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For further details, click on the DIAGNOSTIC SUPPORT TOOL underlined words. Localized and disseminated stages of

This diagnostic support tool is intended mainly for primary care clinicians. It is provided for information purposes only and should not replace the judgement of the clinician who performs the activities reserved under a statute or regulation. The recommendations in this tool were developed using a systematic process and are supported by the scientific literature and the knowledge and experience of Québec health professionals, experts and patients. For further details, go to the “Publications” section of INESSS’s website inesss.qc.ca. This tool does not deal with other -borne infections or with the much-debated form of Lyme disease, which is sometimes referred to as the chronic form.

WHAT IS LYME DISEASE ? WHAT ARE THE DIFFERENT STAGES OF THE DISEASE? GENERAL INFORMATION

• Lyme disease is an infectious disease caused by bacterial Localized stage (sometimes called the early stage): Beginning Patient with a tick genospecies of burgdorferi, which are transmitted of the infection before dissemination of the bacteria in the • If tick is attached, refer to the procedure for removing it. to humans by black-legged that are carriers. bloodstream. • Refer to the tick surveillance procedure. • Main manifestation observed: • It is a notifiable disease (MADO) • Consult the decision support tool or the Québec’s national and is on the increase in Québec. Ž Not always present or noticed. medical protocol on post-exposure prophylaxis. • It can affect several anatomical systems at the same time. Ž If present, usually appears • Identifying the tick and obtaining proof that it carries of Lym 3 to 30 days after infection or e d B. burgdorferi are not required in order to make the diagnosis. ct is Isolated cutaneous manifestation but can appear up to 3 months e e a (isolated migrans) post-bite. v s e e h Disease’s presentation T Early disseminated stage • The presentation, the severity of the manifestations, their duration and Bacterial dissemination via the bloodstream. the speed of progression of the disease from one stage to the next • Generally occurs when the local infection has not been T h k vary from patient to patient. Arthritis can be the first manifestation. e ic detected or has not been treated effectively. bl d t ack-legge • Occurs a few days after isolated • The manifestations are not mutually exclusive. Isolated erythema to a few weeks after infection (usually up to 6 months migrans can persist during the early disseminated stage. of Lym post-bite). • Clinical cases can occur throughout the year. Isolated or e d ct is e e • Can include general systemic symptoms. erythema migrans is less common in the winter. a v s e e • Main manifestations observed: • It is difficult to link the symptoms to when the bite occurred because the bite h T often goes unnoticed, can be repeated and does not always lead to an infection.

T h ck e b ti lack-legged Diagnostic principles Cutaneous (multiple Neurological Cardiac • The diagnosis is based on the entire clinical picture. erythema migrans) () (Lyme carditis) • Serological tests are not always indicated. If they are, they serve to complement and should be interpreted in light of the clinical picture. Late disseminated stage Complication of the early disseminated stage. • It is not necessary for the exposure to have occurred in a high-risk area or for the bite to be documented to make the diagnosis. • Occurs a few weeks or even a few months after infection (usually up to a year post-bite). • Main manifestation observed in North America: Management and monitoring • Management depends on the manifestations present (consult the OUG). • The effectiveness of the treatment is evaluated Articular clinically, not with serological tests. (Lyme arthritis)

UPDATED MARCH 2021 2 / 11

When to consider Isolated or multiple cutaneous manifestation Neurological manifestation Cardiac manifestation Musculoskeletal manifestation Lyme disease

Evaluating the clinical picture How to make • Assess the exposure risk: lifestyle, outdoor activities (recreation and work), geographical areas (residence or visited – potential risk throughout Québec), the diagnosis being around pets that have been outdoors. • Perform a physical examination that includes a neurological examination (look for erythema migrans and manifestations of the disseminated stages). • Consider other possible clinical conditions.

