• 1

    World Health Organization, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–S90.

  • 2

    Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, Matteelli A, Clerinx J, Corachan M, Puente S, Gjorup I, Harms G, Kollaritsch H, Kotlowski A, Bjorkmann A, Delmont JP, Knobloch J, Nielsen LN, Cuadros J, Hatz C, Beran J, Schmid ML, Schulze M, Lopez-Velez R, Fleischer K, Kapaun A, McWhinney P, Kern P, Atougia J, Fry G, da Cunha S, Boecken G, 2002. Imported falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases. Clin Infect Dis 34 :572–576.

    • Search Google Scholar
    • Export Citation
  • 3

    Christen D, Steffen R, Schlagenhauf P, 2006. Deaths caused by malaria in Switzerland, 1988–2002. Am J Trop Med Hyg 75 :1188–1194.

  • 4

    Matteelli A, Colombini P, Gulletta M, Castelli F, Carosi G, 1999. Epidemiological features and case management practices of imported malaria in northern Italy, 1991–1995. Trop Med Int Health 4 :653–657.

    • Search Google Scholar
    • Export Citation
  • 5

    Spinazzola F, Nicastri E, Vlassi C, Ghirga P, De Marco M, Pittalis S, Paglia MG, Ferrari C, Narciso P, 2007. Imported malaria at Italy’s National Institute for Infectious Diseases Lazzaro Spallanzani, 1984–2003. Eur J Clin Microbiol Infect Dis 26 :175–179.

    • Search Google Scholar
    • Export Citation
  • 6

    Bruneel F, Hocqueloux L, Alberti C, Wolff M, Chevret S, Bedos JP, Durand R, Le BJ, Regnier B, Vachon F, 2003. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 167 :684–689.

    • Search Google Scholar
    • Export Citation
  • 7

    Corne P, Klouche K, Basset D, Amigues L, Beraud JJ, Jonquet O, 2004. Severe imported malaria in adults: a retrospective study of 32 cases admitted to intensive care units [in French]. Pathol Biol (Paris) 52 :622–626.

    • Search Google Scholar
    • Export Citation
  • 8

    Espinosa G, Tortajada C, Gascon J, Miquel R, Nicolas JM, Nadal P, Corachan M, 1997. Severe Plasmodium falciparum malaria. Description of 5 cases [in Spanish]. Rev Clin Esp 197 :631–634.

    • Search Google Scholar
    • Export Citation
  • 9

    World Health Organization, 1990. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2):1–65.

  • 10

    Knaus WA, Draper EA, Wagner DP, Zimmerman JE, 1985. APACHE II: a severity of disease classification system. Crit Care Med 13 :818–829.

  • 11

    Salvado E, Pinazo MJ, Muñoz J, Alonso D, Mayor A, Quinto Ll, Gascon J, 2008. Clinical presentation and complications of falciparum malaria in two populations: travelers and immigrants [in Spanish]. Enferm Infecc Microbiol Clin 26 :282–284.

    • Search Google Scholar
    • Export Citation
  • 12

    Legros F, Bouchaud O, Ancelle T, Arnaud A, Cojean S, Le BJ, Danis M, Fontanet A, Durand R, 2007. Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996–2003. Emerg Infect Dis 13 :883–888.

    • Search Google Scholar
    • Export Citation
  • 13

    Bouchaud O, Cot M, Kony S, Durand R, Schiemann R, Ralaimazava P, Coulaud JP, Le BJ, Deloron P, 2005. Do African immigrants living in France have long-term malarial immunity? Am J Trop Med Hyg 72 :21–25.

    • Search Google Scholar
    • Export Citation
  • 14

    Jennings RM, De Souza JB, Todd JE, Armstrong M, Flanagan KL, Riley EM, Doherty JF, 2006. Imported Plasmodium falciparum malaria: are patients originating from disease-endemic areas less likely to develop severe disease? A prospective, observational study. Am J Trop Med Hyg 75 :1195–1199.

