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Home , Anaplasmosis, Boutonneuse fever, Lower Normandy, Lyme disease

Focus on... -borne diseases DS20-INTGB - June 2017 With an increase in forested areas, The : an increase in the number of large mammals, and developments in forest The main vector of these diseases are use and recreational activities, the hard ticks, acarines of the family. In , more than 9 out of 10 ticks incidence of tick-borne diseases is on removed from humans are the rise. and it is the main vector in Europe of human-pathogenic Lyme borreliosis (LB) In addition to , which has , the tick-borne encephali- an estimated incidence of 43 cases tis virus (TBEV) and other pathogens of per 100,000 (almost 30,000 new cases humans and domesticated mammals. identified in France each year), ticks can It is only found in ecosystems that are transmit numerous . favourable to it: deciduous forests, gla- des, and meadows with a temperate Although the initial manifestations of climate and relatively-high humidity. these diseases are often non-specific, Therefore, it is generally absent above a they can become chronic and develop height of 1200-1500 m and from the dry into severe clinical forms, sometimes Mediterranean region. with very disabling consequences. They Its activity is reduced at temperatures respond better to treatment if above 25°C and below 7°C. As a result, it is initiated quickly, hence the need for its activity period is seasonal, reaching a early diagnosis. maximum level in the spring and autumn.

Larva Adult female Adult male

Nymph

0 1.5 cm

It is a blood-sucking ectoparasite with 10 days. A female tick can ingest up to 3 distinct stages of development: larva, 150 times its weight in blood. At the end nymph, adult. of the meal, the tick detaches from its During its life-cycle, the tick climbs above and falls to the ground. the herbaceous layer on the lookout for a Several months (between 9 and 12) are host, which it detects using various sen- needed to pass onto the next stage. sory organs on its first pair of legs; these Egg laying (about 20,000 eggs) kills the are sensitive to mechanical, thermal and female tick. chemical stimuli generated by the host. The total duration of the life-cycle is on The blood-meal can last between 3 and average between 2 and 4 years. DS20-INTGB - June 2017

2/12 At each stage Finding a host of the tick's The larvae fall to the development, Hatching of ground and molt the relative size the larvae of the animals Stage 1 host represents their importance as a host. Eggs Nymphs

The engorged females fall to the ground

Stage 3 host Stage 2 host

Blood-meal for females Blood-meal for nymphs

Source: EUCALB

Man is an accidental host: it is a stage regions, it is the tick most commonly 2 host from which the nymphs (approx. found on dogs (at every stage), and it 2 mm in size) feed. can also bite humans, especially if the infestation is heavy. The distribution of ticks throughout France shows regional disparities, with some areas having higher densities of nymphs, Lyme disease but vector studies are incomplete (data from JF Chapuis, BEH 2010): Lyme disease is the most common 1. (146 nymphs/100m2) vector-borne zoonotic disease in the 2. (121 nymphs/100m2) . Monitoring of the 3. Lower (111 nymphs/100m2) disease is a priority because of its emerging and its potential severity. 4. Île-de-France (Essonne) (73 nymphs/ 100m2) The agent responsible is a spiral bacterium of the group collectively known as Other ticks involved in the spread of burgdorferi sensu lato, which comprises disease are: many species. B. garinii, B. afzelli and - sp (mainly reticulatus): B. burgdorferi sensu stricto are the main found outside forests, including in European species. urban areas, with activity period that extends until winter; it is the adult, The distribution throughout France is which is more readily identifiable, that consistent with the distribution of the vector. can feed on humans. The incidence of Lyme disease is estimated - sanguineus: found at 43 cases per 100,000 inhabitants. in the southern and Mediterranean DS20-INTGB - June 2017

3/12 Estimated mean annual incidence of Lyme disease in France by region 2009-2011 (Sentinelles Network, source: InVS)

