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Home , Babesia microti, Colorado tick fever, Deer tick virus, Dermacentor variabilis, Ixodes holocyclus, Ixodes persulcatus

Ann Nestlé [Engl] 2009;67:121–130 DOI: 10.1159/000250697

Emerging -Borne

Ingomar Mutz

Abteilung für Kinder und Jugendliche, Landeskrankenhaus Leoben, Leoben , Austria

Key Words ther due to the virulence of the , non-utilization of - ؒ ؒ Borreliosis ؒ ؒ preventive measures or due to delayed diagnosis and treat Rickettsial diseases ؒ Spotted ؒ Tick-borne ment, mortality rates may vary, but the tick-borne infections ؒ Tick-borne diseases ؒ still cost lives. Copyright © 2009 Nestec Ltd., Vevey/S. Karger AG, Basel

Abstract Tick-borne infections occur worldwide and have been well Introduction known for more than 100 years. Some tick-borne diseases are very common while others are extremely rare. Modern Tick-borne infections have been well known for more molecular genetic techniques (and the wider availability of than 100 years. They occur with variable incidence with polymerase chain reaction) have lead to the discovery and respect to time and geography, depending on different classification of new pathogenic agents, especially for the circumstances such as reservoirs, climate, eco- order of . This review deals with viral, bacterial logic conditions and lifestyle. Preventive measures such and protozoal agents that may cause human disease. Most as repellents and clothing which covers most parts of the tick bites, and hence the tick-borne diseases, occur during body offer only limited protection. prevention is the warmer time of the year. With respect to the natural res- only available for some tick-borne infections and even ervoirs, there is a strong geographic variation among differ- then is not always sufficiently used. ent tick-borne diseases. The history of a tick bite is not always In the past, continuous progress has been made in reliable, because a tick bite may go unnoticed. The most terms of etiologic and therapeutic clarification; due to common diseases are Lyme borreliosis and tick-borne en- modern molecular genetic techniques, the discovery and cephalitis due to a flavivirus. The viral infections more often classification of new pathogenic agents is ongoing. Some have neurologic signs of encephalitis, while the rikettsial tick-borne diseases are very common while others are ex- infections are characterized by fever (biphasic), systemic tremely rare, so that only few physicians will encounter symptoms of and often a rash with petechiae. them during their professional life time. Often, labora- Some of the tick-borne diseases are preventable by immuni- tory diagnosis is not available, except in specialized labo- zation, such as tick-borne encephalitis. The non-viral infec- ratories, and a high index of suspicion may be necessary tions should be treated early with antibiotics, mostly follow- to order the right test at the right time. This makes diag- ing clinical suspicion, to achieve a satisfactory outcome. Ei- nosis difficult, may delay treatment and may be detri-

© 2009 Nestec Ltd., Vevey/S. Karger AG, Basel Prof. Dr. Ingomar Mutz 0517–8606/09/0673–0121$26.00/0 Schaldorferstrasse 2 Fax +41 61 306 12 34 AT–8641 St. Marein i.M. (Austria)

