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Recent research on human babesiosis – the Scandinavian perspective |
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Lars Victor von Stedingk(1), Jeremy Gray(2), Marta Granström (1) 1. Department of Clinical Microbiology, Karolinska
Hospital, Stockholm, Sweden Introduction The best known tick-borne infections in Scandinavia are tick-borne encephalitis (TBE) and Lyme borreliosis (LB). In recent years, ehrlichiosis and babesiosis have received more attention, especially in the US (1). There are however strong indications that these infections are also relevant for Europe and Scandinavia. An important common feature for all of these infections is the tick vector, i.e. members of the Ixodes complex, mainly represented in Europe by Ixodes ricinus but for some infections in Eastern Europe also by I. persulcatus. Correspondingly, the main vector in the US is I. scapularis, which is replaced by I. pacificus on the West Coast. For these ticks, a major source of blood-meal is the deer population, which has been noted to have increased in recent decades and could be a major cause of the increase in tick-borne infections in both hemispheres. Babesiosis is a diseases caused by a parasite belonging to the class of Sporozoa in the subclass Piroplasmea, the piroplasms (1). Over 100 Babesia species are known and new ones are being recognised as interest in the organisms increases. The taxonomic relationship between the species seems to be more complex than previously suspected (2). Two agents are of known importance as human pathogens; B. divergens in Europe and B. microti in the United States (1). Babesia was first described as a new species from Central Europe at the end of the 19th century. The species, now known as B. divergens, also caused the first identified human case of babesia infection, reported from the former Yugoslavia in 1957.
B. divergens is a major bovine pathogen in most parts of Europe. It is acquired by adult female ticks and passed to the offspring by transovarial transmission. Ixodes ricinus ticks may remain infected for more than one generation, even in the absence of alimentary infection. Thus ticks, in addition to cattle, may serve as long-term reservoirs of the infection. Until now, more than 30 cases have been reported in Europe, the vast majority of occurring in splenectomised patients. The possibility of the infection in immunocompetent individuals has not been extensively studied but serological reports indicate antibodies in healthy individuals or Lyme borreliosis patients (3, 4). Babesia divergens infection in splenectomised individuals has a
severe and fulminate clinical course, with parasitaemia sometimes exceeding 50%
(3, 4). Clinical manifestations include haemoglobinuria, jaundice, high fever,
headache, severe myalgia and abdominal pain. As illustrated in the above case, rapid diagnosis is essential and is based on detection of parasites in thin blood smears with accompanying clinical signs. Differentiation from malaria is important since most anti-malaria drugs are ineffective against babesiosis. Babesia parasites may resemble Plasmodium ring forms but infected erythrocytes lack parasitic pigment. Pyriform parasites in pairs or occasionally in tetrads are especially diagnostic. We have also developed a PCR based on the 18S rRNA gene which successfully detected B. divergens DNA in a serum sample from the Swedish patient obtained on day 6 of the disease. B. divergens infection can also be confirmed by immunofluorescence (IF) staining of parasites, which in the Swedish case showed rising antibody titres during the acute phase of the disease, followed by a negative sample drawn one year later (own unpublished observations). A reverse line blot assay based on the 18S rRNA gene has also been described (6). The first described cases of B. divergens infections were almost all fatal, but with aggressive treatment, including exchange transfusions, of more recent cases the mortality rate has fallen to approximately 40%. Also in this respect, the Swedish case (3) was illustrative: the patient received whole blood exchange transfusion and the parasitaemia declined from >40% to 1% over 2-3 days. Intravenous therapy with quinine and clindamycin was given for 10 days, and the patient recovered and left the hospital six weeks after admission. Atovaquone, a recently introduced drug for treatment of a variety of protozoan human diseases has been shown to be active against Babesia divergens in vitro and in gerbils (7). Atovaquone appears to be at least as active as imidocarb against B. divergens and is much less toxic. It has not yet been used to treat human cases of the disease, but might be a future option.
