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Epidemiological and clinical features of imported malaria at the three main hospitals of the Friuli-Venezia Giulia Region, Italy

Published:October 13, 2017DOI:https://doi.org/10.1016/j.idh.2017.08.007

      Highlights

      • Imported malaria cases continue to occur in non-endemic regions among travellers returning from malaria endemic countries.
      • At particular risk of acquiring malaria is the group of immigrants identified as visiting friends or relatives (VFRs).
      • The goal of this study is to review the current trends of imported malaria in the Friuli-Venezia Giulia region (FVG).

      Abstract

      Background

      Imported malaria cases continue to occur in non-endemic regions among travellers returning from tropical and subtropical countries. At particular risk of acquiring malaria is the group of travellers identified as immigrants who return to their home country with the specific intent of visiting friends or relatives (VFRs) and who commonly believe they are immune to malaria and fail to seek pre-travel advice. Our aim was to review the current trends of imported malaria in the three main hospitals of the Friuli-Venezia Giulia region (FVG), North Eastern Italy, focusing in particular on patient characteristics and laboratory findings.

      Methods

      In this retrospective study, we examined all malaria cases among patients admitted from January 2010 through December 2014 to the emergency department of the three main hospitals located in FVG.

      Results

      During the 5-year study period from 2010 to 2014, there were a total of 140 patients with a diagnosis of suspected malaria and who received microscopic confirmation of malaria. The most common species identified was P. falciparum, in 96 of 140 cases (69%), followed by P. vivax (13%), P. ovale (4%), P. malariae (4%), and mixed infection (4%). The most common reason for travel was VFRs (54%), followed by work (17%), and recent immigration (15%). Moreover, 78% of all patients took no chemoprophylaxis, 80 (79%) of whom were foreigners. Notably, the percentage of Italian travellers who took chemoprophylaxis was only 20% (8 of 39 Italian cases), and the regimen was appropriate in only four cases. Parasitaemia greater than 5% was observed in 11 cases (10%), all due to P. falciparum infection.

      Conclusions

      We highlight that VFRs have the highest proportion of malaria morbidity and the importance of improving patient management in this category. These data are useful for establishing appropriate malaria prevention measures and recommendations for international travellers.

      Keywords

      Introduction

      According to the latest World Health Organization (WHO) estimates, there were 212 million new cases of malaria worldwide in 2015 (range, 148–304 million), with the heaviest burden in the WHO African Region, which accounted for most global cases (90%) []. International travel to endemic regions is growing steadily and despite attempts to increase the availability of adequate chemoprophylaxis in recent years, imported malaria cases continue to occur in non-endemic regions among travellers returning from tropical and subtropical countries. At particular risk of acquiring malaria is the group of travellers identified as immigrants who return to their home country with the specific intent of visiting friends or relatives (VFR) and who commonly believe they are immune to malaria and fail to seek pre-travel advice [
      • Odolini S.
      • Gautret P.
      • Parola P.
      Epidemiology of imported malaria in the Mediterranean region.
      ,
      • Warne B.
      • Weld L.H.
      • Cramer J.P.
      • Field V.K.
      • Grobusch M.P.
      • Caumes E.
      • et al.
      Travel-related infection in European travelers, EuroTravNet 2011.
      ,
      • Casuccio A.
      • D'Angelo C.
      • Casuccio N.
      • Di Carlo P.
      • Immordino P.
      Visiting friends and relatives (VFRs) travellers and imported malaria in the Palermo District (Sicily).
      ]. The latest data on reported malaria cases in Europe are available from the European Centre for Disease Prevention and Control (ECDC) Annual Epidemiological Report. In 2014, 6017 confirmed malaria cases were reported by 26 European Union (EU) or European Economic Area (EEA) countries [
      • European Centre for Disease Prevention and Control
      Annual epidemiological report 2016 – malaria.
      ]. About 6377 cases of imported malaria were diagnosed in Italy from 2000 to 2008; 4621 cases in foreigners and 1756 in Italian citizens. Plasmodium falciparum accounted for up to 83.1% of cases, followed by Plasmodium vivax (8.4%), the second most common species identified among malaria cases diagnosed in Italy [
      • Romi R.
      • Boccolini D.
      • D'Amato S.
      • Cenci C.
      • Peragallo M.
      • D'Ancona F.
      • et al.
      Incidence of malaria and risk factors in Italian travellers to malaria endemic countries.
      ,
      • Romi R.
      • Boccolini D.
      • D'Amato S.
      • Cenci C.
      • Pompa M.G.
      • Majori G.
      Malaria surveillance in Italy: the 2000-2008 national pattern of imported cases.
      ,
      • Boccolini D.
      Principali lineamenti epidemiologici della malaria d'importazione in Italia, analisi 2011-2015.
      ]. The goal of this study is to review the current trends of imported malaria in the three main hospitals (University Hospital of Trieste, Hospital of Pordenone, and Santa Maria della Misericordia University Hospital of Udine) of the Friuli-Venezia Giulia Region (FVG), a little-investigated area of north-eastern Italy, focusing in particular on patient characteristics and laboratory findings among adults and children diagnosed with imported malaria.