E-Mail [email protected] Accessible online at: E-Mail mutz.ingomar @ speed.at www.karger.com www.karger.com/ane mental for the outcome. For physicians dealing with such cur, persist and develop into a so-called ‘tick bite granu- patients, continuous education as well as timely specialist loma’. Rarely, systemic reactions are associated with tick consultation is important. bites. Any tick should be removed as soon as possible belong to the class Arachnida of the without crushing the tick, which may inject infectious [1]. is the name for the ‘soft’ tick family, Ixodi- material into the skin. The increasing length of feeding, dae for the ‘hard’ tick family. The important vectors for when a tick is not detected, does not always matter; it is the transmission of human are the genera Ixo- disadvantageous after about 24 h for the transmission of des, , , Haemaphysalis, Hya- conorii, burgdorferi or . lomma and Rhipicephalus of the family and the Ornithodorus of the Argasidae family. Most cases of tick-borne infections occur between March and Octo- Tick paralysis is an ascending flaccid paralysis follow- ber. During feeding, the ticks remain attached to the ing the tick attachment within 2–7 days. It can be caused for hours or days. More than 1 tick-borne agent may cause by over 40 of ticks worldwide. It can kill , disease at the same time because multiple tick exposure mainly cows and sheep. The 5 North American species of may be lifestyle-associated and/or ticks may transmit ticks thought to cause tick paralysis are widely distrib- more than 1 infection simultaneously. uted throughout the United States. Human cases are rare The clinical picture of tick-borne diseases is usually and usually occur in children under the age of 10 years. characterized – after an incubation period of less than 10 Tick paralysis occurs when an engorged and gravid days – by a sudden fever and nonspecific symptoms of a (egg-laden) female tick produces a neurotoxin (holocy- systemic infection, such as chills, sweat, headache, myal- clotoxin) in its salivary glands and transmits it to its host gias, arthralgias, anorexia, nausea and vomiting. Often during feeding [3] . The greatest amount of toxin is pro- the fever is biphasic. The viral infections mostly show duced between the 5th and 7th day of attachment and can neurologic signs of encephalitis. Patients with Crimean- only continue to be released in the presence of the tick. Congo hemorrhagic fever, and Once the tick is removed, symptoms usually diminish (KFD) may develop gastrointes- rapidly. However, in some cases, profound paralysis can tinal bleeding. Rickettsial spotted are character- develop and even become fatal before anyone becomes ized by an often biphasic fever, systemic symptoms of in- aware of a tick’s presence. fection and frequently, but not always, a diffuse maculo- Symptoms begin with fatigue, numbness of the legs, papular rash with petechiae or purpura. They may also difficulties to walk or stand, and muscle pains. Paralysis exhibit a local cutaneous ulcer or (tache noir) at rapidly develops from the lower to the upper extremities the tick bite site. Lyme borreliosis is a symptomatic cha- and, if the tick is not removed, is followed by tongue and meleon with various signs and symptoms, which can give facial paralysis. The most severe complications may in- misleading diagnostic clues and is erroneously accused of clude convulsions, respiratory failure and, in up to 12% causing many unrelated complaints. is com- of untreated cases, death. mon in and tularemia. Tularemia also presents as Diagnosis is based on symptoms and the rapid im- a systemic or an ulceroglandular form of illness. Babesio- provement of the patient once the engorged tick is re- sis is characterized by prolonged fever and anemia (ta- moved. Treatment is simply removing the feeding tick(s). ble 1 ) [2] . It is important to remove all the mouthparts, since they contain the salivary glands which may continue to infect the patient even after the body of the tick has been re- L o c a l R e a c t i o n s moved.

Tick Bites Tick bites – which actually are tick stings by the den- Tick-Borne Viral Diseases tate hypostoma (a handle-like process) of the tick – fre- quently go unnoticed, because the tick saliva contains Crimean-Congo Hemorrhagic Fever substances with anesthetic and antihistaminic proper- Crimean-Congo hemorrhagic fever is caused by a ties. In most cases, there is no local inflammatory re- member of the Nairovirus genus of the family Bunya- sponse. Tick bites can cause local reactions such as a small viridae. The occurs in Africa, Asia and Eastern papule, an ulcer or an eschar. Seldom, local signs may oc- Europe in cattle, sheep and small animals such as hares.

122 Ann Nestlé [Engl] 2009;67:121–130 Mutz

Table 1. Human diseases caused by a tick [2] Disease Agent Tick bite Tick paralysis Holocyclotoxin Crimean-Congo hemorrhagic fever Nairovirus KFD Flavivirus Omsk hemorrhagic fever Flavivirus , TBE Flavivirus Asian tick R. sibirica Japanese (Oriental) R. japonica Mediterranean spotted fever, fièvre boutonneuse R. conorii R. australis RMSF R. rickettsii Spotted fever group Rickettsia R. helvetica, R. monacensis Tick-borne R. slovaca Human granulocytic anaplasmosis A. phagocytophilum HME E. chaffeensis, E. ewingii, E. sennetsu B. burgdorferi B. duttoni Q fever C. burnetii Tularemia, rabbit fever F. tularensis Babesiosis B. microti, B. divergens

It was isolated in 1956 in Congo and in 1967 in the virus isolation or ELISA. No specific prevention (vaccine) Crimean region [4] . Human infection occurs from tick or treatment is available. bite (mostly Hyalomma ) or from contact with blood or other tissues of infected livestock. The liver is the major Deer Tick Virus site of virus replication; mononuclear phagocytes and Deer tick virus is related to the tick-borne Powassan endothelial cells are also targets of virus infection [5] . virus (Powassan virus lineage II) and is a member of the The disease is usually characterized by a febrile illness flavivirus group; it has been first isolated from with headache, and petechial rash (on the 3rd scapularis ticks in 1997 in North America [7] . The Pow- to 6th day of illness), frequently followed by a hemor- assan virus can cause severe encephalitis with a fatality rhagic state with necrotizing hepatitis. The case fatality rate of up to 60% and long-term neurologic sequelae rate is around 30% [6]. Diagnosis is made by virus isola- in survivors. Diagnosis is made by virus isolation or tion or ELISA. No specific prevention (vaccine) or treat- ELISA. No specific prevention (vaccine) or treatment is ment is available. available.