Clinical picture consistent with Lyme disease (the three items listed above included)

Nontypical isolated Multiple skin lesions Nontypical isolated EM skin lesion EM skin lesion Typical isolated EM documented, with or without and/or cardiac Articular involvement documented, with no other documented, with other manifestations OR involvement and/ with or without manifestations of the early other manifestations • Circular or oval redness or neurological other manifestations disseminated stage of the early involvement • Diameter of at least 5 cm disseminated stage • Annular or homogeneous (not always bull’s-eye-like in appearance) Serological test Serological test Serological test • Can be very pale and have poorly defined contours Have discussion to determine if initiating Have discussion to determine • Lasts for at least 48 hrs treatment before receiving serology results if initiating treatment before Lesion < 5 cm Lesion ≥ 5 cm is indicated receiving serology results is indicated

Monitor expansion (24-48 hrs) • Mark contour and take photo Result Result Serological test Result Result • Do not rule out the diagnosis • Reconsider other conditions • Make the diagnosis Confirmed Not confirmed Reevaluation • Do not rule out • MADO notification • Discuss the diagnosis

Reevaluation • Reconsider Serological test 4-6 weeks later, other conditions if indicated • Discuss • Make the diagnosis • Refer patient to Initiate • Discuss a specialist, if • Make the diagnosis • MADO • Tell the patient necessary treatment (OUG) • MADO notification the symptoms of Result Result notification the disseminated stages they should Several anatomical systems can be affected at the same time. watch for, even if the If the patient is symptomatic, refer • Discuss • Discuss It is not unusual for general systemic symptoms to be present. diagnosis has been him to a microbiologist and infectious ruled out • Initiate treatment disease specialist, an internist or a • Initiate The diagnosis is based on the entire clinical picture, which serological tests (OUG) pediatric infectious disease specialist treatment (OUG) serve to complement.

Action to be taken after a joint discussion with one or Talk to one or more medical specialists Indicate the possible continent(s) of exposure on the requisition Not indicated Indicated more medical specialists or an experienced colleague or an experienced colleague and when the first symptoms appeared (if known) 3 / 11

1 ISOLATED CUTANEOUS MANIFESTATION

Isolated EM: An isolated erythematous skin lesion that persists or even progresses for several days. Erythema migrans generally expands concentrically from the bite site to a diameter of 5 cm or greater. It is associated with little or no pain or itching. However, its features (size, shape and appearance) and duration vary considerably from patient to patient. Although a bull’s-eye lesion (concentric redness) is not always due to Lyme disease, it is highly suggestive of it in cases of high-risk area exposure. • Starts during the localized stage but can persist during the early disseminated stage. • Usually appears 3 to 30 days after infection but can appear up to 3 months post-bite.

Typical isolated EM Other possible but less typical features of EM • Circular or oval redness (not necessarily present at the same time) • At least 5 cm in diameter (does not progress consistently, so is not always appreciable) • Diameter less than 5 cm (progression generally noticeable) • Can be annular or homogeneous (not always bull’s-eye-like in appearance) • Can be hemorrhagic • Can be very pale in appearance, with poorly defined contours • Can have vesicles, scales, crusts or petechiae • Lasts at least 48 hours • Can have a shape other than circular, annular or oval

The absence of EM should not be used to rule out Lyme disease because it is not always present or noticed.

Isolated EM vs. local hypersensitivity reaction

Early EM more likely if: Hypersensitivity reaction more likely if: If in doubt about the nature of the redness, it is advisable to monitor • Redness appears a few days post-bite • Redness appears within the first 24 hours post- its course and to wait for 24 to 48 hours, the patient’s overall • Gradually expands for several days bite and regresses in a few days condition permitting. (the most specific criterion) • Is pruriginous (but not always) • Size ≥ 5 cm (but can be smaller) • Size < 5 cm To monitor the course of the redness: • Mark the contour and measure the diameter of the redness during the visit. A photo of the redness before and after monitoring may make comparison easier.

Isolated EM vs. infectious

Isolated EM more likely if: Infectious cellulitis more likely if: If in doubt about the nature of the redness, a therapeutic approach • Expands concentrically • Expands proximally suitable for both types of lesion can be adopted (consult the OUG). • Little pain • Pain • Little heat • Heat

Isolated EM vs.

