- Email: [email protected]
Leishmania donovani leishmaniasis in Cyprus
Reflection and Reaction
3
4 5
Hubner R. Chikungunya—Italy (Emilia Romagna) (05): confirmed. ProMED Mail. Archive number 20070918.3102. Sep 18, 2007. http:// www.promedmail.org (accessed Nov 28, 2007). Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks—the globalization of vectorborne diseases. N Engl J Med 2007; 356: 769–71. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis 2006; 12: 1493–99.
6 7
Romi R. History and updating on the spread of Aedes albopictus in Italy. Parassitologia 1995; 37: 99–103. Beltrame A, Angheben A, Bisoffi Z, et al. Imported chikungunya infection, Italy [letter]. Emerg Infect Dis 2007; 13(8). http://www.cdc.gov/EID/ content/13/8/1264.htm (accessed Nov 28, 2007).
Leishmania donovani leishmaniasis in Cyprus In their Review on cutaneous leishmaniasis (CL), Richard Reithinger and colleagues1 emphasised the spreading of species causing this neglected disease to previously non-endemic areas. In line with the above, we present data that support the emergence and spread of nonEuropean Leishmania species in Europe. Visceral leishmaniasis (VL), a vector-borne (re)-emerging disease, is the most severe form of leishmaniasis. VL can be caused by Leishmania infantum or Leishmania donovani, which differ in their disease pathology, vectors, and reservoir hosts.2 L infantum is found in Mediterranean countries, the middle east, Asia, and South America, and is responsible for zoonotic visceral leishmaniasis (ZVL), with dogs as the main reservoir hosts. ZVL is an emerging veterinary and public-health problem in Mediterranean countries. L donovani, an anthroponotic species, causes VL as well as post-kala-azar dermal leishmaniasis (PKDL), and is also responsible for epidemic VL outbreaks in the Indian subcontinent and east Africa (figure).3 In India, mostly in
L donovani L donovani (MON-37) L infantum
Figure: Distribution of Leishmania donovani complex species in the Old World and localisation of the MON-37 zymodeme
6
Bihar, 70% of cases of L donovani VL are unresponsive to treatment with pentavalent antimony.4–5 In Cyprus, leishmaniasis was considered, until now, to be a problem of dogs. No human cases had been officially reported, although under-reporting cannot be excluded. In 2006, however, three CL and two VL human cases were diagnosed. The patients with VL, aged 9 months and 73 years, although of Turkish and British origin, respectively, were permanent residents of Cyprus. The patients with CL were Cypriots aged 44, 50, and 55 years. None had visited a country outside Europe. In the CL cases, clinical symptoms had become evident 1 year before the diagnosis of leishmaniasis was established. Laboratory diagnosis included serology, PCR, and isolation of the parasite. Typing of the isolates was first carried out using K26-PCR assay, which is capable of discriminating species/subspecies of the L donovani complex, based on the amplicon size.6 The five isolates were not found to be L infantum MON-1 (626 bp amplicon), the prominent taxon in the Mediterranean countries and the only species found, until now, in Cyprus. Rather, they were typed as L donovani (700 bp amplicon). The isolates were subsequently typed using multilocus enzyme electrophoresis,7 which provided the infraspecific position of the parasite as pertaining to MON-37 zymodeme. Interestingly, one of the 20 canine isolates studied, originating from a dog living in the same district as the three human CL cases, gave two amplicons, one corresponding to MON-1 and the other to MON-37. Analysis with nine microsatellite polymorphic markers8 confirmed the peculiarity of the strain, suggesting that the dog was co-infected with both parasite species. A generation of hybrids, which may circulate in nature through sandflies and infect human beings, is an alarming hypothesis since Leishmania major/L infantum hybrids that exhibit an increased transmission potential have recently been isolated in Portugal.9 http://infection.thelancet.com Vol 8 January 2008