    • Search Google Scholar
    • Export Citation
  • 15

    Muhlberger N, Jelinek T, Behrens RH, Gjorup I, Coulaud JP, Clerinx J, Puente S, Burchard G, Gascon J, Grobusch MP, Weitzel T, Zoller T, Kollaritsch H, Beran J, Iversen J, Hatz C, Schmid ML, Bjorkman A, Fleischer K, Bisoffi Z, Guggemos W, Knobloch J, Matteelli A, Schulze MH, Laferl H, Kapaun A, McWhinney P, Lopez-Velez R, Fatkenheuer G, Kern P, Zieger BW, Kotlowski A, Fry G, Cuadros J, Myrvang B, 2003. Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID Surveillance Data. Clin Infect Dis 36 :990–995.

    • Search Google Scholar
    • Export Citation
  • 16

    Centers for Disease Control and Prevention, 2007. Health Information for International Travel 2008. Atlanta: US Department of Health and Human Services, Public Health Service Atlanta.

  • 17

    World Health Organization, 2007. International Travel and Health: Situation as on 1 January 2007. Geneva: World Health Organization.

  • 18

    World Health Organization, 2006. Guidelines for the Treatment of Malaria. Geneva: World Health Organization.

  • 19

    Jones KL, Donegan S, Lalloo DG, 2007. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev CD005967.

  • 20

    Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, 2007. UK malaria treatment guidelines. J Infect 54 :111–121.

    • Search Google Scholar
    • Export Citation
  • 21

    Jelinek T, 2005. Intravenous artesunate recommended for patients with severe malaria: position statement from TropNetEurop. Euro Surveill 10 :E051124.

    • Search Google Scholar
    • Export Citation
  • 22

    Riddle MS, Jackson JL, Sanders JW, Blazes DL, 2002. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 34 :1192–1198.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

Severe Imported Malaria in Adults: Retrospective Study of 20 Cases

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  • 1 Barcelona Centre for International Health Research, CRESIB, CIBERESP, Hospital Clinic, Barcelona, Spain; Intensive Care Unit and Parasitology Unit, Hospital Clínic, Barcelona, Spain

Severe imported malaria is an important problem in many countries in which this disease is not endemic. This retrospective study describes the characteristics of 20 adults with severe imported malaria admitted to our intensive care unit from 1991 through 2007. All episodes were caused by Plasmodium falciparum and all patients had returned from sub-Saharan Africa, except for one transfusion recipient. All persons were considered non-immune, and none had taken appropriate chemoprophylaxis. The median time between the initiation of symptoms and the diagnosis was seven days. Five patients died (mortality rate = 25%). A higher frequency of unrousable coma and acidosis and a higher median Apache II score at admission was noted in the persons who died. Mortality by severe malaria remains high despite high quality management, which highlights the importance of chemoprophylaxis and early diagnosis and treatment.

INTRODUCTION

Malaria is a major international health problem, causing 300–500 million infections worldwide and approximately 1 million deaths every year. Almost all deaths and severe episodes are caused by Plasmodium falciparum malaria and most occur in sub-Saharan Africa, mainly among children less than five years of age.1 Nonetheless, imported malaria is an important and growing problem in many countries in which this disease is not endemic because international travels to disease-endemic areas continues to increase. The number of reported imported cases is 11,000 patients per year in European Union countries, with P. falciparum malaria episodes estimated at nearly 8,000 per year.2 Because significant under-reporting is assumed, the actual figures are probably higher. Mortality rates for imported malaria range from 0.3% to 2.2% globally25 and from 11% to 30% in person with severe malaria episodes.48

The criteria defining severe malaria were established by the World Health Organization (WHO) in 19909 and revised in 2000.1 These criteria were mainly developed with data from disease-endemic countries and were focused on guiding medical care in these settings. Their use in countries in which malaria is not endemic has not been extensively analyzed. The purpose of this retrospective study was to investigate patients with severe malaria at our hospital in a country in which malaria is not endemic and analyze clinical and epidemiologic characteristics, intensive care management, and outcomes of these patients.

PATIENTS AND METHODS

Patients.

The study population included adults with a diagnosis of severe malaria admitted to an intensive care unit (ICU) at the Hospital Clinic, University of Barcelona, Barcelona, Spain, from January 1991 through December 2007. The clinical charts of the patients included in the study were reviewed and the data extracted were collected in a standardized case report form.

