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A local outbreak of autochthonous Plasmodium vivax malaria in Laconia, Greece—a re-emerging infection in the southern borders of Europe?

Open AccessPublished:October 24, 2012DOI:https://doi.org/10.1016/j.ijid.2012.09.009

      Summary

      Objectives

      Malaria is considered to have been eradicated in Greece and only sporadic cases in travelers are reported. However the migration of populations from endemic countries of Asia to Greece may have caused a re-emergence of the disease.

      Methods

      A cluster of nine human malaria cases due to Plasmodium vivax infection in the area of Laconia (southern Peloponnesus) from 2009 to 2010 is presented. Patients were hospitalized in Sparta General Hospital.

      Results

      Eight patients were diagnosed in 2009 and one in 2010. Two were refugees from Pakistan and Afghanistan and five were Romas living in a local camp. Apart from the two immigrants, no other patient had any history of travel, blood transfusion, or organ transplantation. All patients had a febrile illness, hematological abnormalities, and irregular liver function tests. Parasites were identified in peripheral blood smears, and PCR confirmed the presence of P. vivax. Sensitivity testing showed chloroquine susceptibility. Combined treatment with chloroquine followed by primaquine was completed uneventfully. Entomological surveillance disclosed the presence of Anopheles saccharovi as the predominant mosquito species, however PCR testing failed to identify P. vivax in the mosquito population.

      Conclusions

      We have presented the first large outbreak of the local transmission of autochthonous malaria cases in Greece since the 1950s. Enhanced entomological surveillance and early detection of malaria cases are crucial in order to prevent the re-emergence of malaria, not only in Greece, but in Europe as well.

      Keywords

      1. Introduction

      Malaria is the most prevalent vector-borne disease in the world.
      • Sachs J.
      • Malaney P.
      The economic and social burden of malaria.
      In 2008, there were an estimated 243 million (5th–95th percentile, 190–311 million cases) cases of malaria worldwide. The vast majority of cases (85%) were reported from the African region, followed by the South-East Asia region (10%) and the Eastern Mediterranean region (4%).
      World Health Organization
      World Malaria Report 2009.
      The global incidence of malaria due to Plasmodium vivax is estimated at approximately 70–80 million cases annually, while P. vivax is considered the second most common of the Plasmodium species causing human disease.
      • Mendis K.
      • Sina B.J.
      • Marchesini P.
      • Carter R.
      The neglected burden of Plasmodium vivax malaria.
      Approximately 10–20% of the world's cases of P. vivax infection occur in Sub-Saharan Africa. P. vivax is causally associated with approximately 10% of malaria cases in Eastern and Southern Africa, but less than 1% of cases in Western and Central Africa. Outside of the African continent, P. vivax accounts for more than 50% of all malaria cases; 80–90% of such cases occur in the Middle East, Asia, and the Western Pacific, mainly in the tropical regions, and 10–15% in Central and South America.

      World Health Organization/Global Malaria Programme. Roll Back Malaria. World malaria report 2005. Malaria burden. Available at: http://www.rollbackmalaria.org/wmr2005/html/1-2.htm (accessed November 4, 2010).

      Malaria is considered by the World Health Organization (WHO) to have been eradicated in Europe. It was endemic in Greece until 1973, at which time the country was declared malaria-free.
      World Health Organization
      Synopsis of the world malaria situation in 1979.
      Malaria is a reportable disease in Greece and is included in the national mandatory notification system. An increase in non-autochthonous malaria cases has been recorded from 1998 onwards in Greece (less than 50 cases in total), which reflects cases imported through non-screened migrants.

      Economopoulou A, Andreopoulou A, Pavli A. Descriptive analysis of malaria cases in Greece 1998–2008. Presented at the 11th Conference of the International Society of Travel Medicine, Budapest, Hungary, May 24–28, 2009.

      Sustained local transmission had not been identified prior to the detection of the cases reported herein.
      We present a cluster of nine human infections with P. vivax malaria occurring in the southern Greek peninsula of Peloponnesus and more specifically in the area of Laconia. Eight cases were hospitalized in the Sparta General Hospital, Laconia Greece in 2009 and one in 2010. This case-series represents the first large outbreak of local transmission of autochthonous malaria cases in Greece since the 1950s.

