29 | 04 | 2017
Overview of Zoonotic Babesiosis

Overview of Zoonotic Babesiosis

(a pdf of a recent review may be accessed here )

 

History

Babesiosis is caused by tick-transmitted protozoa of the genus Babesia (Phylum Apicomplexa), which invade and multiply in vertebrate erythrocytes. Although best known as an animal disease, human babesiosis is attracting increasing attention as a worldwide emerging zoonosis. The first case was recorded in Croatia (then Yugoslavia) in 1956 and this fatal case was probably caused by the cattle parasite, B. divergens, which appears to be responsible for the majority of cases in Europe (Zintl et al. 2003). Recently a related though quite distinct babesia, B. venatorum (EU1), found naturally in deer, was incriminated in similar, though generally milder cases in Austria, Italy and Germany (Hunfeld et al. 2008).

The index case of human babesiosis in the USA occurred in 1969 (Western et al. 1970) and was caused by B. microti, for which several species of rodents are reservoirs. This form of babesiosis is now by far the most common on a global scale, mostly occurring in the USA, but isolated cases have been reported throughout the world. Although B. microti occurs in Europe, most strains do not seem to be zoonotic, and so far only one authenticated endemic European case has been recorded (Hildebrandt et al. 2007).

 

Clinical features

B. divergens causes heavy infections life threatening infections in immunocompromised patients, the majority of whom have been asplenic or with dysfunctional spleens. The acute illness appears suddenly, with haemoglobinuria as a presenting symptom.tends to cause heavy infections in immunocompromised patients, in whom acute illness appears suddenly, with haemoglobinuria as a presenting symptom. Persistent non-periodic high fever (40-41°C), shaking chills, intense sweats, headaches, myalgia, and lumbar and abdominal pain are characteristic, and vomiting and diarrhoea may occur.  Jaundice can develop as a result of the high level of haemolysis  (Hunfeld et al., 2008). Respiratory, cardiac, renal or hepatic failure can be caused by anoxia and toxic waste products. The few known infections with B. venatorum have shown similar though generally milder manifestations (Hunfeld et al., 2008). In highly immunocompromised individuals the disease may be prolonged (Häselbarth et al., 2007), but otherwise there is no reliable evidence that B. divergens-like parasites cause chronic disease or asymptomatic infections. However, B. divergens has been recently incriminated in two cases in which an influenza-like illness was evident in immunocompetent patients. In one French case the infection appears to have been transitory and no specific anti-babesials were required for resolution (Martinot et al., 2011), but in the second case from Spain, the disease was severe showing jaundice and haemoglobinuria, necessitating treatment with quinine and clindamycin. However, this regimen did not clear the infection and eventually atovaquone/proguanil and azithromycin were resorted to, which resulted in recovery (Gonzalez et al., 2014). In another recent study a parasite resembling both B. divergens and B. venatorum was detected in a Lyme borreliosis patient who had not been splenectomised. No details of the illness or any intervention are available. Despite these cases and also reports of low levels of antibodies to B. divergens in healthy individuals (Hunfeld et al., 2002), there is no good evidence to suggest that B. divergens-like parasites can persist in immunocompetent individuals.

Patients infected by B. microti in the USA show a wider range of signs and symptoms, including acute infections in immuncompromised patients and mild infections in immunocompetent individuals. Asymptomatic infections are thought to be common. The only case thought to be due to a European-contracted infection occurred in an immunocompromised individual, who presented with fever and chest pain and responded well to treatment (Hildebrandt et al. 2007). The infection probably arose as a result of a blood transfusion.

 

Biology of the infectious agents

The parasites appear as erythrocytic inclusions of varying shape. The most characteristic forms are paired pyriforms (see ‘1’), but these are less common than single round and oval forms (see ‘3’). In humans four connected parasites (a tetrad in the form of a Maltese Cross) may occur (see ‘2’). This is particularly the case for B. microti.

Image

B. divergens, the most frequent cause of European babesiosis, has long been known as a significant cause of disease in cattle, though there is evidence that some strains may occur in red deer (Zintl et al., 2011). The infection is mainly acquired from the host by I. ricinus adult females and transmitted transovarially to larvae. The parasite persists through the tick moults and the F1 generation may also be infected without the occurrence of reinfection. All feeding stages, larva, nymph and adult female, are capable of transmission but most of the evidence suggests that adult females are the primary vectors (Zintl et al., 2003). B. venatorum is also transmitted by Ixodes ricinus; several deer species, particularly  roe deer, Capreolus capreolus, have been implicated as reservoir hosts (Bonnet et al., 2007). Although the definitive experiments have not yet been done, like its close relative B. divergens, this species is probably acquired by adult female I. ricinus and transmitted transovarially.