Isolated EM more likely if: Contact dermatitis more likely if: If in doubt about the nature of the redness, it is advisable to discuss • Little itching • Pruriginous or burning sensation the case with a medical specialist or an experienced colleague. • Circular or oval shape • Highly variable shape • Lesion smooth and not scaly • , vesicles or scales

EM : erythema migrans. Photos available as a diagnostic aid Back to algorithm 4 / 11

2 MULTIPLE CUTANEOUS MANIFESTATIONS

Multiple erythema migrans : A set of erythematous skin lesions that appear after bacterial dissemination. Although they may share certain features of isolated erythema migrans, their presentation (number, colour, shape, appearance and extent) varies widely. • A manifestation of the early disseminated stage. • Appear a few days after the isolated EM to a few weeks after infection (usually up to 6 months post-bite).

The lesions: • May share certain features with isolated EM • May be less than 5 cm in diameter • Are often pale, raised or macular, smooth and non-scaly

Back to algorithm 5 / 11

ISOLATED ERYTHEMA MIGRANS

1 Granby 2 Granby 3 Saint-Hyacinthe 4 Saint-Hyacinthe 5 Saint-Hyacinthe 6 Saint-Hyacinthe 7 Saint-Hyacinthe 8 Saint-Hyacinthe

9 © CDC (USA) 10 © LDA (UK) 11 © Hofmann et al. 2017 12 © Hofmann et al. 2017 13 © Hofmann et al. 2017 14 © Hofmann et al. 2017 15 © LDA (UK)

16 © Hofmann et al. 2017 17 © LDA (UK) 18 © PCDS (UK) 19 © Cureus 20 © New York Times 21 © Brown Skin Matters

MULTIPLE ERYTHEMA MIGRANS OTHER CONDITIONS

22 Saint-Hyacinthe 23 Granby 24 © PCDS(UK) 25 Local hypersensitivity reaction 26 Infectious cellulitis 27 Contact dermatitis

Source: All the photos in this tool were reproduced with their authors’ permission. For further details on the sources of these photos, consult the supplemental appendices to the report in support of this tool. Back to algorithm 6 / 11

3 MAIN MANIFESTATIONS SUGGESTIVE OF LYME DISEASE OTHER THAN ISOLATED OR MULTIPLE EM (list not exhaustive; more rarely, other systems can be affected as well1)

Definition Symptoms Signs and presentation

Neurological manifestations Neuroborreliosis: involvement of the nervous system • Facial palsy (sometimes bilateral) • Cranial (peripheral or central) or the meninges in response to the • Facial numbness • Facial palsy bacterial dissemination. The neurological manifestations • Deafness • Other involvement of the cranial nerves is possible vary according to the location of the inflammatory foci and • Diplopia can occur alone or in combination. Some occur as soon as the bacteria spread, while others are more rare and occur months later. • Lower motor neuron-type weakness affecting • Mononeuropathy • A manifestation of the early disseminated stage. one or more nerve or root territories • Multiple mononeuritis • Occurs a few days after isolated EM to a few weeks • Paresthesia or hypoesthesia affecting • with no other cause after infection (usually up to 6 months post-bite). one or more nerve or root territories • Plexopathy • Abolition of one or more deep tendon reflexes

• Headache • Aseptic • Nuchal pain or stiffness • Photophobia • Nausea • Vomiting

Cardiac manifestations Lyme carditis: cardiac involvement in response to • Palpitations • Atrioventricular block (1st to 3rd degree) More rare in children the bacterial dissemination. Its main manifestation is • Dizziness • Nonspecific arrythmia (SVES/VES) atrioventricular block. • Syncope • Pericardial syndrome (with or without block) • A manifestation of the early disseminated stage. • Chest pain • Heart failue (rare) • Occurs a few days after isolated EM to a few weeks • Dyspnea after infection (usually up to 6 months post-bite).

Musculoskeletal Lyme arthritis: inflammation of one or a few joints that • Joint swelling often worse than the pain • Swelling of one or more joints (mainly the knee, manifestations begins a few months after the bacterial dissemination. The and the other associated symptoms but other, smaller joints can be affected) Only joint involvement is one inflammatory episodes can last for several weeks or even • In most cases, the knee is affected • Possible flare-up of arthritis alternating with of the main manifestations several months, alternate with episodes of remission and periods of remission without treatment Common in North America migrate from one joint to another. • A manifestation of the late disseminated stage. • Occurs a few weeks or even a few months after infection (usually up to 1 year post-bite).