      2. Materials and methods

      Eight patients were admitted to the Internal Medicine Department of the Sparta General Hospital between August 5 and October 11, 2009 with non-specific symptoms of a febrile illness: fever, malaise, abdominal pain, and mild jaundice. The first patient was an immigrant from Afghanistan who lived in Sparta, and who reported prior treatment for malaria with chloroquine for 3 days while in Afghanistan a year ago. The second patient was an immigrant from Pakistan who had been living in a small village called Skoutari (approximately 50 kilometers south of Sparta) for the past 4 months, since his arrival from Pakistan. The third patient was a Roma living in a camp situated in the area of Skala, Laconia, 30 km southeast of Sparta. During the 6 weeks that followed the initial presentation of these three patients, five more patients were admitted with similar symptoms to the same hospital; two inhabitants of Skala and a village called Glykovrisi (situated 10 km from Skala) and three more Romas from the same camp where the third patient lived. All of these patients resided or worked during the summer in the fields of Skala near the Eurotas River, in an area called ‘Elos’, which in Greek means swamp.
      After the diagnosis of P. vivax malaria was established for the first patient, the Hellenic Center for Disease Control and Prevention (HCDCP) was notified and an enhanced surveillance system was implemented in order to evaluate, control, and prevent the disease. Any patient living in the area and seeking medical care for a persistent febrile illness during the period of August to November 2009 was suspected of malaria infection. The identification of parasites in peripheral blood smears was considered diagnostic for malaria. Since malaria is a reportable disease in Greece, an HCDCP questionnaire was completed; when no history of travel, blood transfusion, or organ transplantation, or prior infection was mentioned, the case was considered autochthonous. Blood donation in the area was suspended and close contacts of the patients were examined. An entomological survey was conducted in the region to examine the presence of Anopheles mosquito species and to identify any pools of infection within that mosquito population. Water samples containing larvae were collected from the river irrigating the area, and traps were used to collect adult mosquitoes. Blood samples for all patients were sent to the Athens School of Public Health for confirmation of the Plasmodium species by a previously described PCR-based method.
      • Patsoula E.
      • Spanakos G.
      • Sofianatou D.
      • Parara M.
      • Vakalis N.C.
      A single-step, PCR based method for the detection and differentiation of Plasmodium vivax and Plasmodium falciparum.
      Sensitivity tests were also performed to evaluate susceptibility of the P. vivax strain to the antimalarial agent chloroquine. A year later (July 2010) another Roma from the same camp presented with similar symptoms.

      3. Results

      3.1 Clinical and epidemiological data

      Figure 1 illustrates the distribution of cases over time and the short time trend associated with this cluster in 2009. Figure 2 depicts a spot map of the cases. The median age of the patients from both 2009 and 2010 was 45.2 years.
      Figure thumbnail gr1
      Figure 1Time trend of the malaria cluster during the outbreak, August–October 2009.
      Figure thumbnail gr2
      Figure 2A spot map showing the area of residence of the cases in the region of the cluster of Plasmodium vivax infections.
      Laboratory values on presentation for all patients are shown in Table 1. All presented with mild hemolytic anemia and neutropenia, and also thrombocytopenia, which is not a common finding in P. vivax malaria.
      • Mendis K.
      • Sina B.J.
      • Marchesini P.
      • Carter R.
      The neglected burden of Plasmodium vivax malaria.
      All had an elevated erythrocyte sedimentation rate and C-reactive protein, mild jaundice, and abnormal liver function tests. There was no consistent fever pattern and only two patients exhibited tertian fever. Diagnosis was made after examination of peripheral blood smears, which revealed parasites consistent with P. vivax malaria. Typing was performed using a PCR. Sensitivity tests showed that all the strains were chloroquine-sensitive. Patients were tested and all had normal levels of glucose-6-phosphate dehydrogenase. They were treated with a combined regimen of chloroquine followed by primaquine, in accordance with the US Centers for Disease Control and Prevention (CDC) protocol for the treatment of P. vivax malaria.

      US Centers for Disease Control and Prevention. Malaria Diagnosis and treatment in the United States. Available at: http://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf (accessed November 4, 2012).

