8.8.3 Babesiosis 1414

8.8.3 Babesiosis 1414

section 8  Infectious diseases 1414 sensitivity. When there is uncertainty, drugs effective against re- sistant P.  falciparum should be used (atovaquone–​proguanil, or doxycycline). Chemoprophylaxis is never entirely reliable, and mal- aria should always be considered in the differential diagnosis of fever in patients who have travelled to endemic areas, even if they have been taking prophylactic antimalarial drugs. Pregnant women travelling to malarious areas should be warned about the potential risks. All pregnant women at risk in endemic areas should be encouraged to attend regular antenatal clinics. Mefloquine is the only drug advised for pregnant women travel- ling to areas with drug-​resistant malaria, except for areas with mefloquine-​resistant falciparum malaria in Southeast Asia; this drug is generally considered safe in the second and third trimesters of pregnancy, and the data on first-​trimester exposure, although limited, are reassuring. Chloroquine and proguanil are regarded as safe, but are no longer effective in the prevention of falciparum malaria. The safety of other prophylactic antimalarial agents in pregnancy has not been established. Children born to non​immune mothers in endemic areas (usually expatriates moving to malaria endemic areas) should receive prophylaxis from birth. Travellers should start taking antimalarial drugs 2 days to 2 weeks before departure so that any untoward reactions can be detected and so that therapeutic antimalarial blood concentrations will be present when needed. Antimalarial prophylaxis should continue for 4 weeks after the traveller has left the endemic area, except if atovaquone–​proguanil or primaquine has been taken; these drugs have significant activities against the liver stage of the infection (causal prophylaxis) and can be discontinued 1 week after departure from the endemic area. If suspected malaria develops while a trav- eller is abroad, obtaining a reliable diagnosis and antimalarial treat- ment locally is a top priority. Presumptive self-​treatment for malaria with atovaquone–​proguanil (for three consecutive days) or another drug can be considered under special circumstances; medical advice on self-​treatment should be sought before departure for malarious areas and as soon as possible after illness begins. Every effort should be made to confirm the diagnosis by parasitologic studies. FURTHER READING Dondorp A, et al. (2010). Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): An open-​label randomized trial. Lancet, 376, 1647 (erratum Lancet (2011), 377, 126). Dondorp AM, et al. (2009). Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 361, 5. Gomes MS, et al. (2009). Pre-​referral rectal artesunate to prevent death and disability in severe malaria: a placebo-​controlled trial. Lancet, 373, 557. Moore KA, et al. (2016). Safety of artemisinins in first trimester of prospectively followed pregnancies: an observational study. Lancet Infect Dis, 16, 576–​83. Nayyar GML, et  al. (2012). Poor-​quality antimalarial drugs in Southeast Asia and sub-​Saharan Africa. Lancet, 12, 6. White NJ (2013). Primaquine to prevent transmission of falciparum malaria. Lancet Infect Dis, 13, 175–​81. White NJ, et al. (2014). Malaria. Lancet, 383, 723. World Health Organization (WHO) (2013). Policy recommendation: seasonal malaria chemoprevention (SMC) for plasmodium falciparum malaria control in highly seasonal transmission areas of the Sahel sub-​region in Africa. http://​www.who.int/​malaria/​publications/​atoz/​ who_​smc_​policy_​recommendation/​en/​ World Health Organization (WHO) (2014). Severe malaria. Trop Med Int Health, 19 (Suppl 1), 7–​131. World Health Organization (WHO) (2015). Guidelines for the treat- ment of malaria, 3rd edition. http://​apps.who.int/​iris/​bitstream/​ handle/​10665/​162441/​9789241549127_​eng.pdf;jsessionid=E2DC3 90064A9EA2C038A2E509DC6D863?sequence=1 8.8.3  Babesiosis Philippe Brasseur ESSENTIALS Babesia are intraerythrocytic, tick-​transmitted, protozoan para- sites that infect a broad range of wild and domesticated mammals including cattle, horses, dogs, and rodents. Human babesial infec- tion is uncommon, mainly caused by B. microti in North America and B. divergens in Europe, with most infections occurring in asplenic people. Presentation is typically with non​specific ‘viral-​type’ symp- toms. Haemolytic anaemia is a characteristic feature and can be severe, particularly with B.  divergens. Diagnosis is by discovering babesia organisms in Giemsa-​stained blood smears, or detection of its DNA in blood by polymerase chain reaction. Aside from sup- portive care, treatment is usually with combinations of clindamycin and quinine or atovaquone and azithromycin. Mortality ranges from 5 to 40%. Prevention is by use of repellents, removing ticks from the skin, and avoidance of exposure in asplenic and immuno- compromised individuals: there is no vaccine. Epidemiology Although several species of babesia can infect humans, two species, Babesia microti and B. divergens, are responsible for most cases of human babesiosis. In the United States of America, thousands of cases of B. microti infections have been reported since 1988, mostly from the north-​east coast including Nantucket, Martha’s Vineyard, and Block Island. B.  microti is transmitted by Ixodes scapularis
(previously I. dammini) and its reservoir host is the common white-​ footed mouse Peromyscus leucopus. B. duncani, a new species, has been identified in nine patients in Washington State. B.  equi cases have been identified in California and a single fatal case of B. divergens infection in Missouri. The zoonotic Borrelia burgdor­ feri, causing Lyme disease, is also transmitted by I. scapularis and coinfections are documented. The risk of both babesiosis and Lyme disease is highest in June when nymphal I.  scapularis are most abundant. Babesiosis may also be acquired through infected blood transfusion or rarely by transplacental transmission. More than 170 cases of transfusion-​transmitted babesiosis have been reported in