1. For example, the ocular system (non-neurological eye involvement: , keratitis, conjunctivitis, episcleritis, retinitis and choroiditis). EM: erythema migrans; VES: ventricular extrasystole; SVES: supraventricular extrasystole. Back to algorithm 7 / 11

4 GENERAL SYSTEMIC SYMPTOMS (list not exhaustive)

These symptoms may occur a few days after isolated EM to a few weeks after infection (usually during the first 2 months post-bite).

• and chills • Muscle pain • Headache • Asthenia • Malaise • Joint pain • Isolated lymphadenopathy • Lethargy • Fatigue • Concentration and memory problems • Flu-like syndrome • Anorexia (consistent with LD, particularly if it occurs during the summer) • Mononucleosis syndrome (consistent with LD, particularly if it occurs during the summer)

EM: erythema migrans; LD: Lyme disease. Back to algorithm 8 / 11

5 CLINICAL PICTURE – TICK EXPOSURE RISK ASSESSMENT AND PHYSICAL EXAMINATION

Tick exposure risk Consistency of certain information with LD

Lifestyle • Lifestyle and outdoor activities (recreation and work): Consistency with LD Information à Ticks prefer damp places (woods, wooded areas and fields, but also gardens, Low Moderate High landscaped areas and piles of leaves). Duration of attachment < 24 hrs if tick is flat, not • Tick transported by a person or a pet: < 24 hrs if tick engorged > 24 hrs à Short survival in household climate (susceptible to desiccation); (if bite documented) engorged à If attached, no significant risk to persons around the individual because ticks Areas not at high risk Location of exposure Environment not conducive High-risk area identified generally take a single blood meal per developmental stage; where the environment is (residency or place(s) to tick survival (e.g., the by the INSPQ or near such conducive to tick survival - If present, sign of tick exposure, since other ticks may have been visited) Northern Québec) an area transported. (e.g., Québec City) Location of exposure Exposure associated Very unlikely Unlikely Possible • In Québec, there is a potential risk throughout the province: with lifestyle à Risk higher in certain areas identified by the INSPQ; à Lower where the environment is less conducive to tick survival. By integrating all the gathered information, the clinician A documented bite: • Risk present in other Canadian provinces, the United States, Europe, North can determine whether or not the clinical picture is à Is evidence of tick exposure; consistent with Lyme disease. Africa and Asia. à Is not necessarily the one at the origin of the infection; à Example: A patient for whom tick exposure is very Season à Estimate of the duration of attachment not always reliable; • Potential risk throughout the year: unlikely, based on their lifestyle, may nevertheless have a clinical picture consistent with LD if they live in an area à Not necessary for making the diagnosis. à Higher in the summer; where there is a high risk of contracting Lyme disease. Possible location of exposure à Minimal in the winter in Québec; Non-tick transmission of the bacterium is poorly à Not necessary to have been in a high-risk area to make à Independent of the season when traveling to places where the environment the diagnosis. documented in the scientific literature and probably rare. is conducive to tick survival.

Physical examination Course of the disease if untreated

• Look for isolated EM, as its presence facilitates the diagnostic process. Often Isolated cutaneous manifestation located in places where the tick can go unnoticed and stay attached for a long of Lym or e d ct is e e period of time: a Multiple cutaneous manifestations v s e e à Examples: chest, , inguinal area, popliteal fossa, lower buttocks, lower h T Neurological manifestations back, scalp, behind the ears, eyebrows, navel and between the toes. Cardiac manifestations • Look for other manifestations of the disseminated stage, since: T h ck e b ti à The constellation of several manifestations can facilitate the diagnostic lack-legged Articular manifestations process; 1 month 2 months 3 months 4 months 5 months 6 months 12 months à Management depends on the manifestations present (especially neurological manifestations; peripheral nervous system vs. central nervous It is difficult to link the symptoms to when the bite occurred Arthritis can be the first manifestation of LD and have been system and meningitis). because the bite often goes unnoticed, can be repeated and present for a long period of time. does not always lead to an infection. Available scientific data do not enable to rule on the The presentation, the severity of the manifestations, their plausibility that Lyme disease bacteria cause, directly or duration and the speed of progression of the disease from one indirectly, general systemic symptoms that persists. stage to the next vary from patient to patient. It is not unusual for general systemic symptoms to be present. They can occur a few days after EM to a few weeks after infection (usually during the first 2 months post-bite).

