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Possible autochthonous malaria from Marseille to Minneapolis.

We report 2 cases of Plasmodium falciparum malaria in southern France in a French woman and an American man of Togolese origin who reported no recent travel to malaria-endemic countries. Both infections occurred after a stay near Marseille, which raises the possibility of autochthonous transmission. Entomologic and genotypic investigations are described.

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Endemic malaria was eradicated from France during the middle of the past century. However, Plasmodium falciparum malaria has recently been reported in several Western European countries in persons with no history of travel or blood transfusion (1-3). The most recent case of an autochthonous case of vivax malaria was reported in 2006 in Corsica, where susceptible vectors persist (4). In southern France, a favorite destination for tourists, the last malaria cases in patients without any recent travel in malaria-endemic areas were reported in 1994 and 2000 (5,6). We report 2 cases that occurred in southern France during early spring and early summer 2006.

The Cases

On June 30, 2006, a 4l-year-old woman was admitted to the North University Hospital in Marseille, France, with a 12-day history of fever, chills, and diarrhea. She had never traveled outside Europe and had no history of blood transfusion or injection drug use. She was born in Marseille and had lived there her entire life. Her home residence was >20 km from the nearest airport and 10 km from the seaport. The case-patient did not work outside the home and did not report any recreational activities near either location. Her neighborhood included families of Comorian descent. Laboratory testing demonstrated low leukocyte and erythrocyte counts and thrombocytopenia. Peripheral blood smear also demonstrated intra-erythrocytic forms consistent with P. falciparum infection with a parasitemia level of 0.1%. P. falciparum antigen was detected (Test NowICT; Fumouze, Levallois-Perret, France) and subsequently confirmed by PCR. Treatment comprised a 3-day regimen of quinine-clindamycin (7) and the case-patient recovered.

A 34-year-old man with tactile fever, bilateral frontal headache, and diarrhea was examined at a clinic in Minneapolis, Minnesota, on May 1, 2006. This man had lived in Togo, his birth country, all of his life until he emigrated to Minnesota in April 2000. Before becoming ill, he had traveled to Paris and from Paris by train to Marseille on April 7, 2006. Also during this timeframe, he reported a day trip to Camargue (Sorgues, France) where he sustained multiple mosquito bites. On April 24, 2006, he returned to Paris by train and then traveled by air a few hours later to Minneapolis. The first symptoms of malaria developed on April 27. His medical history included 4 episodes of malaria in childhood (none in the past decade) and no blood transfusions. On his last visit to Togo in December 2004, the case-patient had reported no chemoprophylaxis for malaria and had experienced no illness or intervening fevers since that time. Physical examination showed a moderately ill person with hematologic test results indicating thrombocytopenia and intra-erythrocytic ring forms consistent with P. falciparum malaria with a 3% parasitemia level. PCR testing confirmed P. falciparum. He was given 4 tablets of atovoquone-proguanil once a day for 3 days and recovered completely.

We conducted entomologic surveillance on July 26, 2006, in and around the first case-patient's residence in Marseille, 26 days after she became ill. No adult mosquitoes were found in the patient's home, on external staircases, in cellars located around the patient's home, or in surrounding buildings. Two pools of standing water were identified: a single pool (1 [m.sup.2], 2 cm deep) within a cellar in her building and another pool (10 [m.sup.2], 5 cm deep) located 20 m outside the building. No other containers or places that could collect water were identified. Several Culex theileri larvae were identified in the outdoor pool, but there was no evidence of Anopheles larvae.

DNA was extracted from blood samples by using the ENZA blood DNA kit according to the manufacturer's recommendations (Biofidal, Vaulx en Velin, France) and eluted in 100 [mu]L of elution buffer per 250 [micro]L of whole blood. Microsatellites loci (C4M79, Pf2689, TRAP, Pf2802, 7A11, and C4M69) were genotyped by fluorescent end-labeled PCR. Primers sequence, PCR conditions, and methods for genotyping have been described elsewhere (8,9). Drug-resistant mutations were genotyped. Genotyping of the 2 isolates demonstrated different alleles for the 6 microsatellite loci. We also observed different alleles from codon 59 (dihydrofolate reductase), 437 (dihydropteroate synthase), and (P. falciparum chloroquine-resistance transporter) (Tables 1,2).

Conclusions

The World Health Organization defines introduced autochthonous malaria as that acquired by mosquito transmission from an imported case in an area where malaria is not a regular occurrence (10) In France, it is rare to find P. falciparum in a blood smear from patients who have not traveled to a malaria-endemic area in the previous 12 months. History of transfusion, organ transplantation, intravenous drug use, or mother-to-fetus transmission must also be excluded (10).