      All patients made a rapid clinical recovery and laboratory results returned to normal within the first week after treatment. No patient required admission to an intensive care unit. Follow-up after the completion of treatment revealed no parasites in the peripheral blood.
      Table 1Clinical and laboratory data of the affected patients. Data are presented as the median (range) unless otherwise indicated.
      Age45.2 (24–65)
      Gender, male, n (%)6 (67%)
      Hematocrit (%)32.1 (25–36)
      Hemoglobin (g/dl)10.7 (9.2–11.1)
      White blood cells (×109/l)3.258 (3.105–3.250)
      Platelets (×109/l)63.500 (56.000–72.500)
      Erythrocyte sedimentation rate (mm/h)37.5 (31.5–47.2)
      C-reactive protein (mg/dl)10.98 (7.4–14.5)
      Lactate dehydrogenase (U/l)867.87 (547–1012)
      Aspartate aminotransferase (U/l)73.5 (42–96)
      Alanine aminotransferase (U/l)78 (54–98)
      Alkaline phosphate (U/l)110.5 (95–114)
      γ-Glutamyltransferase (U/l)65.87 (35–89)
      Total bilirubin (mg/dl)2.15 (1.5–3.5)
      Direct bilirubin (mg/dl)0.6 (0.2–0.9)
      Blood donation in the area was suspended until December 2009. Thirty-five blood samples were collected from the residents of the Roma camp where the Roma patients lived, as well as from the seven Pakistanis who were close contacts of the second patient residing in Skoutari. All these samples tested negative for the presence of Plasmodium spp, both by blood smear examination and by PCR. No other case was reported in 2010, but in 2011 a new cluster of malaria cases occurred and another intervention program was implemented.
      • Danis K.
      • Baka A.
      • Lenglet A.
      • Van Bortel W.
      • Terzaki I.
      • Tseroni M.
      • et al.
      Autochthonous Plasmodium vivax malaria in Greece, 2011.

      3.2 Entomological data

      The mosquito monitoring data collected in the area with the insect traps and the examination of water samples showed that Anopheles saccharovi was the predominant (80%) mosquito population in the area. PCR testing of the mosquito population disclosed no infestation of any of the adult mosquitoes or larvae. An enhanced entomological surveillance system remained operational in the area for the next 2 years with no infected mosquitoes until September 2011,
      • Danis K.
      • Baka A.
      • Lenglet A.
      • Van Bortel W.
      • Terzaki I.
      • Tseroni M.
      • et al.
      Autochthonous Plasmodium vivax malaria in Greece, 2011.
      when a new cluster of cases occurred.

      3.3 Ecological parameters

      The area in Laconia where the patients lived or worked was the delta of the Eurotas and Vassilopotamos rivers. The place was originally called ‘Elos’, which in Greek means swamp. Agriculture is the main occupation, relying on water channels from these rivers, which tend to dry out in the summer making the conditions favorable for potential malaria vectors such as mosquitoes.

      4. Discussion

      We report the first outbreak of autochthonous malaria cases (according to the definition of the WHO) since 1973 in the area of Laconia, in the Peloponnesus peninsula in southern Greece. This outbreak occurred in 2009. In total, eight cases of malaria were notified from the area between August and December 2009 and one in July 2010. The first two cases were refugees from countries where malaria is endemic (imported cases) and the majority of the other cases involved Romas living in a camp situated close to a local river (autochthonous cases). Evidence of local transmission of the pathogen was found within the closed population of the Roma camp, and also none of the other patients had a history of travel to endemic countries or other possible exposure. Microbiological testing of samples collected from camp inhabitants as well as samples from the local circulating mosquito population were negative. Greece was declared malaria-free by the WHO in 1973; this is the first time since then that the local transmission of malaria has occurred in our country.
      Before the introduction of antimalarial drugs, P. vivax malaria caused a chronic disabling disease that reduced the average life span, and was endemic in Europe, North America, and the tropics.
      • Sina B.
      Focus on Plasmodium vivax.
      The clinical presentation of the disease is associated with non-specific symptoms such as chills, vomiting, malaise, headache, myalgias, fever, and diarrhea, which complicate the differential diagnosis of P. vivax malaria from other febrile illnesses,

      Economopoulou A, Andreopoulou A, Pavli A. Descriptive analysis of malaria cases in Greece 1998–2008. Presented at the 11th Conference of the International Society of Travel Medicine, Budapest, Hungary, May 24–28, 2009.