Definitions.

Severe malaria was defined according to the 1990 and 2000 WHO criteria as the presence of one or more of the following features in a patient with P. falciparum asexual parasitemia and no other confirmed cause for their symptoms 1,9: 1) unrousable coma with a Glasgow Coma Scale score ≤ 9; 2) anemia with a hemoglobin level < 5 g/L; 3) renal failure with a serum creatinine concentration > 3 mg/dL and/or a 24-hour urine output < 400 mL despite rehydratation; 4) pulmonary edema or acute respiratory distress syndrome; 5) hypoglycemia with a blood glucose level < 40 mg/dL; 6) circulatory collapse with a systolic blood pressure < 80 mm of Hg despite adequate volume repletion; 7) abnormal bleeding and/or disseminated intravascular coagulation (DIC); 8) repeated generalized seizures; 9) acidosis (pH < 7.35 or a serum bicarbonate level < 15 mmol/L) orhyperlactatemia (plasma lactate level > 5 mmol/L); 10) macroscopic hemoglobinuria if definitively related to acute malaria; 11) jaundice or total bilirubin level ≥ 3 mg/dL; and 12) parasitemia > 5%.

Data regarding sex, age, origin, chemoprophylaxis, area visited, clinical characteristics, treatment, and outcome were collected. Chemoprophylaxis was considered incomplete if the patient did not take it properly or discontinued the prophylaxis, and it was considered inadequate if the patient took a drug not recommended for the area visited. Clinical severity at ICU admission was assessed using the Apache II score. 10 Bacterial co-infections were defined as community-acquired if diagnosed within the first 48 hours after admission and nosocomial if diagnosed thereafter.

Statistical analysis.

Statistical analysis was performed with SPSS version 12 (SPSS Inc., Chicago, IL). Comparisons were made using the Fisher exact test for categorical data and the Student’s t-test or Mann-Whitney U test for continuous data as appropriate.

RESULTS

Twenty patients were admitted to the ICU with a diagnosis of severe malaria according to WHO criteria during 1991–2007. All patients had P. falciparum malaria and all had returned from sub-Saharan countries in Africa, except for one patient with suspected transfusional transmission (Table 1). A total of 500 P. falciparum malaria cases were admitted to the hospital during the same period. Thus, severe malaria patients accounting for a 4% of the total cases. Four hundred seventy-eight patients (95.6%) had traveled to the sub-Saharan region of Africa (west Africa = 256 patients, central Africa = 188, east Africa = 33, southern Africa = 1). A small percentage had traveled to other malaria-endemic areas (South America = 10, Indian subcontinent = 4, Southeast Asia = 4, north Africa = 1, Central America = 1, Caribbean region = 1).

The median age of patients with severe malaria was 44 years (range = 16–68 years); 15 (75%) were being men and 5 (25%) were women. All patients were originally from areas not endemic for malaria, and all were considered non-immune to malaria (Table 1). None of the 19 patients who had traveled had taken appropriate chemoprophylaxis. Fifteen patients had not taken any chemoprophylaxis, two had taken drugs not recommended because of P. falciparum resistance described in the visited area (one patient had taken chloroquine in 2000 and another had taken chloroquine and proguanil in 2007), and two had discontinued prophylaxis with appropriate drugs (one patient had taken only two doses of mefloquine and one patient had discontinued doxycycline because of epigastric pain).

All travelers had symptoms within the first month after their return. The median time between the initiation of symptoms and the time when patients seeked medical attention for the first time was 4.5 days (interquartile range [IQR] = 3.00–8.50 days) in 14 patients for whom this information was available. The median time between the initiation of symptoms and the diagnosis was 7 days (IQR = 3.75–9.25 days) in 18 patients for whom this information was available. Data reflecting diagnostic delay (time between patient consulting and correct diagnosis) could be inferred for 15 travelers. A correct diagnosis achieved the same day they sought medical assistance was made in only six patients. The median delay in diagnosing malaria was 2 days (range = 1–9 days) in the remaining 9 patients.