In Europe, some recent autochthonous malaria cases have been related to close proximity to airports and shipping ports receiving flights and water craft from malaria-endemic areas (5,6,11). Inadvertent carriage of infective Anopheles mosquitoes by airplane, ship, baggage, or bilge water may be responsible for these occurrences. Also, large populations of migrants from areas highly endemic for malaria (12) may act as human reservoirs for potential gametocyte carriers. Marseille has a large population of persons of Comorian origin, and most of the patients with imported malaria cases diagnosed in Marseille contracted the disease during a trip to the Comoros Islands (13,14). Our first case-patient's malaria may have been linked to her neighborhood, which included Comorian families who had recently traveled to Comoros. Despite the absence of Anopheles larvae near the first patient's neighborhood, local transmission cannot be excluded during the late spring and summer. Summer temperatures in Marseille induce a short P. falciparum sporogonic cycle ([approximately equal to] 11 days at 28 [degrees]C), which is compatible with mosquitoes' longevity at that time.

The Minnesota case-patient likely represents a second case of autochthonous malaria. First, this patient had no illness to suggest an untreated, active infection since his last trip to Togo. Second, even if he had been persistently infected with P. falciparum and was semi-immune, this case would still represent an extremely long incubation period (16 months). Third, onset of symptoms was acute, hematologic testing showed infection with a 3% parasitemia level, and the case-patient was moderately ill, which suggests a more recent exposure. Moreover, the genotype was monoallelic for each locus, indicating a clonal infection, which would be expected in areas of relatively low transmission frequency. In contrast, in areas of frequent endemic transmission, such as Togo, multiple allelic polymorphisms would be expected (9). Finally, genotyping demonstrated different clones of P. falciparum; this finding suggests potential multiple introductions, temporally related, of the parasite into the environment

The last malaria focus in continental France occurred near the end of World War II in the Camargue region, which was visited by our second case-patient in April 2006. However, large Anopheles populations, including potential vectors such as An. hyrcanus, An. melanoon, and An. atroparus, are still present from March to November (N. Poncon and D. Fontenille, unpub.data) in southeastern France, generating an "anophelism without malaria" situation (15).

Migrants from malaria-endemic countries, climate, and Anopheles populations make southern France a favorable area for sporadic cases of autochthonous malaria in Europe. Given these 2 temporally related cases, clinicians should suspect malaria in patients with unexplained fevers who have recently traveled to areas of southern France.

Acknowledgments

We are grateful to the Geo Sentinel Network, whose findings led to the connection of these 2 cases.

This work was partly supported by the Programme Hospitalier de Recherche Clinique Regional 2003, Assistance PubliqueHopitaux de Marseille, and the French Armed Forces Health Service.

References

(1.) Baldari M, Tamburro A, Sabatinelli G, Romi R, Severini C, Cuccagna G, et al. Malaria in Maremma, Italy. Lancet. 1998;351:1246-7.

(2.) Kruger A, Rech A, Su XZ, Tannich E. Two cases of autochthonous Plasmodium falciparum malaria in Germany with evidence for local transmission by indigenous Anopheles plumbeus. Trop Med Int Health. 2001;6:983-5.

(3.) Kampen H, Maltezos E, Pagonaki M, Hunfeld KP, Maier WA, Seitz HM. Individual cases of autochthonous malaria in Evros Province, northern Greece: serological aspects. Parasitol Res. 2002;88:261-6.

(4.) Armengaud A, Legros K Quatresous I, Barre H, Valayer P, Fanton Y, et al. A case of autochthonous Plasmodium vivax malaria, Corsica, August 2006. Eurosurveillance Weekly Releases. 2006; 11: E061116.3

(5.) Delmont J, Brouqui P, Poullin P, Bourgeade A. Harbour-acquired Plasmodium falciparum malaria. Lancet. 1994;344:330-1.

(6.) Baixench MT, Suzzoni-Blatger J, Magnaval JF, Lareng MB, Larrouy G. Two cases of inexplicable autochthonous malaria in Toulouse, France. Med Trop (Mars). 1998;58:62-4.

(7.) Parola P, Ranque S, Badiaga S, Niang M, Blin O, Charbit JJ, et al. Controlled trial of 3-day quinine-clindamycin treatment versus 7-day quinine treatment for adult travelers with uncomplicated falciparum malaria imported from the tropics. Antimicrob Agents Chemother. 2001;45:932-5.

(8.) Nair S, Brockman A, Paiphun L, Nosten F, Anderson TJ. Rapid genotyping of loci involved in antifolate drug resistance in Plasmodium falciparum by primer extension, Int J Parasitol. 2002;32:852-8.

(9.) Bogreau H, Renaud F, Bouchiba H, Durand P, Assi SB, Henry MC, et al. Genetic diversity and structure of African Plasmodium falciparum populations in urban and rural areas. Am J Trop Med Hyg. 2006;74:953-9.