      Methods

      In this retrospective study, we examined all malaria cases among patients admitted from January 2010 through December 2014 to the emergency department of the University Hospital of Trieste, Hospital of Pordenone, and Santa Maria della Misericordia University Hospital of Udine.
      Data were collected anonymously at each hospital and entered into standardised data forms. Demographic and clinical variables collected were as follows: date of birth, sex, nationality, countries of travel, reasons for travelling [VFR, work, tourism, immigration (including people who recently immigrated to Italy), or other reasons], laboratory diagnosis (species detected), and use of chemoprophylaxis.
      The diagnosis was based on the microscopic observation and identification of P. falciparum, P. vivax, Plasmodium ovale, Plasmodium malariae or mixed infection, on Giemsa-stained thick and thin blood smears. If the morphological characteristics of parasites were uncertain, samples were diagnosed as Plasmodium spp.
      Anaemia and thrombocytopenia were considered present for detected values <11 g/dL haemoglobin (Hb) and <150,000 platelets/μL. Two degrees of anaemia were defined, as follows: moderate-mild anaemia was defined as Hb level ≥8.0 g/dL and severe anaemia as Hb < 8.0 g/dL. Furthermore, two degrees of thrombocytopenia were defined, as follows: moderate-mild thrombocytopenia if platelet count was 30,000–150,000 platelets/μL, severe thrombocytopenia if count was <30,000 platelets/μL.
      A descriptive analysis of the data was carried out. Percentages were calculated for categorical variables and means with standard deviations were calculated for numerical variables. Differences in proportions were estimated using the chi-squared test or Fisher's exact test, as appropriate. A comparison of independent means was performed using a one-tailed t-test. The significance level was set at p < 0.05.