      or other malaria infections.
      • Kochar D.K.
      • Saxena V.
      • Singh N.
      • Kochar S.K.
      • Kumar S.V.
      • Das A.
      Plasmodium vivax malaria.
      High fever and rigors are more common in P. vivax than Plasmodium falciparum malaria, reflecting synchronicity of schizont rupture. The classic paroxysms of fever lasting 4–8 h and occurring with a 48–56 h periodicity, take several asexual cycles to develop in primary infections, although relapses often start synchronously with rigors.
      • Collins W.E.
      • Jeffery G.M.
      • Roberts J.M.
      A retrospective examination of reinfection of humans with Plasmodium vivax.
      The most common finding on clinical examination is enlargement of the spleen. Compared to P. falciparum, P. vivax has a slightly longer incubation period (12 days to several months), a similar erythrocytic cycle (42–48 h), and produces fewer merozoites per schizont.
      • Price R.N.
      • Tjitra E.
      • Guerra C.A.
      • Yeung S.
      • White N.J.
      • Anstey N.M.
      Vivax malaria: neglected and not benign.
      Infection associated with P. vivax is rarely fatal; however relapses often occur months to years after the primary infection due to dormant parasites in the liver. Cases of malaria similar to the ones presented herein may become of growing concern in Europe, since populations migrating from Asia to Europe living in poor sanitary conditions may be involved in the propagation of outbreaks due to local transmission.
      • Mühlberger N.
      • Jelinek T.
      • Gascon J.
      • Probst M.
      • Zoller T.
      • Schunk M.
      • et al.
      Epidemiology and clinical features of vivax malaria imported to Europe: sentinel surveillance data from TropNetEurop.
      • Millet J.P.
      • Garcia de Olalla P.
      • Carrillo-Santisteve P.
      • Gascón J.
      • Treviño B.
      • Muñoz J.
      • et al.
      Imported malaria in a cosmopolitan European city: a mirror image of the world epidemiological situation.
      • Ponçon N.
      • Tran A.
      • Toty C.
      • Luty A.J.
      • Fontenille D.
      A quantitative risk assessment approach for mosquito-borne diseases: malaria re-emergence in southern France.
      Increased vector access to such a population is another potential scenario. Other potential reasons include the expansion of the vector populations in specific geographic areas whenever the climatic conditions are appropriate. Indeed the continuous arrival of refugees from endemic countries probably led to the new cluster in 2011.
      • Danis K.
      • Baka A.
      • Lenglet A.
      • Van Bortel W.
      • Terzaki I.
      • Tseroni M.
      • et al.
      Autochthonous Plasmodium vivax malaria in Greece, 2011.
      • Florescu S.A.
      • Popescu C.P.
      • Calistru P.
      • Ceausu E.
      • Nica M.
      • Toderan A.
      • et al.
      Plasmodium vivax malaria in a Romanian traveller returning from Greece, August 2011.
      • Loupa C.V.
      • Tzanetou K.
      • Kotsantis I.
      • Panopoulos S.
      • Lelekis M.
      Autochthonous Plasmodium vivax malaria in a Greek schoolgirl of the Attica region.
      The first report was a Romanian worker in the area of Skala who returned to his home country after the febrile illness,
      • Florescu S.A.
      • Popescu C.P.
      • Calistru P.
      • Ceausu E.
      • Nica M.
      • Toderan A.
      • et al.
      Plasmodium vivax malaria in a Romanian traveller returning from Greece, August 2011.
      and in the following months further cases and a much bigger cluster occurred.
      • Danis K.
      • Baka A.
      • Lenglet A.
      • Van Bortel W.
      • Terzaki I.
      • Tseroni M.
      • et al.
      Autochthonous Plasmodium vivax malaria in Greece, 2011.
      • Loupa C.V.
      • Tzanetou K.
      • Kotsantis I.
      • Panopoulos S.
      • Lelekis M.
      Autochthonous Plasmodium vivax malaria in a Greek schoolgirl of the Attica region.
      As a result the WHO was notified again and an enhanced surveillance system was implemented,
      • Danis K.
      • Baka A.
      • Lenglet A.
      • Van Bortel W.
      • Terzaki I.
      • Tseroni M.
      • et al.
      Autochthonous Plasmodium vivax malaria in Greece, 2011.
      since Greece is on the southern border of Europe and has been handling an increasing number of immigrants coming to the country each year – refugees from Asian countries that are malaria-endemic (Afghanistan and Pakistan) according to the WHO.

      Illegal immigration in Greece. Border burden: Greece struggles to deal with a European problem. Economist; August 19, 2010. Available at: http://www.economist.com/node/16847278 (accessed May 5, 2012).

      Research Institute for European and American Studies. Immigration to Greece (March 2012). RIEAS; April 14, 2012. Available at: http://www.rieas.gr/research-areas/illegal-immigration/1746-immigration-to-greece-march-2012.html (accessed May 5, 2012).

      US Centers for Disease Control and Prevention. CDC malaria map application. Available at: http://cdc-malaria.ncsa.uiuc.edu/ (accessed May 5, 2012).

      In conclusion, we present the first local cluster of autochthonous cases of malaria due to P. vivax in the area of Laconia over the last four decades. We believe that this outbreak may have important public health implications. Enhanced surveillance of the mosquito population and the application of vector control measures (preferably within an integrated vector management project), as well as the early detection of malaria cases through awareness and education of clinicians in areas where autochthonous malaria cases appear, are crucial in order to prevent the re-emergence of malaria, not only in Greece, but in other European countries as well.
      Conflict of interest: No conflict of interest to declare.

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