Incidence per 100,000 inhabitants

0 1 - 28 29 - 65 66 - 89 90 - 157 > 157

1. of Borrelia to its host spirochetes. Secondly, the interaction Approximately 10 to 20% of ticks are between the salivary protein Salp15 and infected with Borrelia, and the bacterium OspC results in protection from the can be found in all stages of the tick's bactericidal effects of anti-OspC . development. Suppression of the expression of OspC, which is highly immunogenic, and the When the bacterium is ingested by the over-expression of the protein VlsE, which tick, it produces an outer surface protein has high , constitute (OspA) which interacts with a protein in the essential mechanisms to evade the the gut of the tick (TROSPA): this interac- host's immune response: the bacterium is tion enables the bacterium to attach within not destroyed by the very early anti-VlsE the intestine of the vector and protects it antibodies. from the tick's . Thus, all of these mechanisms allow The bacterium multiplies, then migrates of the host and dissemination to from the intestines to the salivary glands. its target organs. Saliva is an essential element in the The risk of Borrelia transmission transmission phase and for the initiation increases with the time that the tick is of the infection. Various mechanisms then attached to the host. The risk is very low contribute to the transmission of Borrelia with an attachment time of less than to the vertebrate host. Firstly, suppression 7 hours, and very high after 48 hours: of the production of OspA and expression primary and secondary preventive of OspC constitute a major virulence measures are therefore essential to

factor to enable the transmission of the prevent the transmission of Borrelia. DS20-INTGB - June 2017

4/12 2. Clinical information: the 3 stages of infection and how to diagnose them - European consensus

Recommended essential Stages of Clinical forms tests for diagnosis, and Optional tests infection their respective results Early localised migrans: stage or primary - Bull's-eye (≥ 5 cm in phase diameter), with or without a clear centre, developing in a ring, with elevated edges NO TESTS = diagnosis None if lesion is - Spontaneous resolution (up to 6 based on clinical examination typical months without treatment, in a few days on antibiotic therapy) Incubation 7 to 21 Antibiotic therapy helps days prevent complications and progression to the other stages

- reaction Neurological Lyme disease in CSF and/or elevated In adults: protein levels in CSF. - mainly meningoradiculitis, - Positive IgG in ; CSF; sometimes delayed in the blood. - in rare cases: , PCR on CSF ; - Intrathecal synthesis of specific IgG. In early - in very rare cases: cerebral cases, intrathecal vasculitis synthesis of specific In children, mainly meningitis and antibodies may still be Early facial paralysis. absent at the time of the disseminated initial sample. stage or secondary - Analysis phase Lyme - Positive serology in the of synovial - Arthritis of one or more large blood, normally with tissue or fluid - Some weeks or joints elevated levels (IgG) months after the - Detection of primary phase - Possibility of recurrence - Inflammatory Bb sl using PCR - Dissemination of the pathogen via Borrelial lymphocytoma - Histological the blood - Painless erythematous or purplish - Seroconversion or positive confirmation blue nodular swelling serology - Detection of - Usually on the lobe or helix of the - Histological confirmation in Bb sl using ear, nipple or ambiguous cases PCR on skin - More common in children (especially on the ear) - Histological Multiple lesions - Specific serology confirmation

Cardiac manifestations (rare) - Detection of Atrioventricular conduction disorders Bb sl using (first, second or third degree AV - Specific serological testing PCR on block), arrhythmias, sometimes myocardial myocarditis or pancarditis biopsy

Late disseminated - Histological stage or tertiary Joint symptoms, neurological confirmation phase and cutaneous symptoms - Specific IgG serology with - Detection of Several months and Acrodermatitis chronica atrophicans elevated levels Bb sl using years after the onset (ACA) PCR on skin of the infection biopsy DS20-INTGB - June 2017

5/12 3. Natural course of Lyme disease presence of the bacterium. Lyme disease occurs following a bite from - the tertiary phase; this phase develops an infected tick: the risk of transmission of late in the absence of treatment, but it the bacterium is estimated at 1 or 2%. can also be the inaugural phase of the If transmission takes place, clinical mani- disease. It is caused by pathophysiolo- festation of the disease is seen in 5% of gical mechanisms where the role of cases. Lyme disease develops in three Borrelia is indirect; the clinical phases: manifestations observed are the result - the primary phase, in which erythema of autoimmune-like reactions associated migrans is the most common with the presence of bacterial molecules manifestation (77-90% of cases); forming antigenic communities with - the secondary phase of dissemination, joint, neurological and cutaneous tissue in which neurological manifestations components. are the most frequent in France (48%), The clinical expression of Lyme disease is followed by joint manifestations (about highly variable. The different phases may 27%). overlap, and progression from one to the In these two phases, the clinical next is not systematic. Furthermore, the manifestations are directly linked to the early phase may be .

