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Abstract Background Previous studies investigating the travellers’ knowledge, attitudes and practices (KAP) profile indicated an important educational need among those travelling to risk destinations. Initiatives to improve such education should target all groups of travellers, including business travellers, those visiting friends and relatives (VFRs), and elderly travellers. Methods In the years 2002 to 2009, a questionnaire-based survey was conducted at the Dutch Schiphol Airport with the aim to study trends in KAP of travel risk groups towards prevention of malaria. The risk groups last-minute travellers, solo-travellers, business travellers, VFRs and elderly travellers were specifically studied. Results A total of 3,045 respondents were included in the survey. Travellers to destinations with a high risk for malaria had significantly more accurate risk perceptions (knowledge) than travellers to low-risk destinations. The relative risk for malaria in travellers to high-risk destinations was probably mitigated by higher protection rates against malaria as compared with travellers to low risk destinations. There were no significant differences in intended risk-taking behaviour. Trend analyses showed a significant change over time in attitude towards more risk-avoiding behaviour and towards higher protection rates against malaria in travellers to high-risk destinations. The KAP profile of last-minute travellers substantially increased their relative risk for malaria, which contrasts to the slight increase in relative risk of solo travellers, business travellers and VFRs for malaria. Conclusions The results of this sequential cohort survey in Dutch travellers suggest an annual 1.8% increase in protection rates against malaria coinciding with an annual 2.5% decrease in intended risk-seeking behaviour. This improvement may reflect the continuous efforts of travel health advice providers to create awareness and to propagate safe and healthy travel. The KAP profile of last-minute travellers, in particular, substantially increased their relative risk for malaria, underlining the continuous need for personal protective measures and malaria chemoprophylaxis for this risk group.

Abstract Background Copeptin has recently been identified to be a stable surrogate marker for the unstable hormone arginine vasopressin (AVP). Copeptin has been shown to correlate with disease severity in leptospirosis and bacterial sepsis. Hyponatraemia is common in severe imported malaria and dysregulation of AVP release has been hypothesized as an underlying pathophysiological mechanism. The aim of the present study was to evaluate the performance of copeptin as a predictor of disease severity in imported malaria. Methods Copeptin was measured in stored serum samples of 204 patients with imported malaria that were admitted to our Institute for Tropical Diseases in Rotterdam in the period 1999-2010. The occurrence of WHO defined severe malaria was the primary end-point. The diagnostic performance of copeptin was compared to that of previously evaluated biomarkers C-reactive protein, procalcitonin, lactate and sodium. Results Of the 204 patients (141 Plasmodium falciparum, 63 non-falciparum infection), 25 had severe malaria. The Area Under the ROC curve of copeptin for severe disease (0.66 [95% confidence interval 0.59-0.72]) was comparable to that of lactate, sodium and procalcitonin. C-reactive protein (0.84 [95% CI 0.79-0.89]) had a significantly better performance as a biomarker for severe malaria than the other biomarkers. Conclusions C-reactive protein but not copeptin was found to be an accurate predictor for disease severity in imported malaria. The applicability of copeptin as a marker for severe malaria in clinical practice is limited to exclusion of severe malaria.

Abstract Background In the pathophysiology of hyponatraemia in malaria, the relative contribution of appropriate and inappropriate arginine vasopressin (AVP) release is unknown; the trigger for inappropriate AVP release is also unknown. Methods Serum copeptin, a stable and sensitive marker for AVP release, was analysed in a large cohort of patients with imported malaria (204 patients) and in a small prospective substudy (23 patients) in which urine sodium and osmolality were also available. Hyponatraemia was classified as mild (serum sodium 131-134 mmol/l) and moderate-to-severe (< 131 mmol/l). Results Serum copeptin on admission was higher in patients with moderate-to-severe hyponatraemia (median 18.5 pmol/L) compared with normonatraemic patients (12.7 pmol/L, p < 0.05). Despite prompt fluid resuscitation, the time to normalization of serum sodium was longer in patients with moderate-to-severe hyponatraemia (median 2.9 days) than in patients with mild hyponatraemia (median 1.7 days, p < 0.001). A poor correlation was found between serum sodium and copeptin levels on admission (rs = -0.17, p = 0.017). Stronger correlations were identified between serum C-reactive protein and copeptin (rs = -0.36, p < 0.0001) and between serum C-reactive protein and sodium (rs = 0.33, p < 0.0001). Data from the sub-study suggested inappropriate AVP release in seven of 13 hyponatraemic malaria patients; these patients had significantly higher body temperatures on admission. Conclusions In hyponatraemic patients with imported malaria, AVP release was uniformly increased and was either appropriate or inappropriate. Although the exact trigger for inappropriate AVP release remains unknown, the higher body temperatures, correlations with C-reactive protein and long normalization times of serum sodium, suggest an important role of the host inflammatory response to the invading malaria parasite.