Colorado Tick Fever Kyasanur Forest Disease Colorado tick fever is transmitted by Dermacentor an- KFD is endemic in South Asia. The disease was first dersoni which is also transmitting Rocky mountain spot- reported from Kyasanur forest of Karnataka in . The ted fever (RMSF). The incubation period is 0–14 days. disease was noticed in 1957 among monkeys, and hence, Symptoms are fever, chills, malaise, headache, retro-or- is also known as monkey disease. KFD is limited to the bital pain, lumbar pain, myalgia, hyperesthesia, some- Karnataka State, India, where several hundred cases oc- times lymphadenopathy and/or hepatosplenomegaly, cur each year. However, recently, a virus very similar to rarely rash, as well as significant leukopenia (neutropenia the KFD virus was discovered in [8] . most significant after 5–6 days). Diagnosis is made by

Emerging Tick-Borne Infections Ann Nestlé [Engl] 2009;67:121–130 123 The main hosts of the KFD virus are small ticks are carriers of the virus. Contrary to the transmis- (shrews, rats), but also porcupines, bats and monkeys. sion of B. burgdorferi, only a short period of sucking is The vector for disease transmission is Haemaphysalis spi- sufficient for transmission to the human. Rarely, the vi- nigera, a forest tick. rus can be transmitted by unpasteurized infected milk After an incubation period of 3–8 days, infected hu- from goats. mans suddenly develop fever, headache, severe muscle The first report on TBE in Europe dates back to 1931 pain, backpain, cough, dehydration, gastrointestinal when Schneider [11] in Austria described a ‘meningitis symptoms, conjunctivitis and bleeding problems. Pa- serosa epidemica’ of unknown etiology. In the Far East- tients may experience an abnormally low ern Soviet Union, the disease was described in 1934. The and low platelet, red blood cell and white blood cell virus was isolated and tick transmission demonstrated in counts. After 1–2 weeks of symptoms, some patients re- 1937. cover without complication. However, in most patients, More than 10,000 cases of TBE occur each year in Eu- the illness is biphasic and a second wave of symptoms rope. The countries with the highest number of infec- starts at the beginning of the third week. These symp- tions are Austria, Croatia, Czech Republic, Hungary, toms include fever and signs of encephalitis [9] . The case Slovenia and Slovakia. The disease also occurs in the fatality rate is 3–5%. Often, the recovery period lasts for southern parts of Germany, Finland, Poland, Sweden and several months with myalgia and weakness. Diagnosis is Switzerland. At present, the Benelux countries and Por- made by virus isolation or ELISA. No specific prevention tugal are the only European countries in which TBE has (vaccine) or treatment is available. not been shown to occur. A high number of cases also oc- curs in the Asian part of the Russian Republic, in the Omsk Hemorrhagic Fever northern part of China, and in neighboring areas. Omsk hemorrhagic fever is caused by the Omsk hem- The seasonal distribution of TBE depends on tick ac- orrhagic fever virus, a flavivirus. The virus was detected tivity in nature related to weather conditions such as tem- in 1945 and recently – as with the other – the peratures and humidity. The maximum activity in Cen- has been completely analyzed [10] . It is found in tral Europe is between May and October. The number of Western Siberia, mostly among muskrat trappers. The cases varies from year to year according to the climate infection is transmitted by ticks (Dendrobates reticulatus, and leisure time activity. It seems to expand into western Dermacentor marginatus, ) or directly and mountainous regions due to climatic changes. Above from muskrats or contaminated water. an altitude of 1,000 m, where the mean annual tempera- ! After an incubation period of 3–7 days, a first febrile ture is 8 ° C, the ticks and the virus did not exist until attack with chills, headache and pain in the extremities recently, when TBE infection has occurred as high as may also show a papulovesicular rash on the soft palate, 1,600 m. cervical lymphadenopathy, conjunctival effusion, signs The disease can be mild or asymptomatic or, in about of pneumonia and gastrointestinal hemorrhage; during 10%, manifests as meningitis, encephalitis, myelitis or the second fever wave, signs of a mild encephalitis appear. any combination thereof. The disease is usually milder in The case fatality rate is ! 5%. No specific prevention (vac- children, although cases of encephalitis with permanent cine) or treatment is available. neurologic sequelae have been described [12] . Antiviral treatment is not available. T i c k - B o r n e E n c e p h a l i t i s For diagnosis, an ELISA is available, which has a cross- Tick-borne encephalitis (TBE) – also known as Cen- reactivity against Japanese B encephalitis virus. Use of tral European encephalitis – is caused by an RNA virus the neutralization test circumvents this problem. belonging to the family , which is a sub- TBE is a vaccine-preventable disease [13]. The vaccine group of the togavirus group. Infection with this virus covers all 3 subtypes (European, Central-Siberian and induces the production of against the outer Far-Eastern subtypes). From 1970 till 2008, a total sum of surface glycoprotein E, which have neutralizing proper- 8,848 cases of TBE were diagnosed in Austria. Almost all ties. of the patients who had serologically confirmed diagno- The vector of the virus is the tick (or I. sis were hospitalized. Despite the high coverage rate (88%) persulcatus in the Far East), which transmits the virus via and efficacy (98%) of the vaccine, 50–100 cases occur its saliva while sucking. The natural reservoirs are small each year in Austria [14] . rodents and game. In endemic areas, 0.2–0.5% of the