CLINICAL LYME DISEASE 5%

Disseminated infection Erythema migrans as first manifestation 75-90% 14% Neurological Lyme Arthritis disease 48% 27% Spontaneous recovery 92% Treatment 1% 2% Recovery 99% 8% do not overcome Chronic the disease manifestations

Cases of neurological Lyme disease serological testing (80-95% of cases) in either or CSF (presence of IgG). In France, cases of Lyme disease in the disseminated stage are most commonly discovered Negative results in blood serum do not rule out the as the result of neurological manifestations. diagnosis of neurological Lyme disease in the acute phase: investigation for IgG in CSF is essential. Typically, meningoradiculitis in the form of very severe pain at the site of the bite, increasing at Investigation for intrathecal synthesis of specific night, develops after one month. This responds antibodies based on Reiber's hyperbolic formula poorly to pain relief and non-steroidal anti- is required to secure the diagnosis: this makes it inflammatory drugs, and is often accompanied by possible to distinguish between local synthesis and paraesthesia. passive transudation of serum antibodies through the blood-brain barrier. The intrathecal synthesis , a frequent and early index is calculated by comparing the levels of manifestation (within two weeks), presents in the specific antibodies between CSF and serum form of a without meningeal stiffness. collected on the same day and by adjusting the Cranial nerve involvement is frequently found in two compartments based on total IgG levels and children, manifesting as facial paralysis. albumin levels in serum and CSF. Laboratory diagnosis is based on positive DS20-INTGB - June 2017

6/12 4. Laboratory diagnosis Borrelia, but it is not possible to distinguish In accordance with the recommendations between a serological scar and an active from the SPILF ([French Society for infection, even in the presence of IgM. Infectious Diseases] and the EUCALB), The antibodies secreted are not protective. serological diagnosis is performed in two steps: 5. Treatment - Sensitive quantitative detection methods The aim of treatment is to eradicate the - Using automated immunoenzymatic spirochetes present at the lesion sites techniques and to prevent progression to late forms - Separate detection of IgG and IgM of the disease. - Specific qualitative methods for Treatment is based on the recommenda- confirmation tions of the French Society for Infectious - In the event of a positive or Diseases (SPILF) and involves the use of ambiguous result which exert their effect at skin, - Using IgG or IgM joint or meningeal level. Medical pathologists are often confronted Example: with difficulties regarding the interpretation First-line treatment of erythema migrans of the laboratory tests, especially if these in adults: 1g 3x/day for 14 to are prescribed in situations where the 21 days. tests are invalidated (primary phase, after use of antibiotics). In addition, it is necessary to take into consideration a certain level Boutonneuse of prevalence of IgG in healthy subjects in areas. As demonstrated by This disease is caused around the world by Stanek (The Lancet, 2012), the presence approximately twenty species of . of IgG is an indicator of contact with It is characterised by fever, rash and . In France, (also Good practice for serological known as Mediterranean ) diagnostics is caused by and is Serological testing is not to be transmitted in the summer by the dog tick, performed: . - in asymptomatic subjects After 7 days of incubation, a black mark - for systematic screening of exposed subjects appears at the site of the bite, accompa- - in the event of a tick bite without nied by fever with headache and . clinical manifestations Three days later, a maculopapular rash - in the event of typical erythema develops over the entire body. migrans: do not expect antibodies to be present Although usually a benign disease, it has - for systematic serological monitoring potentially serious complications in 5% of of treated patients cases.

The importance of serological In terms of laboratory results, typical findings testing lies in the diagnosis of the are elevated parameters of , secondary and tertiary phases of Lyme , and increased LDH. disease, possibly in combination with Serological testing confirms the diagnosis detection of the bacteria using PCR with the presence of antibodies or elevated (synovial fluid, skin biopsy, CSF) in cases where there is a doubt about the serum concentrations of IgG and IgM. diagnosis. The standard treatment is , or