      Results

      Main epidemiologic characteristics

      During the 5-year study period from 2010 to 2014, there were a total of 140 patients with a diagnosis of suspected malaria and who received microscopic confirmation of malaria. The most common species identified was P. falciparum, in 96 of 140 cases (69%), followed by P. vivax (13%), P. ovale (4%), P. malariae (4%), and mixed infection (4%). Morphological characteristics of parasites were uncertain in 9 of 140 cases (6%); these were identified as Plasmodium spp. The number of annual cases observed increased gradually from 2010 to 2013, with the highest recorded number in 2013 when 25 of 140 cases were due to P. falciparum (68%) (Fig. 1).
      Fig. 1
      Figure 1Malaria cases owing to Plasmodium species in Friuli-Venezia Giulia, Italy 2010–2014.
      The epidemiological features of all imported malaria cases were analysed separately for P. falciparum, P. vivax, P. ovale, P. malariae, and mixed infections; these are summarised in Table 1. During the study period, 127 cases in adults (91%) and 13 in children (9%) were reported. Seventy-five percent were male (105 of 140 patients). Of the total cases, 39 (28%) occurred in Italian citizens and 101 (72%) in foreigners. Most cases were acquired in Africa (87%), of which more than half (52%) were in three West African countries: Ghana, Burkina Faso, and Nigeria. The etiological agent was P. falciparum in 90 of 120 African cases (75%). Infections attributed to P. vivax accounted for 50% of cases acquired in Africa, 39% of those acquired in Asia, and 11% were unknown. The most common reason for travel was VFRs (54%), followed by work (17%), and recent immigration (15%).
      Table 1Epidemiologic characteristics of imported malaria cases according to Plasmodium species (n = 140).
      Total (n = 140)P. falciparum (n = 96)P. vivax (n = 18)P. malariae (n = 5)P. ovale (n = 6)Mixed (n = 6)Plasmodium spp. (n = 9)
      Sex, n (%)
      Male105 (75)72 (75)16 (89)2 (40)3 (50)4 (67)8 (89)
      Female35 (25)24 (25)2 (11)3 (60)3 (50)2 (33)1 (11)
      Age (years), n (%)
      <15 (children)13 (9)7 (7)3 (17)01 (17)1 (17)1 (11)
      >15 (adults)127 (91)89 (93)15 (83)5 (100)5 (83)5 (83)8 (89)
      Nationality, n (%)
      Italian39 (28)20 (21)9 (50)1 (20)1 (17)2 (33)6 (67)
      Foreigners101 (72)76 (79)9 (50)4 (80)5 (83)4 (67)3 (33)
      Area of acquisition, n (%)
      Africa120 (87)90 (94)9 (50)3 (60)4 (67)5 (83)9
       Ghana32 (27)30 (33)01 (33)01 (20)0
       Burkina Faso16 (13)14 (16)0002 (40)0
       Nigeria15 (12)11 (12)2 (22)01 (25)01 (11)
       Other West African countries38 (32)23 (26)1 (11)2 (67)3 (75)2 (40)7 (78)
       East Africa19 (16)12 (13)6 (67)0001 (11)
      Asia9 (6)07 (39)1 (20)01 (17)0
      America1 (1)1 (1)00000
      Unknown10 (6)5 (5)2 (11)1 (20)2 (33)00
      Reason for travel, n (%)
      Recent immigration21 (15)11 (12)6 (33)2 (40)1 (17)01 (11)
      Visiting friends and relatives75 (54)59 (61)4 (22)2 (40)2 (33)5 (83)3 (33)
      Work24 (17)15 (16)4 (22)001 (17)4 (45)
      Tourism6 (4)4 (4)1 (6)0001 (11)
      Missionary4 (3)2 (2)1 (6)01 (17)00
      Unknown10 (7)5 (5)2 (11)1 (20)2 (33)00
      Adherence to chemoprophylaxis, n (%)
      Correct7 (5)1 (1)2 (11)01 (17)03 (33)
      Not correct13 (9)12 (13)01 (20)000
      Not treated109 (78)78 (81)14 (78)2 (40)3 (50)6 (100)6 (67)
      Unknown11 (8)5 (5)2 (11)2 (40)2 (33)00

      Adherence to chemoprophylaxis

      Of the 20 travellers who reported use of malaria chemoprophylaxis, only 7 (5%) had been adequate according to the visited area, dosage regimen, patient's weight, and duration of treatment. In particular, 3 of these 7 patients were P. vivax or P. ovale infection. Relapse most likely occurred in patients taking only a blood schizonticide as chemoprophylaxis, which is ineffective against liver schizonts. In 3 other patients of the 7 above, parasites could not be identified to the species level, and they were identified as Plasmodium spp. In those 3 patients, it is unknown whether the infection was due to a relapse of P. vivax or P. ovale or it was a true prophylactic failure. Finally, 1 of the 7 patients had confirmed P. falciparum malaria despite apparently correct prophylaxis (Table 1). Although rare, failure of the recommended prophylaxis has been reported in P. falciparum malaria [
      • Castelli F.
      • Odolini S.
      • Autino B.
      • Foca E.
      • Russo R.
      Malaria prophylaxis: a comprehensive review.
      ]. However, the interpretation of drug efficacy has hinged on drug compliance. It should be underscored that the prophylactic failures reported in our study may have been related to poor compliance undeclared by the traveller rather than to drug resistance.
      Moreover, 78% of all patients took no chemoprophylaxis, 80 (79%) of whom were foreigners. Notably, the percentage of Italian travellers who took chemoprophylaxis was only 20% (8 of 39 Italian cases), and the regimen was appropriate in only four cases (data not shown).