B. microti occurs throughout Europe but there is little evidence that they cause zoonotic infections, though some are very closely related to American zoonotic strains (Gray et al., 2010). So far one endemic European case has been identified and some serosurveys have detected antibodies in healthy individuals (Hunfeld et al., 2008). The natural hosts of B. microti are several species of microtine rodents and the infection is transmitted transstadially but not transovarially (Gray et al., 2002).

 

Biology of the vector

The non-parasitic (off-host) phases of I. ricinus require a high humidity at the base of the vegetation (RH >85%) and ideal conditions are to be found in temperate deciduous woodland with patches of dense vegetation and little air movement, coupled with high humidity. The need for questing ticks to maintain a stable water balance is an important factor in determining the location and duration of activity. In general, activity will begin in spring and early summer, with ticks being found on vegetation and animals from late March. In habitats where desiccation is high, such as open areas, periods of activity will be shortened to only a few weeks - as opposed to several months in dense woodlands. In some areas a second, less intense, phase of questing activity occurs in the autumn.

The tick ambushes its host from the vegetation and attaches to the skin with specialized mouthparts for several days, the duration depending on the tick life cycle stage. The babesia parasites occur in the salivary glands but are not infective until they have undergone some development, which takes about two days.

For further details of the biology of Ixodes ricinus see  the Lyme borreliosis page, Biology, tick


Diagnosis

The clinical presentation of infections caused by B. divergens and related species is dramatic, usually combining high fever with haemoglobinuria. Definitive diagnosis is usually straightforward with the detection of characteristic paired piriforms in the erythrocytes. However, in B. microti infections the clinical presentation is usually nonspecific, and the diagnostic tetrads (Maltese cross forms ) are uncommon. Single round or oval forms are most frequent in both species and can be differentiated from Plasmodium spp. by the absence of haemozoin deposits. Diagnostic confirmation is obtained by serology (IFAT) and/or PCR analysis (preferably followed by sequencing of the PCR product)

Treatment

Initially the standard drug treatment for all human babesiosis consisted of a combination of quinine and clindamycin (Hunfeld et al., 2008). The more recently developed hydroxynaphathoquinine, atovaquone, is licensed for human use and has good anti-babesia activity, especially against B. divergens (Gray and Pudney, 1999). However, the drug failed to prevent recrudescences of B. microti in laboratory animals unless given in combination with azithromycin or clindamycin, and drug resistance may be induced when atovaquone is administered on its own (Wittner et al., 1996; Gray and Pudney, 1999). The atovaquone/azithromycin combination was shown to be effective in humans in a clinical trial against B. microti (Krause et al., 2000) and is now the recommended drug therapy for mild cases, though in acute cases the quinine/clindamycin combination is still preferred (Wormser et al., 2006). In immunosuppressed patients the efficacy of drugs, whatever the combination, is significantly reduced and in such patients prolonged treatment with antibabesial drugs may be required for cure. For all acute cases, exchange transfusion should be considered as an additional emergency measure.

Risk management

The primary risk factor for infection with Babesia spp. is a tick bite and in view of the additional zoonotic diseases that the vectors of human babesiosis transmit, general measures to prevent tick bites are the most appropriate.  Infectious tick bites are most likely to occur in areas where cattle are maintained on humid and rough pastures (B. divergens) and in deciduous woodland and peri-domestic settings (B. microti). Asplenic and otherwise immunocompromised individuals are at the greatest risk and should take extra care when utilizing such habitats. Total avoidance of tick habitats by the general public is not practical, but increasing the public awareness of the threat posed by ticks and also of personal protection measures, such as the wearing of appropriate clothing, application of repellents and prompt removal of attached ticks, are probably the most effective preventive measures currently available (Piesman and Eisen, 2008). In the USA B. microti presents a growing threat to patients receiving blood transfusions, and while this parasite is present in Europe, zoonotic strains appear to rare. Nevertheless, the only endemic European case to date appears to have arisen from a blood transfusion (Hildebrandt et al., 2007). Infections caused by B. divergens-like parasites usually occur in immunocompromised patients, but recently these parasites have been reported in immunocompetent individuals. Since such infections are likely to be transient, they therefore probably do not pose a blood transfusion risk, but this possibility should be kept under review.