EM: erythema migrans; hr: hour; INSPQ: Institut national de santé publique du Québec; LD: Lyme disease. Back to algorithm 9 / 11

6 CLINICAL PICTURE – OTHER POSSSIBLE CLINICAL CONDITIONS (list not exhaustive)

When ranking the differential diagnoses, it is important to take the patient’s clinical picture into account, including the possibility of tick exposure and where the exposure occurred.

Cutaneous system Isolated lesion • Local hypersensitivity reaction due to a bite • • STARI • Nummular eczema • Late phase • • Fixed • Solitary • Infectious cellulitis • Contact dermatitis • • • Cutaneous infection or herpes zoster

Multiple lesions • Local hypersensitivity reaction due to a bite • Fixed drug eruption • Erythema annulare centrifugum • Urticaria • Granuloma annulare • Subacute cutaneous erythematosus • • Erythema nodosum • Urticarial • Pityriasis rosea • • Sweet’s neutrophilic dermatosis

Nervous system Facial palsy (more • Idiopathic facial palsy (Bell’s palsy) • Guillain-Barré syndrome • Facial palsy secondary to tumoural processes common, sometimes • Herpes zoster oticus (Ramsay • Facial palsy secondary to other infectious • Sjögren’s syndrome bilateral) or other cranial Hunt syndrome) processes (e.g. HIV or ) • Skull base meningitis nerve involvement • Mastoiditis, otitis media • Sarcoidosis ()

Aseptic meningitis • Viral meningitis • Fungal meningitis (cryptococcosis, • Drug-induced meningitis • Syphilitic meningitis ) • Tuberculous meningitis • Leptomeningeal carcinomatosis

Peripheral neurological • Secondary nerve root compression • Vasculitis and connective tissue diseases • Spondylodiscitis, epidural involvement: (e.g., mechanical involvement, for instance, • Idiopathic brachial plexopathy • Leptomeningeal carcinomatosis multiple mononeuritis, foraminal stenosis or herniated disc) (Parsonage-Turner syndrome) polyradiculopathy, • Mono/polyradiculopathy caused by another • Diabetic lumbosacral plexopathy plexopathy pathogenic agent (e.g. HIV or syphilis) (Bruns-Garland syndrome)

Cardiac system • ASHD • AAR • Congenital/acquired heart defect • Atrioventricular block (more common) • Medication (e.g. β-blockers) • Bacterial infection (e.g. Y. enterolitica) • Sarcoidosis • Myo/pericarditis • Viral infections (e.g. coxsakie) • Parasitic infection • Arrhythmia • Connective tissue diseases • Rocky Mountain spotted fever • Kawasaki disease

Musculoskeletal system • Spondyloarthritis (other than reactive), • Reactive arthritis • Connective tissue diseases or vasculitis • Arthritis (more common) psoriatic arthritis and arthritis associated • Septic arthritis • Microcrystalline arthritis with inflammatory bowel disease • RA • Gout • Juvenile idiopathic arthritis • Parvovirus B19 infection (5th disease) • Post-infectious arthritis

Other tick-borne diseases/Co-infection • • Borrelia miyamotoi infection • Viral arbovirosis • Babesiosis • STARI (e.g. Powassan encephalitis)

AAR: acute articular rheumatism; ASHD: atherosclerotic heart disease; HIV: human immunodeficiency virus. RA: rheumatoid arthritis; STARI: Southern tick associated illness. Back to algorithm 10 / 11

7 TWO-TIER SEROLOGY

Refer to the two-tiered serology clinical tool for more details on this laboratory analysis.

Indication

Indicated Not indicated • Manifestations of the early and late disseminated stages if the clinical picture is consistent • If isolated EM, because the sensitivity is too low at this stage and because the result with Lyme disease and there is no typical isolated EM at the same time. would probably be negative (a single exception is presented in the algorithm). • For evaluating the effectiveness of therapy because the antibodies can stay in the bloodstream for a long period of time.