Abstract Background Counts of malaria parasites in peripheral blood are important to assess severity of Plasmodium falciparum malaria. Thin and thick smears are routinely used for this purpose. Methods In this study the Binax NOW® Malaria Test, an easy-to-perform rapid diagnostic test, with Histidine Rich Protein-2 (HRP-2) and aldolase as diagnostic markers, was used for semi-quantitative assessment of parasitaemia of P. faciparum. Results In 257 patients with imported P. falciparum malaria, reactivity of aldolase increased with higher parasitaemia. In all patients with a parasitaemia above 50,000 asexual parasites/μl (> 1%) co-reactivity of HRP-2 and aldolase was observed. Absence of aldolase reactivity in the presence of HRP-2 was a reliable predictive marker to exclude high (> 1%) parasitaemia in P. falciparum malaria. Conclusions Assessment of HRP-2 and aldolase co-reactivity can be of help in clinical decision making in the acute care setting of returning travellers suspected of having malaria.

Abstract Background To describe the epidemiology and trends of imported malaria in the Netherlands from 2000 through 2007. Methods Based on national surveillance data regarding all reported infections of imported malaria, diagnosed 2000 through 2007, incidence and trends of imported malaria in the Netherlands were estimated. Travellers statistics were used to estimate incidence, and data on malaria chemoprophylaxis prescriptions were used to estimate the number of unprotected travellers. Results Importation of malaria to the Netherlands is declining even as more travellers visit malaria-endemic countries. On average, 82% were acquired in sub-Saharan Africa, and 75% were caused by Plasmodium falciparum. The overall incidence in imported falciparum malaria fell from 21.5 to 6.6/10,000 of unprotected travellers. The percentage of unprotected travellers rose from 47% to 52% of all travellers. The incidence of imported falciparum infections is greatest from Middle and West Africa, and decreased from 121.3 to 36.5/10,000 travellers. The import of malaria from this region by immigrants visiting friends and relatives (VFR) decreased from 138 infections in 2000, to 69 infections in 2007. Conclusion The annual number of imported malaria shows a continuing declining trend, even with an increasing number of travellers visiting malaria endemic countries. VFR import less malaria than previously, and contribute largely to the declining incidence seen. The decline is not readily explained by increased use of chemoprophylaxis and may reflect a reduced risk of infection due to decreasing local malaria transmission as observed in some malaria endemic areas. Nevertheless, the increasing number of unprotected travellers remains worrisome.

Abstract Background Most clinicians in developed, non-malaria endemic countries have limited or no experience in making clinical assessments of malaria disease severity and subsequent decisions regarding the need for parenteral therapy or high-level monitoring in febrile patients with imported malaria. In the present study, the diagnostic accuracy of plasma soluble Triggering Receptor Expressed on Myeloid cells 1 (TREM-1), neopterin and procalcitonin levels as biomarkers for severe Plasmodium falciparum disease was evaluated in 104 travellers with imported malaria (26 patients with non-P. falciparum malaria, 64 patients with uncomplicated P. falciparum malaria and 14 patients with severe P. falciparum malaria). Methods TREM-1, neopterin and procalcitonin were determined in serum using commercially available ELISA or EIA tests. The diagnostic performance of these biomarkers for severe disease was compared with plasma lactate, a well-validated parameter for disease severity in patients with malaria, as reference. Severe malaria was defined according to the modified WHO criteria. Results No significant differences in TREM-1 levels were detected between the different patient groups. Patients with severe P. falciparum malaria had significantly higher neopterin and procalcitonin levels on admission when compared to patients with uncomplicated P. falciparum malaria or non-P. falciparum malaria. Receiver Operating Characteristic (ROC) curve analysis showed that neopterin had the highest Area-Under-the-ROC curve (AUROC 0.85) compared with plasma lactate (AUROC 0.80) and procalcitonin (AUROC 0.78). At a cut-off point of 10.0 ng/ml, neopterin had a positive and negative predictive value of 0.38 and 0.98 whereas procalcitonin, at a cut-off point of 0.9 ng/ml, had a positive and negative predictive value of 0.30 and 1.00. Conclusion Although the diagnostic value of neopterin and procalcitonin is limited, the high negative predictive value of both neopterin and procalcitonin may be helpful for a rapid exclusion of severe malaria disease on admission. This may be a valuable tool for physicians only occasionally dealing with ill-returned travellers from malaria-endemic regions and who need to decide on subsequent oral anti-malarial treatment or timely referral to a specialized centre for high-level monitoring and intensified parenteral treatment.