References

Bonnet, S., Jouglin, M, L’Hostis, M., Chauvin, A. 2007. Babesia sp. EU1 from roe deer and transmission within Ixodes ricinus. Emerg. Infect. Dis. 13:1208–1210.

Gray, J.S., Pudney, M., 1999. Activity of atovaquone against Babesia microti in the Mongolian gerbil, Meriones unguiculatus. J. Parasitol. 85, 723–728.

Gray, J., von Stedingk, L.V., Gurtelschmid, M., Granstrom, M., 2002. Transmission studies of Babesia microti in Ixodes ricinus ticks and gerbils. J. Clin. Microbiol. 40, 1259–1263.

Gray, J.S., Zintl, A., Hildebrandt, A., Hunfeld, K-P.,  Weiss, L. 2010. Zoonotic babesiosis: Overview of the disease and novel aspects of pathogen identity Ticks and Tick-borne Dis. 1, 3–10

Häselbarth, K., Tenter, A.M., Brade, V., Krieger, G., Hunfeld, K.P., 2007. First of human babesiosis in Germany - Clinical presentation and molecular characterisation of the pathogen. Int. J. Med. Microbiol. 297, 197–204.

Hildebrandt, A., Hunfeld, K.P., Baier, M., Krumbholz, A., Sachse, S., Lorenzen,T., Kiehntopf, M., Fricke, H.J., Straube, E. 2007. First confirmed autochthonous case of human Babesia microti infection in Europe. Eur. J. Clin. Microbiol. Infect. Dis. 26, 595–601.

Hilpertshauser, H., Deplazes, P., Schnyder, M., Gern, L., Mathis, A. Babesia spp. identified by PCR in ticks collected from domestic and wild ruminants in southern Switzerland. Appl Environ Microbiol 2006, 72:6503–65077.

Hunfeld, K.P., Hildebrandt, A., Gray, J.S. 2008. Babesiosis: Recent insights into an ancient disease. Int. J. Parasitol. 38, 1219–1237.

Hunfeld, K.P., Lambert, A., Kampen, H., Albert, S., Epe, C., Brade, V., Tenter, A.M. 2002. Seroprevalence of Babesia infections in humans exposed to ticks in midwestern Germany. J Clin Microbiol. 40, 2431–2436.

Krause, P.J., Lepore, T., Sikand, V.K., Gadbaw, J., Jr., Burke, G., Telford, S.R., 3rd, Brassard, P., Pearl, D., Azlanzadeh, J., Christianson, D., McGrath, D., Spielman, A. 2000. Atovaquone and azithromycin for the treatment of babesiosis. N. Engl. J. Med. 343, 1454–1458.

Martinot, M, Zadeh, M.M., Hansmann, Y., Grawey, I., Christmann, D., Aguillon, S., Jouglin, M., Chauvin, A., De Briel, D. Babesiosis in immunocompetent patients, Europe. Emerging. Inf. Dis. 17, 114–116.

Piesman. J., Eisen, L., 2008. Prevention of tick-borne diseases. Ann. Rev. Entomol. 53, 323–343.

Welc-Faleciak, R., Hildebrandt, A., Sinski, E. 2010. Co-infection with Borrelia species and other tick-borne pathogens in humans: two cases from Poland. Ann. Agric. Environ. Med. 17, 309–13.

Western, K.A., Benson, G.D., Gleason, N.N., Healy, G.R., Schultz, M.G. 1970. Babesiosis in a Massachusetts resident. N. Engl. J.Med. 283: 854–856.

Wittner, M., Lederman, J., Tanowitz, H.B., Rosenbaum, G.S., Weiss, L.M. 1996. Atovaquone in the treatment of Babesia microti infections in hamsters. Am. J. Trop. Med. Hyg. 55, 219–222.

Zintl, A., Mulcahy, G., Skerrett, H.E., Taylor, S.M., Gray, J.S., 2003. Babesia divergens, a bovine blood parasite of veterinary and zoonotic importance. Clin. Rev. Microbiol. 16, 622–636.

Zintl, A., Finnerty, E, de Waal, T., Murphy, T.M., Gray, J.S. Veterinary Research 2011, 42:7. http://www.veterinaryresearch.org/content/42/1/7

 

 

 

Last Updated on Tuesday, 10 May 2016 20:04