Reflection and Reaction
In the Indian subcontinent, Iraq, and Kenya,10 L donovani MON-37 (figure) causing CL, VL, and PKDL is considered anthroponotic. MON-37 was also recently found in Sri Lanka where it causes CL. This strain differs from the predominant Indian zymodeme MON-2 (which causes VL only) in the mobility of 6-phosphogluconate dehydrogenase.11 Microsatellite analysis showed that MON-37 strains cluster together and are closely related to L donovani strains from India, Bangladesh, and Nepal.12 Knowledge on the epidemiological features, pathogenesis, and clinical phenotype of the disease caused by L donovani MON-37 as well as its response to first-line drugs is poor. Therefore, the emergence and spread of potentially drug-resistant parasites in Cyprus signals a substantial public-health threat. Cyprus, an EU member state, lies at the crossroads of three continents. The island presents a mosaic of risk factors for leishmaniasis, such as urbanisation, extended agricultural projects, environmental/climatic changes, and the daily movement of populations along the Green Line. Additionally, there are high numbers of legal and illegal immigrants from countries outside the EU, where leishmaniases caused by non-European species are endemic. These factors, associated with Cyprus’ sandfly species, which are broadly permissive vectors and can transmit both L infantum and L donovani,13 would allow the circulation of MON-37. The risk of MON-37 spreading in Cyprus and Europe is high. Hence, estimation of the size of this public-health threat, the establishment of a surveillance system, the adoption of trans-border control measures, and the control of canine leishmaniasis are of prime urgency.
Laboratory of Clinical Bacteriology, Parasitology, Zoonoses, and Geographical Medicine, University of Crete, Crete, Greece (MA); Laboratory of Molecular Parasitology, Hellenic Pasteur Institute, 115 21 Athens, Greece (CH, KS); Veterinary Services of Cyprus, Nicosia, Cyprus (AM); and Université Montpellier 1 et Centre Hospitalier Universitaire de Montpellier, Laboratoire de Parasitologie and Centre National de Référence des Leishmania, Montpellier, France (FP, J-PD) [email protected] We declare that we have no conflicts of interest. The study is partly supported by the Research Promotion Foundation in Cyprus (HEALTH/0104/09), the Hellenic Pasteur Institute and EU grants QLK2-CT-2001-01810 and INCO-CT-2004509086. The study sponsors had no role in study design, data interpretation, or in the writing of the report. We thank Petr Volf for constructive discussions in sandfly vector transmission potential and Kyprianos Nicolaides for critical suggestions. 1 2
3 4 5
6
7
8
9
10
11
12
Maria Antoniou, Christos Haralambous, Apostolos Mazeris, Francine Pratlong, Jean-Pierre Dedet, *Ketty Soteriadou
13
Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis 2007; 7: 581–96. Lukes J, Mauricio IL, Schonian G, et al. Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomy. Proc Natl Acad Sci USA 2007; 104: 9375–80. Alvar J, Yactayo S, Bern C. Leishmaniasis and poverty. Trends Parasitol 2006; 22: 552–57. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19: 111–26. Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, Sundar S. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980–2004. Lancet Infect Dis 2005; 5: 763–74. Haralambous C, Antoniou M, Pratlong F, Dedet JP, Soteriadou K. Development of a molecular assay specific for the Leishmania donovani complex that discriminates L donovani/L infantum zymodemes: a useful tool for typing MON-1. Diagn Microbiol Infect Dis 2007; published online Sep 20; DOI:10.1016/j.diagmicrobio.2007.07.019. Rioux JA, Lanotte G, Serres E, Pratlong F, Bastien P, Perieres J. Taxonomy of Leishmania. Use of isoenzymes. Suggestions for a new classification. Ann Parasitol Hum Comp 1990; 65: 111–25. Kuhls K, Keilonat L, Ochsenreither S, et al. Multilocus microsatellite typing (MLMT) reveals genetically isolated populations between and within the main endemic regions of visceral leishmaniasis. Microbes Infect 2007; 9: 334–43. Volf P, Benkova I, Myskova J, Sadlova J, Campino L, Ravel C. Increased transmission potential of Leishmania major/Leishmania infantum hybrids. Int J Parasitol 2007; 37: 589–93. Sharma NL, Mahajan VK, Kanga A, et al. Localized cutaneous leishmaniasis due to Leishmania donovani and Leishmania tropica: preliminary findings of the study of 161 new cases from a new endemic focus in Himachal Pradesh, India. Am J Trop Med Hyg 2005; 72: 819–24. Karunaweera ND, Pratlong F, Siriwardane HV, Ihalamulla RL, Dedet JP. Sri Lankan cutaneous leishmaniasis is caused by Leishmania donovani zymodeme MON-37. Trans R Soc Trop Med Hyg 2003; 97: 380–81. Siriwardana HV, Noyes HA, Beeching NJ, Chance ML, Karunaweera ND, Bates PA. Leishmania donovani and cutaneous leishmaniasis, Sri Lanka. Emerg Infect Dis 2007; 13: 476–78. Volf P, Myskova J. Sand flies and Leishmania: specific versus permissive vectors. Trends Parasitol 2007; 23: 91–92.
Dengue control We read with concern Kathryn Senior’s recent report on the prospects for effective dengue control.1 Although we welcome any report that highlights the global dengue problem, we believe the article painted an inaccurately bleak portrait of the current situation, by ignoring recent achievements and new developments that indicate effective dengue vector management is likely in the http://infection.thelancet.com Vol 8 January 2008
immediate future. Indeed, the WHO Special Programme for Research and Training in Tropical Diseases (TDR) Dengue Scientific Working Group stated this year that “there has never been a more optimistic time to be involved in dengue and dengue research”, and that “there is a unique opportunity to make a tangible and substantial impact on dengue over the next decade”.2 7
3
4 5
Hubner R. Chikungunya—Italy (Emilia Romagna) (05): confirmed. ProMED Mail. Archive number 20070918.3102. Sep 18, 2007. http:// www.promedmail.org (accessed Nov 28, 2007). Charrel RN, de Lamballerie X, Raoult D. Chikungunya outbreaks—the globalization of vectorborne diseases. N Engl J Med 2007; 356: 769–71. Parola P, de Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in travelers returning from Indian Ocean islands. Emerg Infect Dis 2006; 12: 1493–99.
6 7
Romi R. History and updating on the spread of Aedes albopictus in Italy. Parassitologia 1995; 37: 99–103. Beltrame A, Angheben A, Bisoffi Z, et al. Imported chikungunya infection, Italy [letter]. Emerg Infect Dis 2007; 13(8). http://www.cdc.gov/EID/ content/13/8/1264.htm (accessed Nov 28, 2007).
