Our aim was to describe the likelihood of malaria in patients with febrile episodes after returning from endemic regions in the south-west of Madrid. During the study period, 328 patients with suspicion of malaria were evaluated, corresponding to 108 confirmed cases. The positive malaria-test rate was 33%. The majority of severe cases were detected in VFR-migrants, no deaths were recorded, and only two cases (both travellers) could be considered late diagnoses because they sought care 10 and 15 days after symptom onset, respectively. In addition, we aimed to identify distinctive characteristics that could help diagnose malaria in such patients. In this sense, malaria was more frequent among migrants and VFRs, in those that had suffered previous episodes of malaria and who consulted due to fever; lower levels of platelets and increased total bilirubin were the most characteristic biological findings.
Fever is a common symptom among travellers returning from tropical areas17, accounting for up to one-third of diagnoses upon return9,13 and causing up to 77% of hospital admissions18. Furthermore, among the potentially life-threatening tropical diseases acquired by travellers, the vast majority (malaria, typhoid fever, dengue, leptospirosis and melioidosis) present with it14. Hence, fever when returning from the tropics is a symptom that requires prompt evaluation, as it can indicate the onset of a severe illness. This is especially clear in malaria, where delays in diagnosis in imported cases is directly related to mortality15. Therefore, a high index of suspicion is essential, mainly when it does not imply high diagnostic costs (thin/thick smears and RDTs are low-cost exams).
In our study, 33% of samples were positive for malaria among patients with a suggestive clinical picture. To our knowledge, only one other study has disclosed the rate of positivity in patients with fever upon return from the tropics. In the report of Calderaro et al.19, among Italian travellers and foreigners coming from endemic areas and with signs and symptoms consistent with malaria, 30% of the samples were positive. We believe that in similar populations, a proportion of around 30% positive samples might be used as an efficiency marker for malaria suspicion; lower rates (< 10–20%) might incur in higher diagnostic costs and laboratory workload, whereas higher rates (> 70–80%) could potentially imply a very low suspicion index which could lead to late diagnosis and a higher rate of severe disease. Similar parameters have already been proposed as quality control for other microbiological procedures such as blood cultures where a positive rate of < 5% may indicate an excessive blood culture ordering by physicians, whereas a positive blood culture rate of > 12% (Isenberg, 2010) may imply the opposite20–22. Given that we did not find a significant number of delayed diagnoses or severe malaria and that there were no recorded deaths in both studies we believe that a rate around 30% could be an adequate one for our setting.
Imported malaria is more commonly diagnosed in VFRs (migrants and travellers) and visitors, as compared to travellers23,24. However, more severe cases are detected among travellers, followed by VFRs. Furthermore, visitors are found to have a lower risk for severe disease and ICU admission15,25−27. Case fatality rates for imported malaria range from 0.06–1% in the UK, EU. and US14,15,25−30, while figures for severe malaria range between 6% and 20%, being more common for P. falciparum malaria and in individuals with fewer previous episodes of malaria14,15,19,31. The higher frequency of malaria diagnosis in VFRs and migrants is due to high-risk travel and greater exposure to malaria in their countries of origin32–34. Increased severity among travellers could be related to a lower index of suspicion and delayed diagnosis15,2521,25, while the presence of some degree of malaria-immunity among migrants and VFRs would prevent them from presenting more severe cases35. Worst outcomes have also been described in children32, mostly VFR-travellers with P. falciparum malaria acquired in Sub-Saharan Africa, the elderly15, and for cases detected in winter months, probably reflecting initial misdiagnosis of a febrile illness15.
We also found that 92% (303/328) of the diagnoses in our study were made in VFRs and visitors, correlating with the high proportion of African migrants in Móstoles. Therefore, the index of suspicion for malaria in the event of a febrile condition is high in our hospital, probably influencing the absence of both mortality and a seasonal pattern for severe cases. It is noteworthy that one of the two travellers with malaria was a severe case; however because he only attended hospital 15 days after fever onset, he required immediate admission to ICU.
According to what is typically described19,23,24,36, differential clinical characteristics of a patient with malaria in our study were fever, lower levels of platelets/leukocytes, and higher total bilirubin levels. Thus, fever should always be a warning sign in patients returning from a malaria-endemic area. Furthermore, laboratory results such as thrombocytopenia and higher levels of bilirubin are highly suggestive of Plasmodium spp. infection and, if absent, they have been proposed as biomarkers with negative predictive value23,24,37.
In 16 of the 108 cases (7.5%), Plasmodium spp. were only detected by PCR. All cases corresponded to VFR and visitors, none of whom developed severe malaria. A likely explanation is that the presence of a certain degree of immunity allowed better control of parasitemia and lower concentrations of parasites38 that were undetectable in smears. Submicroscopic parasitemia also occurs in asymptomatic subjects, where it represents about 5% (4.5–5.7%)39,40 of screened migrants, even 28 months after returning from an endemic country. Persons with low-grade parasitemia can infect mosquitoes41, and thereby, could act as unidentified reservoirs and contribute to transmission in areas where malaria has been eradicated but that are still hosts to competent vectors7.
Our study’s strength is that we used a systematic approach towards sick patients returning from malaria-endemic areas, and that every case in our cohort was analysed and confirmed by PCR. Thus, our study had a well-characterized population. However, it is a single-centre study with a very concrete migrant population (sub-Saharan Africa) and a high proportion of visitors and VFRs, so the results are not easily generalizable. Our data may not be applicable in settings where conventional travellers constitute the main population.
In conclusion, malaria should always be suspected in individuals seeking medical care after returning from visiting endemic regions. The consequences of a delayed diagnosis can be fatal. This parasitosis should be especially presumed in patients with fever, low platelet levels, and raised levels of serum bilirubin. We propose that an index around 30% of positive malaria samples among demanded tests could be, in terms of efficiency, an adequate index of malaria suspicion for febrile episodes in patients returning from endemic areas. Prospective studies will be needed to validate this index in different populations and its relation to malaria morbimortality.