The WHO criteria for severe malaria at admission are shown in Table 2. The most frequent criteria observed was hyperbilirubinemia. Total bilirubin levels > 3 mg/dL were present in all but 2 patients (90%). Twelve (60%) patients had an initial parasitemia > 5%. The median parasitemia on the first day was 5.95% (IQR = 2.13–18.00%) (Table 3). External bleeding or DIC were present in 11 (55%) patients, renal failure in 7 (35%) patients, and acidosis in 6 (30%) patients. Other criteria were less common: shock (5 patients), unrousable coma (4), hypoglycemia (3), pulmonary edema and seizures (2 patients each) and macroscopic hemoglobinuria (1). No patient fulfilled strict criteria for severe anemia, but 10 received blood transfusions. All patients were treated with a combination of intravenous quinine and either doxycycline (17 patients) or clindamycin (3 patients) at standard doses. Five patients died (mortality rate = 25%). Among the patients who died, three had cerebral malaria with unrousable coma at admission; these developed in the other two patients during follow-up. Multiple organ failure developed in three of the patients who died.

The WHO criteria at admission and other characteristics were compared between survivors and non-survivors (Tables 2–4). No significant differences were found for sex, age, median time to diagnosis, parasitemia levels on the first day, or other laboratory parameters. Evolutive laboratory data were also collected, specifically, the most abnormal values for each parameter observed at any time during hospitalization. No significant differences were found when comparing these values between survivors and non-survivors. There were no significant differences in the frequency of WHO criteria between the groups, except for the number of patients with unrousable coma at admission (1 patient [6.7%] in the survivors versus 3 [60%] in the non-survivors; P = 0.032) and the presence of acidosis (2 patients [13.3%] in the survivors versus 4 (80%) in the non-survivors; P = 0.014). There were no significant differences in time from symptom onset to diagnosis between groups or in days of diagnostic delay when applicable. The median Apache II score was significantly higher in non-survivors (22, IQR = 18–31 versus 15, IQR = 9–21, P = 0.044). The median ICU stay was 5 days (IQR = 3–12 days) with no differences between groups.

Eight patients (40%) required renal replacement therapy, 10 (50%) received a blood transfusion, and 6 (30%) patients received an exchange transfusion. However, there were no differences between groups (Table 4). Exchange transfusions were given to these 6 patients because of high parasitemia levels (> 30%) in three patients and parasitemia levels > 10% and the presence of one or more criteria of severe disease in the remaining three patients. All non-survivors required mechanical ventilation during follow-up compared with only one-third of survivors (P = 0.033). Other simultaneous infections were diagnosed in six patients (five survivors and one non-survivor): five with nosocomial pneumonia and one with acute Epstein-Barr virus infection.

DISCUSSION

All the patients with severe malaria according to the WHO criteria in our series acquired P. falciparum malaria in sub-Saharan countries in Africa (except the patient with transfusional transmission), as did most of the P. falciparum malaria cases. This findings reflect the higher risk of malaria acquisition in this area compared with other areas, 2,3,6 and strengthens current recommendations about chemoprophylaxis. All patients were from areas not endemic for malaria and were considered non-immune. Although African immigrants account for almost half of malaria episodes at our clinic, 11 there were no deaths and no severe cases in this group during the study period. This finding might be related to their acquired semi-immunity (after repeated exposures to malaria), which has been associated with a lower risk of complications and death. 2,3,12 This protection is generally thought to disappear in a few years after non-exposure, but conflicting findings about this issue have been published, 13,14 and it is still a matter of debate that warrants further investigations. Previous studies have suggested that age is a risk factor for severe P. falciparum malaria.15 We did not find a significant difference in the median age between survivors and non-survivors, perhaps because of the small sample size. Other factors that may be implicated in the severity of P. falciparum malaria, such as differences in parasite strains that might be related to virulence, were not assessed in our study.