Leishmania donovani leishmaniasis in Cyprus In their Review on cutaneous leishmaniasis (CL), Richard Reithinger and colleagues1 emphasised the spreading of species causing this neglected disease to previously non-endemic areas. In line with the above, we present data that support the emergence and spread of nonEuropean Leishmania species in Europe. Visceral leishmaniasis (VL), a vector-borne (re)-emerging disease, is the most severe form of leishmaniasis. VL can be caused by Leishmania infantum or Leishmania donovani, which differ in their disease pathology, vectors, and reservoir hosts.2 L infantum is found in Mediterranean countries, the middle east, Asia, and South America, and is responsible for zoonotic visceral leishmaniasis (ZVL), with dogs as the main reservoir hosts. ZVL is an emerging veterinary and public-health problem in Mediterranean countries. L donovani, an anthroponotic species, causes VL as well as post-kala-azar dermal leishmaniasis (PKDL), and is also responsible for epidemic VL outbreaks in the Indian subcontinent and east Africa (figure).3 In India, mostly in
L donovani L donovani (MON-37) L infantum
Figure: Distribution of Leishmania donovani complex species in the Old World and localisation of the MON-37 zymodeme
6
Bihar, 70% of cases of L donovani VL are unresponsive to treatment with pentavalent antimony.4–5 In Cyprus, leishmaniasis was considered, until now, to be a problem of dogs. No human cases had been officially reported, although under-reporting cannot be excluded. In 2006, however, three CL and two VL human cases were diagnosed. The patients with VL, aged 9 months and 73 years, although of Turkish and British origin, respectively, were permanent residents of Cyprus. The patients with CL were Cypriots aged 44, 50, and 55 years. None had visited a country outside Europe. In the CL cases, clinical symptoms had become evident 1 year before the diagnosis of leishmaniasis was established. Laboratory diagnosis included serology, PCR, and isolation of the parasite. Typing of the isolates was first carried out using K26-PCR assay, which is capable of discriminating species/subspecies of the L donovani complex, based on the amplicon size.6 The five isolates were not found to be L infantum MON-1 (626 bp amplicon), the prominent taxon in the Mediterranean countries and the only species found, until now, in Cyprus. Rather, they were typed as L donovani (700 bp amplicon). The isolates were subsequently typed using multilocus enzyme electrophoresis,7 which provided the infraspecific position of the parasite as pertaining to MON-37 zymodeme. Interestingly, one of the 20 canine isolates studied, originating from a dog living in the same district as the three human CL cases, gave two amplicons, one corresponding to MON-1 and the other to MON-37. Analysis with nine microsatellite polymorphic markers8 confirmed the peculiarity of the strain, suggesting that the dog was co-infected with both parasite species. A generation of hybrids, which may circulate in nature through sandflies and infect human beings, is an alarming hypothesis since Leishmania major/L infantum hybrids that exhibit an increased transmission potential have recently been isolated in Portugal.9 http://infection.thelancet.com Vol 8 January 2008
Reflection and Reaction
In the Indian subcontinent, Iraq, and Kenya,10 L donovani MON-37 (figure) causing CL, VL, and PKDL is considered anthroponotic. MON-37 was also recently found in Sri Lanka where it causes CL. This strain differs from the predominant Indian zymodeme MON-2 (which causes VL only) in the mobility of 6-phosphogluconate dehydrogenase.11 Microsatellite analysis showed that MON-37 strains cluster together and are closely related to L donovani strains from India, Bangladesh, and Nepal.12 Knowledge on the epidemiological features, pathogenesis, and clinical phenotype of the disease caused by L donovani MON-37 as well as its response to first-line drugs is poor. Therefore, the emergence and spread of potentially drug-resistant parasites in Cyprus signals a substantial public-health threat. Cyprus, an EU member state, lies at the crossroads of three continents. The island presents a mosaic of risk factors for leishmaniasis, such as urbanisation, extended agricultural projects, environmental/climatic changes, and the daily movement of populations along the Green Line. Additionally, there are high numbers of legal and illegal immigrants from countries outside the EU, where leishmaniases caused by non-European species are endemic. These factors, associated with Cyprus’ sandfly species, which are broadly permissive vectors and can transmit both L infantum and L donovani,13 would allow the circulation of MON-37. The risk of MON-37 spreading in Cyprus and Europe is high. Hence, estimation of the size of this public-health threat, the establishment of a surveillance system, the adoption of trans-border control measures, and the control of canine leishmaniasis are of prime urgency.
