack of sensitivity. PCR resulted in the most sensitive technique (99.2%) allowing to distinguish between species. The disadvantage of molecular techniques is the fact that not being routinely carried out in many hospitals, and it is necessary to send them to reference laboratories, which delays results. In addition, despite being the most sensitive technique, one microscopy positive case resulted negative by PCR. False negatives PCR can occur, showing that not every method is perfect, and evidence for the need for combined diagnostic strategies to avoid false negatives as well as getting over the disadvantages of each technique by itself, allowing to make a reliable diagnosis in the shortest time [15].

Regarding intra-annual distribution of malaria cases, the end of summer in the northern hemisphere shows to be the year period in which more malaria suspicious patients attend to emergency department and more malaria diagnoses are established, this fact was also appreciated both in other Spanish and European studies [16, 18, 19], being mainly related to the return of patients travelling to their original countries in summer holidays.

In our study, VFR was the main group (69.7%) of malaria cases followed by MRA (25%) and finally T&B (5.3%), similar to other studies performed in Spain [20,21,22]. Instead, other studies carried out in Madrid (Spain) showed that MRA was the most important group, constituting close to 50% of malaria cases [23]. These differences may be due to the different populations assigned to each hospital by its influence area.

Most of cases got infected in sub-Saharan West Africa, being Equatorial Guinea the country where most patients got infected, which responded to the narrow relationship between Spain and its former colony, as shown in other national-wide studies [21, 22]. These data are clearly different from those obtained in other European countries, where a higher proportion of patients infected in central and East Africa was notified [24].

Mean age for the malaria patients in our study resulted to be 36 years old, with no significative difference from other studies [23, 24]. When analysing patient age according to their travel motive, MRA patients resulted to be the youngest group, with T&B being the oldest one, with these findings being consistent with other studies [14, 25].

The predominant aetiological agent of malaria was P. falciparum with a minority of P. ovale and P. malariae cases reported and with no P. vivax nor P. knowlesi cases. P. falciparum was also the main species in other European studies with patients being mainly infected in West Africa [19, 25, 26], with increased P. vivax cases being reported in other countries with a higher rate of central and east Africa infected patients [24].

Malaria endemic countries are also endemic for other tropical diseases, so co-infection is common. 14.4% of malaria patients present a concomitant tropical disease, with helminthiasis being the most frequent (7.6%), similar to what was found in a south Spain study carried out by Pousibet-Puerto et al. [14]. SMM (40%) resulted to be the most coinfected group, some studies have postulated that certain helminth infections, such as filariasis, can modulate the immune response to malaria favouring parasitemia control as is the case of SMM [27, 28].

MRA patients show fewer symptoms than VFR or T&B patients and symptoms such as fever were present in a lesser percentage than in the rest of the groups. The existence of malaria semi-immunity has been known for a long time, some studies have described how, after continued exposure to Plasmodium, this semi-immunity is acquired, protecting the host from developing severe and potentially fatal stage of the disease [14, 29,30,31]. This semi-immunity starts to wane with the absence of exposure, rendering that in VFR patients, living out of an endemic area for a long time, semi-immunity is gradually lost, leading to more symptomatic presentations [32]. Despite being most of the cases diagnosed in Spain MM, SMM is supposed an important percentage in this study, consisting in 18.9% of all cases, being lower than the 27.4% obtained in a study carried out in the South of Spain, in an area of high migratory pressure [14]. Instead, those percentages are quite higher than the 5% reported by other studies performed in Spain [13, 16].

As expected, and in general, most malaria cases, 76.2% in this study, are diagnosed in the first month after returning from endemic areas [14, 16, 33]. VFR resulted to be the earlier-diagnosed group probably because they recognize the symptoms, having previously suffered it or seeing cases around them in their countries of origin, and because of their loss of immunity, leaving them susceptible to more symptomatic malaria.

In nine patients the diagnosis was delayed more than 6 months because they did not present any symptoms during that period. These patients constitute malaria reservoirs in endemic areas and in non-endemic countries, where there are still anopheline vectors, they constitute an important risk of occurrence of autochthonous malaria cases and eventually a re-emergence of the illness [34, 35].

Only 2.3% (3) of the patients who took the chemoprophylaxis correctly got malaria caused by P. ovale. Drugs employed as chemoprophylaxis in these patients (Proguanil-Atovaquone and Doxycycline) are theoretically effective in avoiding acute malaria by eliminating blood stages of Plasmodium but only proguanil is effective against the infective sporozoite form. The most probable cause for the infection despite chemoprophylaxis is these drugs eliminate the blood forms and prevent primary infection, but the hypnozoites remain and relapse, in due time, when there is no longer drugs pressure. Several cases of P. ovale malaria related to chemoprophylaxis failure have been reported as being attributed to different causes just as drug resistance, incomplete chemoprophylaxis, or previous latent infection [36,37,38]. The rest of the patients who took chemoprophylaxis did it incorrectly or with ineffective drugs in the area due to resistance [39].

In our study, only one patient (0.75%) required ICU admission. This is a low ICU admission rate, but not significantly different from other South Madrid study [16]. At SOUH, ICU-admission criteria for malaria patients are slightly different from those postulated by WHO [10]. Attending to this last, all patients with a parasitemia higher than 10% must be ICU-admitted, but in our hospital, ICU admission does not depend on parasitemia but in the development of severe complications. Despite these stricter criteria, no malaria-related deceases have been notified in SOUH during the study period, demonstrating that all patients received effective medical attention. An additional reason explaining this fact are early diagnosis strategies carried out in our institution, making possible early treatment and avoiding complications.

In conclusion, it is observed that VFR individuals present malaria with greater symptoms that correspond to MM, unlike MRA individuals who present fewer or no symptoms and which in many cases is only detected by PCR (SMM), but these are those with a higher level of coinfection, possibly because it is the first time they come from an endemic area.

This study shows the need for establishing systems for VFRs to attend pre-travel consultations to increase the use of prophylaxis to reduce malaria imported risk, and in the case of MRA, screening for infectious diseases should be conducted upon their arrival to improve life quality of the patients and reduce the risk of autochthonous cases. Finally, we highlight two cases of malaria co-infection with Dengue and Chikungunya. These cases illustrate that the presence of malaria doesn’t rule out other imported diseases. Additionally, the presence of symptoms resembling malaria from another imported pathogen doesn’t exclude the possibility of malaria.

This study has some limitations, data concerning symptoms and malaria management were missing in some patients, as well as some analytical data. When analysing these parameters, patients with a lack of some of them were not taken into consideration.