a quinolone in the event of contraindications. DS20-INTGB - June 2017

7/12 Human granulocytic in Europe. The prevalence of the disease is 1.5% in areas where the vector and the parasite are present; it is greater than Formerly known as HGE or human 10% in patients with Lyme disease. granulocytic , this disease Serological testing makes it possible to was originally described in cattle and is detect contact with the pathogen, but caused by phagocytophilum, investigation of IgM is not validated, and a coccus of the order . dating of the infection is impossible. In spring or summer, 5 to 21 days after a tick bite, the disease is characterised by the onset of acute flu-like illness. It is Other diseases potentially usually benign, but breathing, bleeding or transmitted by ticks renal complications can occur. is caused by Francisella Laboratory results are typically altered, tularensis and is most often associated with neutropenia, thrombocytopenia, and with skin contact with a hare. It can moderate hepatic cytolysis. Careful present in the form of ulceration and examination of blood smears stained with swelling of lymph nodes. MGG can reveal intragranulocytic morulae. TIBOLA (tick-borne lymphadenitis) is a Serological testing involves 2-3 samples: ricksettial disease caused by R. slovaca one early and 2 later at 1 and 2 months. and R. raoultii, and manifests as flu-like IgG and IgM are investigated. illness with enlarged lymph nodes. Apart from in the event of the Cat-scratch disease or aforementioned complications, recovery lymphoreticulosis is caused by is usually spontaneous, however the time henselae; it causes a lesion at the site of to recovery can be shortened by taking initial infection and regional lymphadeno- doxycycline (or rifampicin in the event of pathy. contraindications). , caused by , is usually transmitted by inhalation of conta- minated dust. Ticks can be a vector of Q Fever between humans (or pets) and wild Babesiosis, or piroplasmosis, is well animals, which constitute an important known in veterinary medicine, where it reservoir for the disease. affects dogs and livestock, causing fever, haemolysis and haematuria. In humans, Tick-borne encephalitis is caused by tick- the clinical course of the disease is borne encephalitis virus, a member of severe in asplenic or immunodeficient the genus Flavivirus. It can be found in patients, with intravascular haemolysis France in the regions of Alsace and the and multiple organ failure. In the rest of Vosges. It initially manifests as flu-like the population it can cause a persistent illness. fever. Serological testing can be used to confirm It is caused by a protozoa which has a these diagnoses with good sensitivity and pear shape or Maltese cross formation specificity. in red blood cells and there are approxi- Co-infections with Lyme disease, mately one hundred different species. In babesiosis, anaplasmosis and TBE are humans, B. microti is most common in the possible. These are to be suspected

USA, and B. divergens is most common based on clinical signs. DS20-INTGB - June 2017

8/12 Prevention and action to be References taken in the event of a tick Boulouis H-J, Lagrée A-C, Dugat T, bite Haddad N. Les animaux vertébrés et les maladies dues à des bactéries vectori- sées par les tiques [Vertebrates and tick- Prevention borne bacterial diseases]; RFL 2015 ; 472 During an "at risk" activity (for example, :77- 87. a walk in the forest), it is recommended Socolovschi C, Mediannikov O, Raoult D, to wear clothing that covers bare skin Parola P. Update on tick-borne bacterial and that gathers at the wrists and ankles. diseases in Europe.Parasite 2009; 16: Light-coloured clothing is preferable, in 259-73. order to be able to spot the ticks easily. Glatz I, Hess C, Wurtz E, Camberein V, for the skin or insect- Tytgat F. A propos d’un cas d’anaplasmose repellent clothing can be used (except for granulocytique humaine [A case of human pregnant women and children). granulocytic anaplasmosis]. Upon returning from an "at risk" activity, Spectra biologie 2010 ;181 :47-50. careful examination of the body and scalp Vannier E, Krause PJ, Human babesiosis, is essential, in order to detect and remove NEJM 2010 ;366: 2397-407. any ticks as quickly as possible. SPILF [French Society for Infectious Diseases]. Conférence de consensus What to do borréliose de Lyme [Consensus confe- Ideally, tick removal should be performed rence on Lyme disease], 2006. http:// with a tick-removal tool. Any use of www.infectiologie.com/site/_congres_ alcohol or other chemical products is to conf_org_spilf.php be avoided, because these encourage the Haut Conseil de la Santé Publique tick to regurgitate. [French Public Health Board]. La Once the tick has been removed, the bite borréliose de Lyme,rapport [Report on area should be disinfected and monitored Lyme disease] - March 2014. http://www. for 4 weeks in order to detect possible hcsp.fr/explore.cgi/avisrap- erythema migrans. portsdomaine?clefr=464 Schramm F., Grillon A., De Martino S., Jaulhac B. La borréliose de Lyme [Lyme Disease]. RFL 2013 ;457 :35-49. European Union concerted action on Lyme borreliosis (EUCALB). http://www. eucalb.com/ Institut de Veille Sanitaire [French Institute for Public Health Surveillance]. Dossiers thématiques -la borréliose de Lyme -mise à jour 2014 [Thematic dossiers - Lyme disease - update 2014]. Stanek G., Wormser G.P. Gray J., Strle F. Lyme borreliosis. The Lancet 2012;379:461-73. DS20-INTGB - June 2017

9/12 Summary In the event of a tick bite followed by the presence of clinical signs, the following laboratory tests can be proposed:

Suggestive clinical and Tests to request / Expected biological signs results / Comments Serological screening for IgG/ Primary phase: erythema IgM + confirmatory tests if positive migrans detection Lyme disease Biological signs only present Intrathecal synthesis index (CSF + in the secondary and tertiary blood) for neurological Lyme disease phases of Lyme disease PCR if in doubt Rickettsia serology for IgG and IgM: 2 serums samples at intervals of 2 Fever, rash, eschar, elevated weeks. parameters of inflammation, Boutonneuse fever In France, Mediterranean spotted thrombocytopenia, elevated fever is caused by R. conorii. LDH present or elevated IgG and IgM concentrations.