Laboratory of Clinical Bacteriology, Parasitology, Zoonoses, and Geographical Medicine, University of Crete, Crete, Greece (MA); Laboratory of Molecular Parasitology, Hellenic Pasteur Institute, 115 21 Athens, Greece (CH, KS); Veterinary Services of Cyprus, Nicosia, Cyprus (AM); and Université Montpellier 1 et Centre Hospitalier Universitaire de Montpellier, Laboratoire de Parasitologie and Centre National de Référence des Leishmania, Montpellier, France (FP, J-PD) [email protected] We declare that we have no conflicts of interest. The study is partly supported by the Research Promotion Foundation in Cyprus (HEALTH/0104/09), the Hellenic Pasteur Institute and EU grants QLK2-CT-2001-01810 and INCO-CT-2004509086. The study sponsors had no role in study design, data interpretation, or in the writing of the report. We thank Petr Volf for constructive discussions in sandfly vector transmission potential and Kyprianos Nicolaides for critical suggestions. 1 2
3 4 5
6
7
8
9
10
11
12
Maria Antoniou, Christos Haralambous, Apostolos Mazeris, Francine Pratlong, Jean-Pierre Dedet, *Ketty Soteriadou
13
Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S. Cutaneous leishmaniasis. Lancet Infect Dis 2007; 7: 581–96. Lukes J, Mauricio IL, Schonian G, et al. Evolutionary and geographical history of the Leishmania donovani complex with a revision of current taxonomy. Proc Natl Acad Sci USA 2007; 104: 9375–80. Alvar J, Yactayo S, Bern C. Leishmaniasis and poverty. Trends Parasitol 2006; 22: 552–57. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006; 19: 111–26. Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, Sundar S. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980–2004. Lancet Infect Dis 2005; 5: 763–74. Haralambous C, Antoniou M, Pratlong F, Dedet JP, Soteriadou K. Development of a molecular assay specific for the Leishmania donovani complex that discriminates L donovani/L infantum zymodemes: a useful tool for typing MON-1. Diagn Microbiol Infect Dis 2007; published online Sep 20; DOI:10.1016/j.diagmicrobio.2007.07.019. Rioux JA, Lanotte G, Serres E, Pratlong F, Bastien P, Perieres J. Taxonomy of Leishmania. Use of isoenzymes. Suggestions for a new classification. Ann Parasitol Hum Comp 1990; 65: 111–25. Kuhls K, Keilonat L, Ochsenreither S, et al. Multilocus microsatellite typing (MLMT) reveals genetically isolated populations between and within the main endemic regions of visceral leishmaniasis. Microbes Infect 2007; 9: 334–43. Volf P, Benkova I, Myskova J, Sadlova J, Campino L, Ravel C. Increased transmission potential of Leishmania major/Leishmania infantum hybrids. Int J Parasitol 2007; 37: 589–93. Sharma NL, Mahajan VK, Kanga A, et al. Localized cutaneous leishmaniasis due to Leishmania donovani and Leishmania tropica: preliminary findings of the study of 161 new cases from a new endemic focus in Himachal Pradesh, India. Am J Trop Med Hyg 2005; 72: 819–24. Karunaweera ND, Pratlong F, Siriwardane HV, Ihalamulla RL, Dedet JP. Sri Lankan cutaneous leishmaniasis is caused by Leishmania donovani zymodeme MON-37. Trans R Soc Trop Med Hyg 2003; 97: 380–81. Siriwardana HV, Noyes HA, Beeching NJ, Chance ML, Karunaweera ND, Bates PA. Leishmania donovani and cutaneous leishmaniasis, Sri Lanka. Emerg Infect Dis 2007; 13: 476–78. Volf P, Myskova J. Sand flies and Leishmania: specific versus permissive vectors. Trends Parasitol 2007; 23: 91–92.
Dengue control We read with concern Kathryn Senior’s recent report on the prospects for effective dengue control.1 Although we welcome any report that highlights the global dengue problem, we believe the article painted an inaccurately bleak portrait of the current situation, by ignoring recent achievements and new developments that indicate effective dengue vector management is likely in the http://infection.thelancet.com Vol 8 January 2008
immediate future. Indeed, the WHO Special Programme for Research and Training in Tropical Diseases (TDR) Dengue Scientific Working Group stated this year that “there has never been a more optimistic time to be involved in dengue and dengue research”, and that “there is a unique opportunity to make a tangible and substantial impact on dengue over the next decade”.2 7