Abstract Background Hyponatraemia (serum sodium < 135 mmol/L) has long been recognized as a complication of malaria. However, few studies have been done in non-immune adult populations. It has not been investigated previously how hyponatraemia is distributed among the various Plasmodium species, and its association with malaria severity is unknown. The aim of this retrospective cohort study was to determine the prevalence of hyponatraemia and its association with malaria severity in a large cohort of patients with imported malaria caused by various Plasmodium species. Methods All patients that were diagnosed with malaria in the Harbour Hospital and Institute for Tropical Diseases in Rotterdam in the period 1999-2009 and who had available serum sodium on admission were included. Severe malaria was defined according to the modified WHO criteria. Prevalence of hyponatraemia and its association with malaria severity were investigated by univariate comparison, ROC analysis and multivariate logistic regression analysis. Results A total of 446 patients with malaria (severe falciparum malaria n = 35, non-severe falciparum malaria n = 280, non-falciparum malaria n = 131) was included. Hyponatraemia was present in 207 patients (46%). Prevalence and severity of hyponatraemia were greatest in severe falciparum malaria (77%, median serum sodium 129 mmol/L), followed by non-severe falciparum malaria (48%, median serum sodium 131 mmol/L), and non-falciparum malaria (34%, median serum sodium 132 mmol/L). Admission serum sodium < 133 mmol/L had a sensitivity of 0.69 and a specificity of 0.76 for predicting severe malaria. Multivariate logistic regression showed that serum sodium < 131 mmol/L was independently associated with severe falciparum malaria (odds ratio 10.4, 95% confidence interval 3.1-34.9). In patients with hyponatraemia, hypovolaemia did not appear to play a significant role in the development of hyponatraemia when prerenal azotaemia and haematocrit were considered as surrogate markers for hypovolaemia. Conclusions Hyponatraemia is common in imported malaria and is associated with severe falciparum malaria. From a clinical point of view, the predictive power of hyponatraemia for severe malaria is limited. The precise pathophysiological mechanisms of hyponatraemia in malaria require further study.

Abstract Background Imported malaria occurs as a relatively rare event in developed countries. As a consequence, most clinicians have little experience in making clinical assessments of disease severity and decisions regarding the need for parenteral therapy or high-level monitoring. In this study, the diagnostic accuracy of procalcitonin (PCT) for severe Plasmodium falciparum disease was assessed in a cohort of 100 consecutive travellers with various species of imported malaria. Methods and results In all patients, PCT was measured on admission with a semi-quantitative 'point-of-care' test. Patients with severe P. falciparum malaria had significantly higher median PCT levels on admission as compared with patients with uncomplicated P. falciparum disease. In addition, PCT levels in patients with non-falciparum malaria were also higher compared with patients with non-severe falciparum malaria but lower compared with severe P. falciparum malaria. At a cut-off point of 10 ng/mL, PCT had a sensitivity of 0,67 and a specificity of 0,94 for severe falciparum disease. However, at lower cut-off points the specificity and positive predictive value were rather poor although the sensitivity and negative predictive value remained high. Discussion Potential drawbacks in the interpretation of elevated PCT levels on admission may be caused by infections with non-falciparum species and by concomitant bacterial infections. Conclusion Semi-quantitative determination of PCT on admission is of limited use in the initial clinical assessment of disease severity in travellers with imported malaria, especially in settings with limited experience with the treatment of malaria.