Anaplasmosis serology for IgG and Flu-like illness IgM: 2 to 3 serum samples: one Human granulocytic Neutropenia, early, then after 1 and 2 months. anaplasmosis thrombocytopenia, hepatic Antibody present or elevated IgG cytolysis and IgM concentrations.

Fever Intravascular haemolysis Serology for babesiosis confirms Babesiosis / multiple organ failure contact. in immunocompromised/ asplenic patients.

Serological testing for Flu-like illness IgG and IgM: 2 serum samples Tularemia Ulceroglandular form. at 2-week intervals Antibody present or elevated IgG and IgM concentrations. Serological testing for Bartonella Inoculation lesion, regional Cat-scratch disease IgG: antibody present or elevated lymph node enlargement IgG concentration PCR Serological testing for Coxiella Fever burnetti: 2 serum samples at an Q Fever Headache, myalgia, interval of 2-3 weeks hepatosplenomegaly Antibody present or elevated IgG and IgM concentrations. Serological testing for tick-borne encephalitis virus (TBEV) IgG/IgM at Tick-borne encephalitis Flu-like illness 2-3 week intervals. (Alsace and Vosges) Antibody present or elevated IgG and IgM concentrations. DS20-INTGB - June 2017

10/12 Practical details for testing at Biomnis

Biomnis Storage and Test Sample test Transport code1 Lyme disease - serological screening 1 mL serum Refrigerated BOR IgG/IgM Borreliosis - serological confirmation IgG2 1 mL serum, CSF Refrigerated WBLYG Borreliosis - serological confirmation IgM2 1 mL serum Refrigerated WBLYM Lyme disease - serological screening - 1 mL CSF Refrigerated BORPL CSF Lyme disease - intrathecal synthesis 1 mL CSF + 1 mL serum Refrigerated BOINT index - IgG - CSF + serum Skin biopsy, joint biopsy, synovial fluid, pericardial Refrigerated - fluid, 0.5 mL CSF Put the (minimum), Borreliosis - direct diagnosis - PCR in a dry tube or BORBM 2 mL (minimum) EDTA with transport whole blood or blood medium (M4RT) derivatives (serum/ plasma) Human babesiosis - serology - serum 1 mL serum Refrigerated PIRO Ricksettial diseases - direct diagnosis Skin biopsy, eschar at Frozen TMP507 - PCR the inocculation site Ricksettial diseases - R. conorii, R. typhi 1 mL serum Refrigerated RICCT - serology - serum Ricksettial diseases - R. helvetica - 1 mL serum Refrigerated RICHE serology - serum Ricksettial diseases - R. prowazecki - 1 mL serum Refrigerated RIPRO serology - serum Ricksettial diseases - R. slovaca and R. 1 mL serum Refrigerated RICAF africae - serology IgG/IgM - serum Tularemia - Francisella tularensis 1 mL serum Refrigerated TUL Tick-borne encephalitis - TBE - serology 1 mL serum Refrigerated TBE IgG/IgM - serum Coxiella burnetii - phase 1 and 2 - 1 mL serum Refrigerated RIB12 serology - serum Coxiella burnetii - serology - serum 1 mL serum Refrigerated RICBU Human granulocytic anaplasmosis - 2 mL serum Refrigerated EHRLI serology - serum Bartonellose - B. henselae - B. quintana 1 mL serum Refrigerated GRIF - IgG serology - serum - direct diagnosis - PCR Lymph node biopsy or aspiration, 2 mL Réfrigéré GRIFB EDTA whole blood, serum or plasma

1You can find all information about the tests offered by Biomnis in the Test Guide at www.biomnis.com; use the code assigned to each test for a quick and easy search. 2 Code cannot be combined DS20-INTGB - June 2017

11/12 Contacts

International Division Eurofins Biomnis 17/19 avenue Tony Garnier BP 7322 69357 LYON Cedex 07 FRANCE Email: [email protected] DS20-INTGB - June 2017

www.biomnis.com

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