B. microti was described in the 1980s as a cause of human infection in the US but in contrast to B. divergens infections the majority of the >500 cases have occurred in immunocompetent individuals (8). The clinical manifestations vary from asymptomatic to fulminant, with a flu-like illness as the most common feature. In severe cases, haemolytic anaemia, haemoglobinuria, splenomegaly, hepatomegaly and jaundice have been described (1). Low-grade parasitaemia may persist for months in asymptomatic, immuncompentent individuals and blood-transfusion transmitted infections with B. microti have been reported in some 20 cases from the US, leading to a fatal outcome for the recipients in a dozen cases (1). As in the case of B. divergens infections, diagnosis of B. microti can, in acute cases, be obtained by examination of stained thin blood smears. In subacute and chronic cases, a PCR based on the 18S rRNA gene applied to EDTA blood (8), serology by immunofluorescence, or xenodiagnosis in hamsters may be used (4). B. microti infections are generally milder than B. divergens infections, but antimicrobial treatment might be even more difficult. Some studies indicate that atovaquone in combination with azithromycin compares favourably with the generally recommended therapy of quinine plus clindamycin (9). Coinfection with B. microti is thought to exacerbate Lyme borreliosis cases and complicate their treatment, as no drugs in use are effective against both B. microti and Borrelia burgdorferi sensu lato (10). Rodents are recognised as the animal reservoir for B. microti in the US. B. microti has also been isolated from rodents from several parts of Europe but no clinical cases in humans have been reported. This has been explained by the suggestion that the principle vector is the rodent tick, I. trianguliceps, which does not bite humans (1,4). However, one study has shown that at least some strains of B. microti may be transmitted by I. ricinus (11). The finding has recently been confirmed in our own transmission experiments (unpublished data). When uninfected larvae and nymphs were allowed to feed on parasitaemic gerbils, parasites of the same European isolate (HK) were detected by PCR in the subsequent nymphal and adult stages, respectively. The infected nymphal ticks then transmitted the infection to naive gerbils. Parallel experiments with the pathogenic American GI strain, morphologically quite different from HK in gerbil erythrocytes, showed this strain to be equally infective for I. ricinus. These findings indicate that other strains of European B. microti are also infective for Ixodes ricinus and that B. microti is a potentially zoonotic species in Europe. Transmission of B. microti to humans in Europe is supported by serological surveys (12). In addition, a recent study in an American laboratory (IGeneX, Palo Alto, USA) on samples from Swiss Lyme borreliosis patients suggests that, not only do coinfections occur in Europe, but also that infection with European B. microti may give rise to clinical symptoms (13). Although highly suggestive of a role for B. microti as a human pathogen in Europe, the results need to be published in a peer-reviewed journal and confirmed in other laboratories. In conclusion, recent experimental studies indicate a potential for B. microtii as a human pathogen in Europe and Scandinavia. The newly developed PCR for B. divergens will be useful to investigate transmission and to diagnose suspected clinical cases.
CRTBI - Extended Abstracts Bunikis J et al.: Structure and Function of the Surface Proteins of Borrelia Spirochetes Dambrauskienè V et al.: Epidemiology of Tick-Born Encephalitis and it's Clinical Manifestations in Panevèzys City County Egenvall A et al.: A serosurvey of granulocytic Ehrlicha spp. and Borrelia burgdorferi sensu lato in 2018 Swedish horses Gray J S et al.: The biology of Ixodes ticks, with special reference to Ixodes ricinus Guillaume B et al.: Human Granulocytic Ehrlichia Infection in Belgium Haglund M et al.: Tick-borne encephalitis (TBE) - an overview Larsen K et al.: Tick species and arthropod-transmitted infections from Danish cats and dogs Lundkvist Å et al.: Characterization of Tick-borne enchephalitis virus from Latvia – evidence for co-circulation of three distinct subtypes Malmgren L et al.: A field trial of the effectiveness of 65% permetrin spot-on and 9.7% fipronil spot-on against ticks (Ixodes ricinus) on dogs Massung R F et al.: Genetic Variants of Ehrlichia phagocytophila in the United States Nilsson I et al.: Serological evidence of Lyme arthritis in Egypt Nyman D et al.: Ticks have preferences in choosing human hosts Ornstein K et al.: Quantification of spirochete burden in Borrelia burgdorferi infected ticks fed on OspA immunized mice by 16S rRNA RT real-time PCR Randolph S et al.: Epidemiological consequences of tick ecology Skarpaas T et al.: Tick-borne encephalitis in Norway Soutschek E et al.: A defined mixture of recombinant antigens from several Borrelia genospecies improves serodiagnosis of Lyme disease von Stedingk L V et al.: Recent research on human babesiosis – the Scandinavian perspective Stuen S et al.: Granulocytic Ehrlichia infection in domestic and wild ruminants in Norway |
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last modified
Friday, June 13, 2003
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