None of the patients had taken correct chemoprophylaxis, and most had not taken any prophylaxis. Despite clear recommendations and national and international guidelines about malaria prevention measures and chemoprophylaxis, which are readily accessible for health care practitioners and well-informed travelers, 16,17 many persons travel to high-risk malaria areas without taking the correct prophylaxis. Few persons are aware of the risk and the recommended measures before, during, and after travel. Incomplete or lack of chemo-prophylaxis is a known risk factor for severe malaria. 3,4,6,7,12 Most patients hesitate several days before seeking medical attention. Moreover, in some cases, the diagnosis of malaria was not achieved on the first visit and correct diagnosis and treatment were delayed. These two components led to an exceedingly long diagnostic and treatment delay, sometimes with fatal consequences.

The WHO criteria for severe malaria were developed to assist clinical and epidemiologic descriptions and to alert healthcare workers to the symptoms and signs associated with progression to life-threatening disease and to guide clinical management.1 However, they were developed based on the information available from studies in developing countries, mainly in children, and little is known about the frequency and prognostic value of these criteria in adults with severe imported malaria. In our study, hypoglycemia, repeated seizures, or hemoglobinuria were infrequent and of questionable prognostic value, as in other series of imported malaria. 6,7 Conversely, hyperbilirubinemia and hyperparasitemia were the most frequent criteria; they were found in 60% and 90% of patients, respectively. A low level of parasitemia does not rule out the possibility of complications and can be found in severe malaria cases. Nonetheless, high parasitemia levels have been associated with an increased risk of mortality in non-immune patients and should prompt rapid treatment and careful follow-up even if no other symptoms are present at the time. 1,7,18 None of the patients fulfilled strict criteria for severe anemia, but 10 patients received a blood transfusion before showing hemoglobin levels < 5 g/L. Transfusional needs may more accurately reflect the degree of anemia in developed countries.5 In our study, only the presence of unrousable coma and metabolic acidosis at admission were significantly associated with a fatal outcome, as was clinical severity assessed by Apache II score. Pulmonary edema and shock have also been correlated with mortality in other studies,6 but we did not find this correlation. However, the number of non-survivors was too small to make broader conclusions.

All patients were treated with a combination of intravenous quinine and either doxycycline or clindamycin. Although there is accumulating evidence that artesunate provides some advantages over quinine in patients with severe malaria or high parasitemias, 19,20 this drug has not yet been licensed in the European Union Community. It is currently available through individual application for selected situations, although efforts are being made to make it more easily available. 21 Exchange transfusion is recommended for patients with high parasitemia levels and organ involvement,1 although its use is controversial because there are no well-conducted controlled trials that support its role. 22 Nevertheless, six patients received exchange transfusion in our series. This treatment was decided on an individual basis when recommended by the WHO guidelines.1

In our series, the mortality rate was as high as 25%. In malaria-endemic areas, the mortality rate in adults with severe malaria treated by highly skilled teams ranges from 10% to 20%. 18 The mortality rate associated with severe imported malaria ranges from 11% to 30% and has not decreased.48 Despite access to specific treatment and sophisticated intensive care management, mortality caused by severe malaria remains high. When correct diagnosis is achieved and treatment is started, patients are sometimes already in an advanced state with multi-organ involvement and even optimal intensive care does not prevent death. Some recent studies have underlined decisive factors implicated in deaths by malaria and how could most of these be prevented. 3,4 Most of these factors are related to patient and physician misinformation and diagnostic and treatment delays (patient and doctor delay). Travelers should be informed about the risk of malaria and preventive measures and the importance of seeking medical attention if symptoms develop during or after travel. All healthcare practitioners should keep the suspicion of malaria in mind. In patients with a history of travel, practitioners should always obtain a blood film in cases with the possibility of malaria, seek expert advice, and remember that malaria cannot be ruled out by a single blood analysis.

In conclusion, mortality caused by severe malaria remains high despite high-quality management. Deaths caused by malaria occur in Europe every year. The WHO criteria may not be as useful for imported severe malaria as they are in malaria-endemic countries. Nonetheless, any symptom or sign of severity or organ involvement in a patient with malaria should prompt rapid treatment and intensive care management to prevent further complications and a fatal outcome. Studies on significant prognostic factors in imported malaria are required. The best way to prevent deaths from imported malaria would be to improve information available to travelers and immigrants regarding the risk of malaria and preventive measures and chemoprophylaxis, and provide clear indications to seek help if illness develops during or after travel. In addition, health care practitioners should always remember to consider the possibility of malaria in symptomatic patients with a history of travel.