8.8.3  Babesiosis 1415 the United States of America since 1980. Several cases have been reported of infection exported to other countries in visitors from the United States. Since the first description of human babesiosis in Europe in 1957, more than 50 cases have been reported. Most of them were due to B. divergens, a common cattle pathogen transmitted by I. ricinus. France, the United Kingdom, and Ireland account for more than 50% of the cases reported in Europe. Farmers, foresters, campers, and hikers are affected, usually between May and October, the season of activity of I.  ricinus. Most infections occur in asplenic people. Only one autochthonus case of B. microti transfusion-​trans- mitted has been reported in Europe in a German patient with a mye- loid leukaemia, but the risk exists for B. divergens which may survive in packed red blood cells for at least 4 weeks at 4°C. B. venatorum, closely related to but distinct from B. odocoilei that infects white-​tail deer in United States of America has been isolated in three asplenic patients in Europe (Italy, Austria and Germany) and recently in China. Few human babesiosis cases have been observed in Africa, Asia, Australia and South America. Pathogenesis Ticks infected with babesia inoculate parasites while feeding on a vertebrate. Babesia enter red blood cells directly and multiply by budding to form two or four parasites, rarely more, in 8 to 10 h. They are released and invade other erythrocytes. The spleen plays a major role in resistance to babesial infections, especially in the case of B. divergens babesiosis. Clinical features B. microti infection In humans, B.  microti babesiosis is characterized by gradually developing malaise, anorexia, and fatigue with subsequent develop- ment of fever, sweats, and generalized myalgia, starting from 1 to 4 weeks after a tick bite; 95% of those infected have intact spleens. Headache, shaking chills, nausea, depression, and hyperaesthesia are less frequent. Mild hepatomegaly and splenomegaly might be detected and spontaneous splenic rupture can occur. A mild to se- vere haemolytic anaemia, sometimes complicated by acute kidney injury, thrombocytopenia, and normal white blood cell count, is generally present. Lactate dehydrogenase, liver enzymes, and unconjugated bilirubin levels are sometimes increased. Parasites are found in peripheral blood of 1–​20% of patients with intact spleens, but in up to 80% of those who are asplenic. The illness is usually more severe in asplenic and older patients. Complications are more likely in the immunocompromised. Acute illness lasts from 1 to 4 weeks, but weakness and malaise often persist for several months. A low, asymptomatic parasitaemia can persist for several weeks after recovery. Case fatality is about 5%. B. divergens infection In Europe, B. divergens infections are usually more severe than those caused by B. microti, with a case fatality up to 42%. After an incu- bation period of 1 to 3 weeks, there is sudden severe intravascular haemolysis resulting in haemoglobinuria, severe anaemia, and jaundice, associated with non​periodic high fever (40–​41°C), hypo- tension, shaking chills, intense sweats, headache, myalgia, lumbar pain, vomiting, and diarrhoea. Peripheral blood B. divergens para- sitaemia varies from 5 to 80%. Patients rapidly develop renal failure, which can be associated with pulmonary oedema, coma, and death. Infection with B. venatorum is usually mild or moderate, even in asplenic patients. Diagnosis Babesiosis should be suspected in any patient from any area who presents with fever and a history of tick bite. Initially, Plasmodium falciparum malaria might be suspected, but lack of recent travel in malaria-​endemic areas or recent blood transfusion and lack of a spleen should lead to suspicion of babesiosis. Diagnosis is based on discovering babesia in Giemsa-​stained blood smears (Fig. 8.8.3.1). Babesia can be distinguished from plasmodia by the absence of gametocytes and pigment in erythrocytes. B. microti is characterized by multiple basket-​shaped parasites. In some cases, parasitaemia is sparse and detection of antibodies, using an indirect fluorescent antibody assay, can be useful for diagnosis. Antibody titres rise during the first weeks and fall after 5 months, but correlation between antibody titre and severity of the disease is poor. A real-​time polymerase chain reaction (RT-​PCR) assay targeting the 18S rRNA gene of B. microti has been developed. B. divergens is characterized in Giemsa-​stained blood smears by double piriform intraerythrocytic parasites or tetrads, but annular, punctiform, and filamentous forms might also be encountered. Serology cannot be used for a rapid diagnosis of B. divergens infec- tion. Amplification of babesial DNA by polymerase chain reaction, using species-​specific primers can establish the diagnosis of both B. microti and B. divergens within 24 h. These assays are more sensi- tive than, but equally specific as, smear detection. Clearance of DNA seems to be related to disappearance of parasites. Treatment and prevention Chloroquine, sulphadiazine, co-​trimoxazole, pentamidine, or diminazene aceturate appear ineffective in completely eliminating babesia parasites. For B. microti infection, the standard treatment is a combination of atovaquone (750 mg every 12 h) and azithromycin (500–​1000 mg orally on day 1, and 250–​1000 mg thereafter) for 7 days. Alternatively, a combination of clindamycin (600 mg intra- venously or orally) with quinine (650 mg orally) every 6 to 8 h for at least 7 days in adults; treatment for children is atovaquone (20 mg/​ kg every 12 h, maximum 750 mg/​dose) and azithromycin (10 mg/​kg per day on day 1 and 5 mg/​kg per day thereafter) or alternatively a combination of clindamycin (7–​10 mg/​kg) and quinine (8 mg/​kg) every 6 to 8 h for at least 7 days. For immunocompromised patients, a treatment for 6 weeks and two additional weeks after blood para- site clearance is recommended. For patients with high parasitaemias (≥10%), haemolysis, or renal failure or those that are immunocom- promised, these therapies might not be sufficient and exchange transfusion should be considered. In Europe, babesiosis should be treated as a medical emergency. Immediate chemotherapy with either a combination of clindamycin