Diagnostic value of two-tier serology (North American tests)

• Screening test (ELISA) more sensitive and less specific than the confirmation test • Sensitivity low for Lyme disease contracted in Europe, Asia or North Africa because the (immunoblotting / Western blot). Used sequentially for better sensitivity and specificity. B. burgdorferi genospecies are different. If need be, different immunoblotting tests • Sensitivity low at the beginning of the infection (25 to 60%, depending on the study and the method) and are used (differences in terms of the choice of antigens and positivity criteria). increases gradually with time (40 to 100%, depending on the manifestation, the study and the method). • Sensitivity high in patients with Lyme arthritis (95 to 100%, depending on the study and the method).

Immunoblotting test and positivity criteria

• Performed only on specimens with a positive or equivocal screening test result. • Positivity criteria recommended by the CDC and used in Canada and the United States: • Consists of two separate assays, one measuring IgM, the other, IgG. à Positive IgM test: at least two bacterial antigens in three are recognized; à Positive IgG test: at least five bacterial antigens in ten are recognized.

Interpreting the results of two-step serological tests Laboratories that perform two-tiered serology

• IgG positive result regardless of the IgM one in a patient with no manifestations suggestive • Public laboratories and a number of private laboratories perform these tests and interpret of Lyme disease: the results in accordance with the CDC’s recommendations. à does not point to Lyme disease because the tests do not distinguish between active and past infection. • Some private laboratories: • Positive IgG result (IgM positive or negative) in a patient with manifestations suggestive à Do not perform the two tiers of the serology in sequence; of Lyme disease: - Risk of false positives if Western blot is used alone à element in favour of the diagnosis that should be used to complement the clinical picture. à Use Western blot tests that differ from those recommended in at least one of the following respects: The diagnosis is based on the entire clinical picture, which serological tests serve to complement. - The choice of antigens • Positive IgM result and negative IgG: - The number of antigens used à High probability that it is a false positive, especially if the patient has had symptoms for more than 6 weeks. - The positivity criteria used (possibility of a large number of false positives) If Lyme disease is strongly suspected, consider talking to an experienced colleague or a medical specialist à Use non-validated tests on which there is little or no scientific literature to determine if a new requisition for serological tests is needed 4 to 6 weeks later. (e.g. the detection of antigens in urine). • Negative IgM and IgG result in a patient with manifestations suggestive of Lyme disease: à Does not rule out Lyme disease without an evaluation of the entire clinical picture because: - The tests are dependent on the establishment of the immune response; - The various B. burgdorferi genospecies and their different strains do not all elicit an immune response against the same antigens (e.g. European strains).

CDC: Centers for Disease Control and Prevention; ELISA: enzyme-linked immunosorbent assay; EM: erythema migrans; Back to algorithm IgG: immunoglobulin G; IgM: immunoglobulin M 11 / 11

MAIN REFERENCES

HAS (2018). Recommandation de bonne pratique - Borreliose de Lyme et autres maladies vectorielles à tiques, Haute autorité de santé:9. Institut national d’excellence en santé et en services sociaux (INESSS). Du diagnostic au traitement de la maladie de Lyme aux stades localisé et disséminés. Rapport en soutien aux outils d’aide à la décision clinique sur le diagnostic et le traitement. Québec, Qc: INESSS; 2019. Available at: https://www.inesss.qc.ca/en/publications/publications/publication/maladie-de-lyme.html. Institut national d’excellence en santé et en services sociaux (INESSS). Valeur diagnostique des analyses de laboratoire pour la maladie de Lyme aux stades localisé et disséminés. Québec, Qc : INESSS ; 2021. Available at: https://www.inesss.qc.ca/en/publications/publications/publication/maladie-de-lyme.html. Institut national d’excellence en santé et en services sociaux (INESSS). Maladie de Lyme dite chronique : état actuel des connaissances scientifiques et portrait des différentes perspectives. Québec, Qc : INESSS ; 2021. Available at: https://www.inesss.qc.ca/en/publications/publications/publication/maladie-de-lyme.html. National Institute for Health and Care Excellence (2018). Lyme disease, NICE guideline. Wormser, G. P., R. J. Dattwyler, et al. (2006). «The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.» Clin Infect Dis 43(9): 1089-1134.DOI: 10.1086/508667