124 Ann Nestlé [Engl] 2009;67:121–130 Mutz

Tick-Borne Rickettsial Diseases Table 2. Rickettsiales

Previously, all intracellular were called ‘rick- Order Family Genus Species ettsia’ [15, 16] . Due to analysis of 16S-RNA, this system- Rickett- Rickettsi- Rickettsia R. and others atic assignment had to be changed and the order Rickett- siales aceae Orientia O. tsutsugamushi siales was divided into 2 families ( table 2 ) [17] . Anaplas- Anaplasma A. phagocytophilum and others After inoculation, the rickettsiae multiply in the endo- mataceae Ehrlichia E. chaffeensis and others thelial cells of small blood vessels and become widely dis- seminated in the vascular system. The symptoms of the rickettsial infections are similar. After an incubation pe- riod of 6–7 days, the patient suffers from a high fever for up to 2–3 weeks and has a maculopapular rash on the ex- tremities. Most cases develop significant thrombocytope- Japanese (Oriental) spotted fever is caused by Rickett- nia. Sometimes, the bite lesion may become necrotic. For sia japonica and is endemic in the southwestern part of patients with potential rickettsioses, a careful clinical ex- Japan. It was described in 1984 [20] . It is a typical spotted amination and epidemiological investigation is critical. fever [21] . Cases of encephalitis have been reported. The presence of a characteristic rash is often the most im- portant clue for diagnosis. Because the simple serologic Mediterranean Spotted Fever diagnosis has a delay of more than a week, rapid diagnosis The disease was first described in Tunesia in 1920 [22] by DNA detection assays or fluorescent or peroxidase- and is encountered in the Mediterranean region, in Sub- tagged testing of a skin biopsy specimen is im- Saharan Africa, India and around the Black Sea. The dis- portant. Rickettsiae are sensitive to ; doxycy- ease is caused by R. conorii and is similar, but milder, than cline is the drug of choice, and treatment should be start- illness due to . For transmission, the ed as soon as possible. Treatment before the 5th day of the tick needs to remain attached for at least 20 h. The mor- disease is important for an optimal outcome and can re- tality rate may reach 2.5% [23] . duce mortality. When tetracycline is contraindicated R. conorii israelensis causes the Israeli spotted fever, (young children, pregnant women), antibiotics such as R. conorii caspia causes the Astrakhan fever. chloramphenicol, josamycin or a combination of rifampin with erythromycin may be used. Before antibiotic treat- Queensland Tick Typhus ment was available, the mortality of RMSF was 25%, and Queensland tick typhus has been recognized in 1946 often, due to the delay of treatment, is still 5–7%. Diseases in Queensland, Eastern [24] . Rickettsia austra- due to rickettsiae other than RMSF are usually milder. lis is transmitted by . The disease is typ- ical, with a sudden onset of high fever, headache, myalgia Asian Tick Typhus and a maculopapular or vesicular rash. An eschar is often Asian tick typhus, also known as -associ- found, and lymphadenopathy is common. A similar dis- ated , mainly occurs in Siberia and Mongolia. ease is found on Flinders island (Tasmania) due to Rick- Therefore, it is also known as Siberian tick typhus. The ettsia honei. reservoirs are rodents and dogs. was originally isolated from a Hyalomma asiaticum tick col- Rocky Mountain Spotted Fever lected in the Alashian region of Inner Mongolia in 1991 R. rickettsii occurs in Southern Canada, through the [18] . Since then, this emerging strain has been detected in United States, Mexico, Central America, Brazil and other Hyalomma species, such as Hyalomma truncatum Argentina. Reservoirs are various rodents, rabbits and and Hyalomma excavatum, and in different areas of the hares. Important vectors are and world [19] . The incubation period is around 4–7 days, D. andersoni. About 500 cases of RMSF occur each year with a range from 3 to 18 days. The tick bite may develop in the USA. into an ulcerated necrotic lesion. It causes a typical mild The illness [25] was first described in the 1890s [26] rickettsial disease with fever, headache, myalgia, regional and originally called ‘black measles’. It begins abruptly lymphadenopathy, central nervous system symptoms 2–12 days after tick exposure. Severe headache, myal- and a – sometimes purpuric – rash. It lasts for 6–10 days gias and a characteristic maculopapular rash beginning without treatment. on the ankles and wrists on the third day are typical;