(10.) WHO regional Office for Europe. From malaria control to elimination in the WHO European region 2006-2015. Copenhagen, 2006. [cited 2007 Mar 28]. Available from http://www.euro.who.int/ document/e88840.pdf

(11.) Mantel CF, Klose C, Scheurer S, Vogel R, Wesirow AL, Bienzle U. Plasmodium falciparum malaria acquired in Berlin, Germany. Lancet. 1995;346:320-1.

(12.) Stauffer WM, Newberry AM, Cartwright CP, Rosenblatt JE, Hanson KL, Sloan L, et al. Evaluation of malaria screening in newly arrived refugees to the United States by microscopy and rapid antigen capture enzyme assay. Pediatr Infect Dis J. 2006;25:948-50.

(13.) Parola P, Gazin R Pradines B, Parzy D, Delmont J, Brouqui P. Marseilles: a surveillance site for malaria from Comoros Islands. J Travel Med. 2004;11:184-6.

(14.) Parola P, Soula G, Gazin P, Foucault C, Delmont J, Brouqui R Fever in travelers returning from tropical areas: prospective observational study of 613 cases hospitalised in Marseille, France, 1999-2003. Travel Med Infect Dis. 2006;4:61-70.

(15.) Pongon N, Toty C, L'Ambert G, Le Goff G, Brengues C, Schaffner F, Fontenille D. Biology and dynamics of potential malaria vectors in southern France. Malar J. 2007 21;6:18.

Address for correspondence: Philippe Parola, Service des Maladies infectieuses et Tropicales, Hopital Nord, AP-HM, Chemin des Bourrely, 13915 Marseille CEDEX, France; email: philippe.parola@medecine. univ-mrs.fr

Dr Doudier is an infectious disease fellow in the University Hospital of Marseille, France. Her research interests include malaria and imported diseases.

Barbara Doudier,*[dagger] Herve Bogreau,*[dagger] Aaron DeVries,[double dagger] Nicolas Poncon,[section] William M Stauffer III,[double dagger] Didier Fontenille,[section] Christophe Rogier,[dagger]

*Hopital Nord, Marseille, France; [dagger] Institut de Medecine Tropicale du Service de Sante des Armees, Marseille, France; [double dagger] University of Minnesota, Minneapolis, Minnesota, USA; and [section] lnstitut de Recherche pour le Developpement, Montpellier, France and Philippe Parola*[dagger]
Table 1. Microsatellite loci genotyping and single nucleotide
polymorphism in drug-resistant genes

 C4M79 Pf2689 Pf2802

Autochthonous 1* 190 87 141
Autochthonous 2 [dagger] 221 95 138
3D7 [double dagger] 221 87 138
W2 [double dagger] 188 87 146

 7A11 C4M69 TRAP

Autochthonous 1* 88 378 132
Autochthonous 2 [dagger] 99 364 149
3D7 [double dagger] 94 364 137
W2 [double dagger] 109 319 140

* Patient 1, Plasmodium falciparum diagnosed in France.
[dagger] Patient 2, P. falciparum diagnosed in the United States.
[double dagger] Two parasite strains (3D7 and W2) were genotyped
as a positive control; water was used as a negative control.

Table 2. Two strains of Plasmodium falciparum obtained from 2
patients with no recent travel history in malaria-endemic areas *

 Dhfr
 51 16 108 164 59

Autochthonous l [dagger] - GCA AAC ATA TGT
Autochthonous 2 [double ATT GCA AAC ATA CGT
 dagger]
3D7 [section] AAT GCA AGC ATA TGT
W2 [section] ATT GCA AAC ATA CGT

 Dhps
 613 540 581 436 437

Autochthonous l [dagger] GCC AAA GCG TCT GCT
Autochthonous 2 [double GCC AAA GCG TCT GGT
 dagger]
3D7 [section] GCC AAA GCG TCT GGT
W2 [section] TCC AAA GCG TTT GGT

 Pfcrt
 76

Autochthonous l [dagger] ACA
Autochthonous 2 [double AAA
 dagger]
3D7 [section] AAA
W2 [section] ACA

* Dhfr, dihydrofolate reductase gene; Dhps, dihydropteroate synthase;
Pfcrt, P. falciparum chloroquine-resistance transporter. Underlines
indicate positions that can be mutated.

[dagger] Patient 1, P. falciparum diagnosed in France.

[double dagger] Patient 2, P. falciparum diagnosed in the United
States.

[section] Two parasite strains (3D7 and W2) were genotyped as a
positive control water was used as a negative control.
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Article Details
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Title Annotation:DISPATCHES
Author:Doudier, Barbara; Bogreau, Herve; DeVries, Aaron; Poncon, Nicolas; Stauffer, William M., III; Fonten
Publication:Emerging Infectious Diseases
Geographic Code:4EUFR
Date:Aug 1, 2007
Words:2142
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