Table 1

Characteristics of the study participants*

Table 1
Table 2

World Health Organization criteria at admission, according to outcome*

Table 2
Table 3

Laboratory results of patients at intensive care unit admission, according to outcome*

Table 3
Table 4

Characteristics of patients in intensive care unit, according to outcome*

Table 4

*

Address correspondence to Ana González, Centre for International Health Research, c/Rosselló 132, 4°, 08036 Barcelona, Spain. E-mail: portana1@gmail.com

Authors’ addresses: Ana González, Jose Muñoz, and Joaquim Gascon, Centre for International Health Research, c/Rosselló 132, 4°, 08036 Barcelona, Spain, E-mail: portana1@gmail.com. Josep M. Nicolás, Pedro Castro, Josep R. Coma, and Jesús Aibar, Intensive Care Unit, Hospital Clínic, c/Villarroel 170, 08036 Barcelona, Spain, E-mail: nicolas@clinic.ub.es. Jordi Mas and Ma Eugenia Valls, Parasitology Unit, Microbiology Department, Hospital Clinic, c/Villarroel 170, 08036 Barcelona, Spain, E-mails: jmas@clinic.ub.es and mevalls@clinic.ub.es.

Acknowledgments: We thank Donna Pringle for suggestions and English language review of the manuscript. This study was presented in part at the Sixth Congress of the Tropical Medicine and International Health Spanish Society, March 5–7, 2008, Segovia, Spain (Abstract PC56). This abstract is available from Enf. Emerg 2008; 10:45.

REFERENCES

  • 1

    World Health Organization, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1):S1–S90.

  • 2

    Jelinek T, Schulte C, Behrens R, Grobusch MP, Coulaud JP, Bisoffi Z, Matteelli A, Clerinx J, Corachan M, Puente S, Gjorup I, Harms G, Kollaritsch H, Kotlowski A, Bjorkmann A, Delmont JP, Knobloch J, Nielsen LN, Cuadros J, Hatz C, Beran J, Schmid ML, Schulze M, Lopez-Velez R, Fleischer K, Kapaun A, McWhinney P, Kern P, Atougia J, Fry G, da Cunha S, Boecken G, 2002. Imported falciparum malaria in Europe: sentinel surveillance data from the European network on surveillance of imported infectious diseases. Clin Infect Dis 34 :572–576.

    • Search Google Scholar
    • Export Citation
  • 3

    Christen D, Steffen R, Schlagenhauf P, 2006. Deaths caused by malaria in Switzerland, 1988–2002. Am J Trop Med Hyg 75 :1188–1194.

  • 4

    Matteelli A, Colombini P, Gulletta M, Castelli F, Carosi G, 1999. Epidemiological features and case management practices of imported malaria in northern Italy, 1991–1995. Trop Med Int Health 4 :653–657.

    • Search Google Scholar
    • Export Citation
  • 5

    Spinazzola F, Nicastri E, Vlassi C, Ghirga P, De Marco M, Pittalis S, Paglia MG, Ferrari C, Narciso P, 2007. Imported malaria at Italy’s National Institute for Infectious Diseases Lazzaro Spallanzani, 1984–2003. Eur J Clin Microbiol Infect Dis 26 :175–179.

    • Search Google Scholar
    • Export Citation
  • 6

    Bruneel F, Hocqueloux L, Alberti C, Wolff M, Chevret S, Bedos JP, Durand R, Le BJ, Regnier B, Vachon F, 2003. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults. Am J Respir Crit Care Med 167 :684–689.

    • Search Google Scholar
    • Export Citation
  • 7

    Corne P, Klouche K, Basset D, Amigues L, Beraud JJ, Jonquet O, 2004. Severe imported malaria in adults: a retrospective study of 32 cases admitted to intensive care units [in French]. Pathol Biol (Paris) 52 :622–626.