Emerging Tick-Borne Infections Ann Nestlé [Engl] 2009;67:121–130 125 nausea and vomiting, abdominal pain, as well as con- Asymptomatic infection with Ehrlichia canis has been re- junctivitis are frequent. Untreated, the fever may persist ported in 1 patient in Venezuela [39] . HME in the USA is for 2–3 weeks, the rash may become petechial or ecchy- transmitted by the lone star tick and possibly other spe- motic. The fatality in the untreated patient with a sys- cies. From 1986 to 1997, 742 cases of HME were reported temic inflammatory response is about 20%; in the USA, in the USA. the fatality rate is about 5%. Serologic diagnosis (indi- After an incubation period of 12–14 days, the infec- rect immunofluorescence assay) is unreliable in early tion causes a febrile illness with headache, anorexia, infection. Polymerase chain reaction (PCR)-based diag- vomiting and myalgia. Leukopenia, nostic techniques have greatly facilitated the diagnosis and abnormal liver enzymes are common. Damage of [27] . Early consideration of the correct diagnosis and the lungs and kidneys, seizures and coma can ensue. A treatment may be life saving. The treatment of choice is macular or maculopapular rash is more common in chil- tetracycline. Therapy is continued until the patient has dren than in adults. HME can become a severe, life- been afebrile for at least 3 days, usually for 7–10 days. threatening illness, especially if left untreated. Due to When tetracycline is contraindicated (young children, the nonspecific nature of the symptoms, the diagnosis is pregnancy), chloramphenicol may be an alternative. No often not made. A PCR test for HME and human granu- vaccine is on the market. locytic anaplasmosis is available. is the treatment of choice. Tick-Borne Lymphadenopathy R. slovaca disease was described in 1997 [28] and is Human Granulocytic Anaplasmosis transmitted by D. marginatus and possibly I. ricinus or D. Human granulocytic anaplasmosis [40] was renamed reticulatus [29]. It causes a characteristic illness with ve- in 2003 from human granulocytic [41] . sicular, ulcerous or eschar lesions at the tick bite followed Anaplasma phagocytophilum is a 0.5- to 2.0-␮ m oblig- by painful enlargement with constitutional atory intracellular Gram-negative bacterium, which symptoms such as mild fever, fatigue, daze, headache, forms intracytoplasmatic microcolonies (morulae) in myalgia, arthralgia and loss of appetite [30] . Cutaneous neutrophil granulocytes. Cell lysis permits infection of rash is extremely rare [31] . R. slovaca has been found in more granulocytes. The most important carriers of ana- many European countries. In Hungary, the disease is plasmosis in the USA are the western black-legged tick known as wood scar or Dermacentor-borne necrosis ery- and the deer tick, both of which also transmit Lyme dis- thema lymphadenopathy [32] . Diagnosis is made by mo- ease. lecular genetic demonstration of the pathogen in lymph In 2005, 786 cases of human granulocytic anaplasmo- node biopsy material. sis and 506 cases of HME were reported to the Centers for R. helvetica has been found in Europe, Japan and Thai- Disease Control and Prevention. In Europe, A. phagocy- land. In Europe 2.5–38% of I. ricinus carry R. helvetica tophilum was cultured for the first time from a patient in [33, 34] . The illness is not yet well defined and shows flu- Slovenia [42] . The vector in Europe is I. ricinus. Although like symptoms with fever, malaise, headache and myalgia A. phagocytophilum is found in about 14% of I. ricinus in without a cutaneous rash [35] . Austria, illness due to this pathogen is extremely rare. Transmission of A. phagocytophilum through blood Human Monocytic Ehrlichiosis transfusion has been reported [43] . Human monocytic ehrlichiosis (HME) was first de- After an incubation period of 1 week (up to 30 days), scribed in 1987 [36] . flu-like symptoms develop: high fever, chills, malaise, Ehrlichia is a Gram-negative 0.2- to 2-␮ m bacterium, headache, myalgia, arthralgia, dizziness, vomiting and which belongs to the order Rickettsiales and is an obliga- dry cough [44] . Possible complications of anaplasmosis tory intracellular parasite. Ehrlichia and Anaplasma are include and damage of the lungs, heart, kidneys veterinary pathogens: Ehrlichia is found in infected dogs, and nerves. The illness lasts for several days up to 2 while Anaplasma is found in sheep, cattle and deer. HME months. Laboratory findings include thrombocytopenia, is mostly caused by , but other Ehr- leukopenia, abnormal liver enzymes and high C-reactive lichia species as causative agents have been described. protein. On microscopic examination of the blood smear, was found in patients receiving immu- the typical morulae within neutrophils may be seen. For nosuppressive therapy [37] . Ehrlichia sennetsu has caused diagnosis, culture is possible, but PCR is more convenient a mononucleosis-like illness in Japan and Malaysia [38] . and is available in specialized laboratories. Detection of