      Laboratory findings of imported malaria cases

      Data on mean values of platelets and Hb and parasitaemia were available for 103 patients who received a diagnosis of malaria. Analysis of these laboratory findings was performed separately for P. falciparum, P. vivax, and non-P. falciparum/non-P. vivax cases, which included infections by P. ovale or P. malariae species. Mixed infections were excluded from this analysis (Table 2).
      Table 2Laboratory findings of imported malaria cases according to Plasmodium species (n = 103).
      All (n = 103)
      Data were available for 103 patients. Mixed infections were excluded from this analysis.
      P. falciparum (n = 83)Non-P. falciparum/Non-P. vivax
      Non-P. falciparum/Non-P. vivax group included only infections caused by P. ovale and P. malariae.
      (n = 9)
      P. vivax (n = 11)P1
      P1: statistical test between P. falciparum group and Non-P. falciparum/Non-P. vivax group.
      P2
      P2: statistical test between P. falciparum group and P. vivax group.
      Laboratory findings
      Platelets, mean (×103/μL ± SD)105.7 (66.8)102.6 (67.14)121.8 (70.3)114.8 (70.8)0.2200.357
      Thrombocytopenia, n (%)79 (77)64 (77)6 (67)9 (82)0.4850.725
      Severe (<30,000 platelets/μL)6 (6)5 (6)01 (9)10.696
      Moderate-mild (30,000–150,000 platelets/μL)73 (71)59 (71)6 (67)8 (73)0.7820.910
      Haemoglobin, mean (g/dL ± SD)12.2 (2.31)12.4 (2.3)11.19 (1.06)12 (2.2)0.1030.349
      Anaemia, n (%)28 (27)17 (20)7 (78)4 (36)<0.001*0.235
      Severe (<8 g/dL)4 (4)4 (5)0011
      Moderate-mild (8–11 g/dL)24 (25)13 (16)7 (78)4 (36)<0.001*0.094
      Parasitaemia, n (%)
       <2%73 (71)55 (66)9 (100)9 (82)0.0367*0.298
       2–5%19 (18)17 (20)02 (18)0.2020.858
       >5%11 (11)11 (13)000.5930.351
      * Result is statistically significant at p < 0.05.
      a Data were available for 103 patients. Mixed infections were excluded from this analysis.
      b Non-P. falciparum/Non-P. vivax group included only infections caused by P. ovale and P. malariae.
      c P1: statistical test between P. falciparum group and Non-P. falciparum/Non-P. vivax group.
      d P2: statistical test between P. falciparum group and P. vivax group.
      Anaemia was detected in 28 of 103 malaria cases, and thrombocytopenia was detected in 79 of 103 cases. Moderate and mild anaemia (Hb level 8–11 g/dL) was more frequent in non-P. falciparum cases (p < 0.05) whereas severe anaemia (Hb level <8 g/dL) was observed only with P. falciparum infection (4 of 28 total cases; 14%). Severe thrombocytopenia (platelet count ≤30,000 platelets/μL) was observed in 6 of 79 cases, all caused by infection with P. falciparum except for one case caused by P. vivax. The percentage parasitaemia was calculated for both P. falciparum and non-P. falciparum cases. As expected, lower parasitaemia (<2%) was more frequent in the non-P. falciparum/non-P. vivax group (p < 0.05). On the contrary, parasitaemia greater than 5% was observed in 11 cases (11%), all due to P. falciparum infection. Moreover, 19 patients (18%) had parasitaemia between 2% and 5%, among whom 17 patients had infection with P. falciparum and 2 had P. vivax infection. Patients with the highest parasitaemia were two adult VFRs (15% and 20%) and two international workers (15% and 30%).