    • Search Google Scholar
    • Export Citation
  • 8

    Espinosa G, Tortajada C, Gascon J, Miquel R, Nicolas JM, Nadal P, Corachan M, 1997. Severe Plasmodium falciparum malaria. Description of 5 cases [in Spanish]. Rev Clin Esp 197 :631–634.

    • Search Google Scholar
    • Export Citation
  • 9

    World Health Organization, 1990. Severe and complicated malaria. Trans R Soc Trop Med Hyg 84 (Suppl 2):1–65.

  • 10

    Knaus WA, Draper EA, Wagner DP, Zimmerman JE, 1985. APACHE II: a severity of disease classification system. Crit Care Med 13 :818–829.

  • 11

    Salvado E, Pinazo MJ, Muñoz J, Alonso D, Mayor A, Quinto Ll, Gascon J, 2008. Clinical presentation and complications of falciparum malaria in two populations: travelers and immigrants [in Spanish]. Enferm Infecc Microbiol Clin 26 :282–284.

    • Search Google Scholar
    • Export Citation
  • 12

    Legros F, Bouchaud O, Ancelle T, Arnaud A, Cojean S, Le BJ, Danis M, Fontanet A, Durand R, 2007. Risk factors for imported fatal Plasmodium falciparum malaria, France, 1996–2003. Emerg Infect Dis 13 :883–888.

    • Search Google Scholar
    • Export Citation
  • 13

    Bouchaud O, Cot M, Kony S, Durand R, Schiemann R, Ralaimazava P, Coulaud JP, Le BJ, Deloron P, 2005. Do African immigrants living in France have long-term malarial immunity? Am J Trop Med Hyg 72 :21–25.

    • Search Google Scholar
    • Export Citation
  • 14

    Jennings RM, De Souza JB, Todd JE, Armstrong M, Flanagan KL, Riley EM, Doherty JF, 2006. Imported Plasmodium falciparum malaria: are patients originating from disease-endemic areas less likely to develop severe disease? A prospective, observational study. Am J Trop Med Hyg 75 :1195–1199.

    • Search Google Scholar
    • Export Citation
  • 15

    Muhlberger N, Jelinek T, Behrens RH, Gjorup I, Coulaud JP, Clerinx J, Puente S, Burchard G, Gascon J, Grobusch MP, Weitzel T, Zoller T, Kollaritsch H, Beran J, Iversen J, Hatz C, Schmid ML, Bjorkman A, Fleischer K, Bisoffi Z, Guggemos W, Knobloch J, Matteelli A, Schulze MH, Laferl H, Kapaun A, McWhinney P, Lopez-Velez R, Fatkenheuer G, Kern P, Zieger BW, Kotlowski A, Fry G, Cuadros J, Myrvang B, 2003. Age as a risk factor for severe manifestations and fatal outcome of falciparum malaria in European patients: observations from TropNetEurop and SIMPID Surveillance Data. Clin Infect Dis 36 :990–995.

    • Search Google Scholar
    • Export Citation
  • 16

    Centers for Disease Control and Prevention, 2007. Health Information for International Travel 2008. Atlanta: US Department of Health and Human Services, Public Health Service Atlanta.

  • 17

    World Health Organization, 2007. International Travel and Health: Situation as on 1 January 2007. Geneva: World Health Organization.

  • 18

    World Health Organization, 2006. Guidelines for the Treatment of Malaria. Geneva: World Health Organization.

  • 19

    Jones KL, Donegan S, Lalloo DG, 2007. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev CD005967.

  • 20

    Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, 2007. UK malaria treatment guidelines. J Infect 54 :111–121.

    • Search Google Scholar
    • Export Citation
  • 21

    Jelinek T, 2005. Intravenous artesunate recommended for patients with severe malaria: position statement from TropNetEurop. Euro Surveill 10 :E051124.

    • Search Google Scholar
    • Export Citation
  • 22

    Riddle MS, Jackson JL, Sanders JW, Blazes DL, 2002. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis. Clin Infect Dis 34 :1192–1198.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Ana González, Centre for International Health Research, c/Rosselló 132, 4°, 08036 Barcelona, Spain, E-mail: portana1@gmail.com.
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