126 Ann Nestlé [Engl] 2009;67:121–130 Mutz

antibodies (immunofluorescence) is less reliable, because Table 3. Clinical symptoms of Lyme borreliosis after infection, antibodies may persist for a long time. Treatment with doxycycline for 7 days leads to fast recov- Stage 1 = localized – , regional lymphadenopathy ery. When tetracycline is contraindicated, rifampicin may be used. Stage 2 = disseminated Recently, 2 lineages of A. phagocytophilum have been – Secondary annular lesions, diffuse erythema or urticaria, lymphocytoma described by discrimination between groEL-G and gro- – Migratory pain, brief arthritis, myositis, osteomyelitis, EL-A genotypes by real-time PCR. While so far the gro- panniculitis EL-G variant was the only genotype found in man, in – Meningitis, cranial neuritis (Bell’s palsy), subtle encephalitis, 2009, the groEL-A variant was for the first time detected mononeuritis multiplex, myelitis, chorea, cerebellar ataxia in a human patient [45] . – Generalized lymphadenopathy, – Atrioventricular nodal block, carditis – Conjunctivitis, iritis, choroiditis, retinal hemorrhage – Mild hepatitis Tick-Borne Spirochetal Diseases – Sore throat – Microscopic hematuria, proteinuria, orchitis Borrelia – Malaise, fatigue Borrelia belongs to the family Spirochaetaceae and has Stage 3 = persistent the unique feature that a number of its outer membrane – Acrodermatitis chronica atrophicans proteins are encoded by plasmid genes. The genome has – Localized scleroderma-like lesions – Prolonged or recurrent arthritis, enthesopathy, periostitis been fully sequenced [46] . In the USA, the species B. burg- – Chronic encephalomyelitis, polyradiculopathy dorferi sensu stricto is the most common, while in Eu- – Keratitis rope, other human pathogens are Borrelia afzelii, Bor- relia garinii, Borrelia lusitaniae, Borrelia spielmani and Borrelia valaisiana. While B. afzelii is mostly responsible for skin disease (acrodermatitis), B. garinii more often causes neurologic disease. symptoms may last for weeks and months. After several weeks, about 5% of untreated patients have signs of car- Lyme Disease diac involvement. Months after the infection, about 60% Lyme disease was first described in 1977 in a cluster of of untreated patients may have joint swelling and pain, arthritis cases among children living near Lyme, Con- primarily in the knee. There is considerable debate necticut [47]. It was defined as an entity in 1982 by Burg- about the existence, criteria and treatment for ‘chronic dorfer et al. [48] , although its manifestations have been Lyme disease’ ( table 3 ) [55] . well described many years earlier: acrodermatitis chron- Diagnosis by culture from biopsy specimen, cerebro- ica atrophicans (1902) [49] , erythema chronicum mi- spinal fluid or blood is rarely possible. For diagnosis of grans (1913) [50], meningopolyneuritis (1941) [51] , and acute disease, PCR is not sufficiently reliable, and other lymphadenosis cutis benigna (1943) [52] . tests (ELISA, Western blotting) are often difficult to in- The symptoms of infected persons vary widely and terpret. Therefore, treatment for erythema migrans or may affect the skin, the nervous system, the joints, the lymphocytoma is recommended without testing. Antibi- heart, the lymph nodes, the liver, the , the eye, and otic treatment includes doxycycline, amoxicillin, cefu- others [53] . The majority of patients develop a charac- roxime, ceftriaxone or penicillin and is recommended teristic slowly expanding skin lesion at the site of the tick according to disease stage [56, 57]. Localized disease is bite (erythema migrans). With or without erythema mi- usually treated orally for 2–3 weeks, while disseminated grans, constitutional influenza-like symptoms, such as and late disease is treated with antibiotics for 2–4 weeks. malaise, fatigue, headache, , fever or regional For recurrent arthritis, carditis or neuroborreliosis, in- lymphadenopathy, may occur initially [54] . Without travenous therapy is preferred. The prognosis of treated treatment, disseminated infection may progress to acute Lyme borreliosis is excellent. neuroborreliosis in about 15%. Manifestations include A recombinant vaccine based on the OspA1 surface lymphocytic meningitis with headache and mild neck antigen of B. burgdorferi sensu stricto was withdrawn stiffness, facial palsy, optic nerve neuritis, encephalitis, from the market in 2002 after 3 years of use in the myelitis, radiculoneuritis or cerebellar ataxia. The USA.