      Discussion

      In this local study of 140 imported malaria cases diagnosed during 2010–2014 in the three main hospitals of FVG in north-eastern Italy, we revealed a quite stable trend, with a slight increase from 2010 to 2013.
      According to the latest national surveillance data [
      • Romi R.
      • Boccolini D.
      • D'Amato S.
      • Cenci C.
      • Peragallo M.
      • D'Ancona F.
      • et al.
      Incidence of malaria and risk factors in Italian travellers to malaria endemic countries.
      ,
      • Romi R.
      • Boccolini D.
      • D'Amato S.
      • Cenci C.
      • Pompa M.G.
      • Majori G.
      Malaria surveillance in Italy: the 2000-2008 national pattern of imported cases.
      ], we found that most patients with malaria were foreigners (72%) travelling to West Africa, particularly to Ghana, Burkina Faso, and Nigeria (45% of all travellers). The East African country at particular risk was Ethiopia (32% of all East African cases), and patients travelling to this area were mostly Italian workers infected by P. vivax. Therefore, the data analysis in our study showed that VFRs represent the highest number of cases (about 54%), followed by people travelling for work (17%) and recently arrived immigrants (15%). In addition, 61 of 75 (81%) VFRs did not take chemoprophylaxis, and 11 of 75 (15%) interrupted or suspended it during their trip (data not shown). Several studies show that VFR travellers are at higher risk of imported malaria, as well as other preventable infectious diseases, than other types of travellers. This greater risk is related to several factors, such as lower use of protective measures and chemoprophylaxis, most likely owing to economic hardship or a low perception of disease risk because they consider themselves immune [
      • Odolini S.
      • Gautret P.
      • Parola P.
      Epidemiology of imported malaria in the Mediterranean region.
      ,
      • Warne B.
      • Weld L.H.
      • Cramer J.P.
      • Field V.K.
      • Grobusch M.P.
      • Caumes E.
      • et al.
      Travel-related infection in European travelers, EuroTravNet 2011.
      ,
      • Casuccio A.
      • D'Angelo C.
      • Casuccio N.
      • Di Carlo P.
      • Immordino P.
      Visiting friends and relatives (VFRs) travellers and imported malaria in the Palermo District (Sicily).
      ]. However, Mascarello et al. (2009) reported that resident immigrants who are not exposed to malaria infection for more than 12 years develop more severe malaria than recently arrived immigrants, demonstrating an increased risk of severe malaria among resident immigrants owing to a loss of semi-immunity. VFRs have long been thought to be at low risk for severe malaria; however, today VFRs are considered to have the same risk of developing severe disease as non-immune Italian citizens [
      • Mascarello M.
      • Gobbi F.
      • Angheben A.
      • Concia E.
      • Marocco S.
      • Anselmi M.
      • et al.
      Imported malaria in immigrants to Italy: a changing pattern observed in north eastern Italy.
      ]. In our study, 6 of 11 patients (54%) with hyperparasitaemia (>5%) were VFRs, of which 4 had severe anaemia or severe thrombocytopenia. No cases of severe anaemia or hyperparasitaemia were found among recently arrived immigrants (data not shown).
      In our analysis, P. falciparum was the most frequently identified species (69%) and P. vivax (13%) was the second most frequently diagnosed agent in our study area. No increasing trend in imported P. vivax cases was observed during the study period. In addition, in line with previous studies, P. vivax occurred less frequently in West Africa (17% of all cases), which has been reported by some authors to be related to the presence of individuals with the Duffy-negative phenotype in this area [
      • Miller L.H.
      • Mason S.J.
      • Clyde D.F.
      • McGinniss M.H.
      The resistance factor to Plasmodium vivax in blacks. The Duffy blood-group genotype, FyFy.
      ].