Emerging Tick-Borne Infections Ann Nestlé [Engl] 2009;67:121–130 127 Lyme disease is the most common tick-borne infec- ing cats and dogs. The infection results from inhalation tion: during 1992–2006, a total of 248,074 cases were re- of contaminated particles in the air, as well as from con- ported to the Centers for Disease Control [58]. In Ger- tact with the milk, urine, feces, vaginal mucus or semen many, about 80,000 cases of Lyme borreliosis (incidence of infected animals. The bacterium is extremely sustain- of 1 100/100,000) and 300–500 cases of TBE occur each able in the environment. It can be considered the most year. In Austria, borreliosis is the most common tick- infectious disease in the world, as a human being can be borne infection (estimated 4,000 cases per year) followed infected by a single bacterium. Tick transfer is possible, by TBE (50–100 cases per year). In TBE-endemic coun- but very rare. Transfer between humans has been de- tries such as Slovenia, where in contrast to Austria the scribed in very few cases. immunization rate for TBE is low, the reverse may be the The incubation period is 9–40 days, usually 2–3 weeks. case. Of 86 Slovenian children suffering from a febrile ill- The most common manifestations are flu-like symptoms ness within 6 weeks after a tick bite, 33 had various well- with abrupt onset of fever, malaise, profuse perspiration, defined illnesses not associated with the tick bite and 28 severe headache, myalgia, joint pain, loss of appetite, up- suffered from a well-defined illness associated with a tick per respiratory problems, dry cough, pleuritic pain, chills, bite: 18 TBE, 13 Lyme borreliosis, 3 monocytic ehrlichio- confusion and gastrointestinal symptoms such as nausea, sis, 1 granulocytic anaplasmosis; 6 of those had more vomiting and diarrhea. The fever lasts approximately 7– than 1 tick-borne agent [59] . 14 days. During the course, the disease can progress to an atypical pneumonia, which can result in a life-threaten- Relapsing Fever ing acute respiratory distress syndrome. Less often, the Q Tick-borne relapsing fever is caused by Borrelia dut- fever causes a granulomatous hepatitis with malaise, fe- toni, while the non-tick-borne -borne relapsing fe- ver, abdominal pain and jaundice. As a late manifestation ver is due to Borrelia recurrentis. Tick-borne relapsing of Q fever, endocarditis [61] can occur months or years fever is found primarily in Africa, Spain, Saudi Arabia, later, which even with treatment may have a mortality Asia and certain areas in the Western US and Canada. around 10%. The agent is frequently transmitted by the soft-bodied For treatment, doxycycline is the preferred antibiotic; African tick moubata. in the case of pregnancy, it is 5 weeks of co-trimoxa- Tick-borne relapsing fever is a multisystem disease zole. that occurs in North America, Europe and Asia. After A whole-cell inactivated (intradermal) vaccine is avail- an incubation period of 5–15 days, patients suffer from able in Australia (1 dose is sufficient). Skin and blood a sudden fever, chills, headaches and muscle or joint tests should be done before vaccination to identify preex- aches, as well as nausea; a rash may also occur. These isting immunity, because already immune persons can symptoms may continue for 2–9 days and may recur for develop a severe local reaction. several weeks if not treated. Relapsing fever is treated with 1–2 weeks of tetracycline with rapid recovery. T u l a r e m i a Treatment may induce a Jarisch-Herxheimer reac- Tularemia is also known as rabbit fever. Francisella is tion – probably mediated by tumor necrosis factor- ␣ – a genus of pathogenic, Gram-negative coccoid or rod- with diaphoresis, fever, tachypnea, tachycardia and hy- shaped bacteria, which are aerobe facultative intracel- potension. Complications and death due to relapsing fe- lular parasites of macrophages; there are 2 types: type A ver are rare. and type B. In 1922, was recog- nized as the causative agent of tularemia [62] . The pri- mary reservoirs are rodents, voles, muskrats and bea- Other Rare Tick-Borne Bacterial Diseases vers, as well as contaminated waters and mud. Francisel- la can survive for several weeks in the environment. The Q Fever domestic rabbit is the prime source of infection in hu- Q fever is caused by , a Gram-negative mans. Transmission occurs through direct contact, aerobe 0.4- ␮m coccoid bacterium, and belongs to the aerosolized bacteria, ingestion of infected tissue or family Coxiellaceae in the order . It lives in- through the bites of colonized ticks or . It has be- tracellularly and was first described in 1937 in Australia come a rare disease since wild rabbits are no longer sold [60] . This organism is uncommon but may be found in on markets. cattle, sheep, goats and other domestic mammals, includ-