      However, in a previous epidemiological survey on imported malaria observed at Udine University Hospital from 2004 to 2007, P. falciparum accounted for more than 90% of 40 detected cases, and P. vivax accounted for 5%; therefore, P. vivax incidence in the study area has increased more than twofold in the last 10 years. Indeed, it should be noted that some characteristics of patients affected by malaria have changed since the first survey. In particular, in the previous survey, 90% of patients were migrants from Africa whereas in the present survey, there were more patients from Asia (especially Pakistan and Afghanistan), as is to be expected from the recent migration flow through Southeast Europe to Western Europe. In addition, the compliance rate for chemoprophylaxis in the first survey was 20%, similar to that found in the present study. These data should suggest that the message about the preventive efficacy of malaria prophylaxis needs to be reinforced among the general population [
      • Arzese A.
      • Beltrame A.
      • Piazza M.
      • Fabbro E.
      • Rorato G.
      • Negri C.
      • et al.
      Malaria da importazione nel nord-est: presentazione di casistica triennale.
      ].
      Infection with P. falciparum is known to cause severe malaria. By contrast, imported P. vivax, P. ovale, and P. malariae infections are known to be less severe. However, cases of P. vivax malaria with severe disease have been reported in the last decade, albeit at low frequency. Further studies are warranted to address the role of other factors that may contribute to severe illness in patients with P. vivax malaria, such as concurrent infections and malnutrition, while being careful to exclude mixed infection with P. falciparum by the use of molecular methods [
      • WHO
      Epidemiology of severe falciparum malaria.
      ].
      A parasitaemia index higher than 2% in low-intensity transmission areas, or one higher than 5% in areas of high stable malaria transmission intensity [
      • WHO
      Epidemiology of severe falciparum malaria.
      ,
      • WHO
      Management of severe malaria.
      ] represent one of the criteria used to define complicated P. falciparum malaria, according to the WHO. In our analysis, laboratory and parasitological findings confirmed that P. falciparum was the only malaria species associated with cases of severe anaemia or hyperparasitaemia (>5%); no cases with these laboratory findings were owing to P. malariae, P. ovale, or P. vivax infection. However, our data are limited to a small sample. Special attention should be paid to several cases of severe P. vivax that have recently been reported in the literature, particularly those associated with severe anaemia [
      • WHO
      Epidemiology of severe falciparum malaria.
      ].
      Interestingly, several recent studies have focused on investigation of an inflammatory marker able to predict malaria severity. In one such study, it has been demonstrated that procalcitonin and C-reactive protein may be useful in predicting complicated forms of P. falciparum malaria [
      • Righi E.
      • Merelli M.
      • Arzese A.
      • Della Siega P.
      • Scarparo C.
      • Bassetti M.
      Determination of PCT on admission is a useful tool for the assessment of disease severity in travelers with imported Plasmodium falciparum malaria.
      ].
      In conclusion, our study describes the epidemiology of a little-investigated region, confirming trends of previous national data, and highlights that VFRs have the highest proportion of malaria morbidity, as has been recently reported. These data are useful for increasing awareness of the importance of this disease in non-endemic countries, and for establishing appropriate malaria prevention measures and recommendations for international travellers.

      Ethics

      This study was deemed exempt from the Regional Friuli-Venezia Giulia Ethics Committee. The study was conducted in a manner consistent with the Declaration of Helsinki.

      Authorship statement

      Stano P. and Camporese A. conceived the idea, designed the study, participated in data collection, performed data analysis and interpretation, contributed to critical review of the manuscript. Arzese A, Merelli M, Mascarello M, Maurel C. participated in data collection, contributed to data interpretation and critical review of the manuscript. The other authors contributed to critical review of the manuscript.

      Conflicts of interest

      The authors have no conflicts of interest to report.

      Funding

      No funding for this work was received.

      Provenance and peer review

      Not commissioned; externally peer reviewed.

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