128 Ann Nestlé [Engl] 2009;67:121–130 Mutz

The clinical form of tularemia reflects the mode of Tick-Borne Protozoal Diseases transmission. Three forms may be distinguished: ty- phoid disease with a predominance of systemic symp- In Europe, the (rare) human infections are commonly toms, pneumonic disease with pulmonary pathology, or caused by Babesia divergens, while in the United States, ulceroglandular disease with regional symptoms (80%). is usually found. Babesiosis [65] was rec- After inoculation by tick bite (11%) [63] , a papule or an ognized in the northeast USA in the 1960s. The natural ulcer may develop followed by swelling of the regional hosts for B. microti include the white-footed mouse and lymph nodes and sometimes fever. In a recent survey in the meadow vole. Tick bite by Ixodes dammini is the usu- Missouri (190 cases from 2000 to 2007), children were al source of human infection. The longer the tick is at- more likely to be diagnosed with glandular tularemia tached, the more likely is the transmission of the sporo- than adults, whereas adults were more likely to be diag- zoites. In addition, infection can be transmitted by blood nosed with pneumonic tularemia, and among 78 cases transfusion. with a documented exposure source, 72% were associ- The parasites invade the red blood cells and replicate ated with tick bite [64]. Without treatment, lymphade- within. Due to their pear-shaped appearance within in- nopathy may persist for months. Mortality of all clinical fected cells, they are called ‘piroplasms’. They may cause forms is around 8% without and 1% with antibiotic ther- with all its consequences; the mortality in di- apy. agnosed cases may be very high [66] . In humans, the in- For diagnostic culture, the laboratory must be in- fection may be subclinical or may present 10–24 days af- formed that F. tularensis may be present in the specimen ter a tick bite as a febrile illness with constitutional symp- to avoid laboratory infections and to use a special medi- toms and anemia. Manifestations are most severe in um. Streptomycin is considered the drug of choice, al- elderly, immunosuppressed or asplenic persons [67] . For though tetracycline, aminoglycosides or fluoroquino- treatment, azithromycin and atovaquone are used. lones have been used.

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