• Make a clinical diagnosis of early Lyme disease in people with erythema migrans and a history of a recent tick bite or possible exposure to ticks (recreation, residence, or work in a forested, heathland, or moorland area, or even in suburban parkland).
• Suspect early Lyme disease in people with a history of a tick bite or possible exposure to ticks when they present with any of the following:
• Flu-like symptoms — these may include fever, headache, tiredness, nausea, vomiting, arthralgia (joint pain), and myalgia (muscle pain); there are no significant respiratory symptoms.
• Neurological symptoms — occur in up to 10% of untreated people, and may present days to months after infection. People may present with one or more of the following:
• Unilateral or bilateral facial nerve palsy (or, rarely, other cranial nerve involvement).
• Radiculopathy (usually associated with pain and/or paresis).
• Meningitis or (rarely) encephalomyelitis.
• Mononeuropathy multiplex — involvement of multiple, anatomically unrelated nerves.
• Cardiac symptoms
• Carditis is a rare manifestation of Lyme disease in the UK.
• It may present with syncope (fainting), breathlessness, or chest pain, usually within 2 months of infection.
• An electrocardiogram shows varying degrees of atrioventricular or first-degree heart block.
• Borrelia lymphocytoma
• This is uncommon in Europe, and extremely rare in the US.
• It is a bluish-red, solitary swelling, with a diameter of up to a few centimetres, most often seen on ear lobes or nipples.
• Consider the possibility of late Lyme disease in people with a history of a tick bite or possible exposure to ticks when they present with any of the following:
• Arthritis
• Rare with UK-acquired infection, but more common when the disease is acquired in some other parts of Europe or in the US.
• Involves recurrent brief attacks of joint swelling in one or more large joints (most commonly the knee or, less frequently, a hip, ankle, shoulder, or temporomandibular joint) and occasionally progresses to chronic arthritis.
• A large knee effusion (that is often out of proportion to the pain) is typical and a Baker's cyst may develop and rupture.
• Neurological disease
• Late neurological Lyme disease can present as a slowly progressive central nervous system disorder (encephalomyelitis) or peripheral neuropathy.
• Acrodermatitis chronica atrophicans
• This is an uncommon, bluish-red discolouration and swelling, on the extensor surfaces of legs and arms, that develops several years after infection.
• There is often associated peripheral neuropathy.
• If the person may have been bitten by a tick whilst abroad, consider the possibility of other tick-borne diseases (or possible co-infection), particularly if the person has symptoms atypical of Lyme disease.

These recommendations are based on guidance from the UK Health Protection Agency (HPA) [HPA, 2009e], US [Wormser et al, 2006] and European [Brouqui et al, 2004; Mygland et al, 2010] guidelines, case definitions on clinical features of Lyme disease by the European Union Concerted Action on Lyme Borreliosis [EUCALB, 2008], and narrative reviews [Hengge et al, 2003; Hytonen et al, 2008].

• The recommendation to consider Lyme disease not only in people with a history of a recent tick bite but also in people with a history of possible exposure to ticks (work or recreation in a forested, heathland, or moorland area, or even in suburban parkland) is based on HPA guidance [HPA, 2009e] and on evidence from a systematic review [Tibbles and Edlow, 2007]. The systematic review reported that a history of a known tick bite was present in only 64% (95% CI 52 to 74) of people with erythema migrans in European studies, and in just 26% (95% CI 18 to 37) of people in US studies.
• The recommendation to make a clinical diagnosis of Lyme disease on the basis of the presence of erythema migrans in people with a history of a tick bite or possible exposure to ticks is derived from a US guideline, produced by the Infectious Diseases Society of America [Wormser et al, 2006] which has been endorsed by the HPA [HPA, 2009b], and from a European guideline [Brouqui et al, 2004].
• The recommendation to suspect but not diagnose Lyme disease when suggestive symptoms are present but erythema migrans is absent is based on the US guideline [Wormser et al, 2006]. Reports from observational studies in the US of the proportion of people with Lyme disease without erythema migrans vary from 10% to 16% [Krause et al, 2002; Steere et al, 2003].
• The list of flu-like symptoms is derived from HPA guidance [HPA, 2009e] and a systematic review of history and physical examination findings for the diagnosis of erythema migrans [Tibbles and Edlow, 2007].
• The recommendation to consider other tick-borne diseases, and the possibility of co-infection, is derived from HPA guidance [HPA, 2009e].

• Primary (or solitary) erythema migrans has the following features:
• Appearance (see www.hpa.org.uk for a photo)
• Round or oval in shape; pink, red, or purple in colour.
• Usually flat, but a vesicle or pustule is present at the centre in 5% of people, and the border may be slightly raised.
• There is often a central clearing or a target-like appearance (in 65–80% of people infected in Europe, but in only 20–35% of those infected in the US), or the lesion may be uniformly red (more common in the US).
• Size
• Usually expands over days to weeks.
• Diameter is usually larger than 5 cm (median 16 cm), and can be as large as 1 metre.
• Location
• At the site of a tick bite. However, in Europe, only two thirds of people with erythema migrans recall the tick bite.
• Often on the legs, at flexor creases (knees, axillae, and groins), around the waistband, under the breasts, near to straps (which impede the forward progress of ticks), or (particularly in children) at the hairline or the upper parts of the body.
• Timing
• Typically appears 7–10 days (range 3–36 days) after the tick has detached or was removed.
• An erythematous skin lesion presenting while the tick is still attached or which develops within 48 hours of detachment is most likely to be a tick bite hypersensitivity reaction.
• Associated symptoms
• The rash may be mildly painful or itchy.
• In Europe, around a third of people with erythema migrans experience flu-like symptoms, including fever, headache, tiredness, nausea, vomiting, arthralgia (joint pain), and myalgia (muscle pain). Flu-like symptoms are more common in the US.
• Rarely, neurological features may also be present, but these usually occur later in the disease.
• Secondary (or disseminated) erythema migrans may occur following haematogenous dissemination of infection, resulting in multiple lesions, usually smaller than 5 cm in diameter.
• Erythema migrans may be confused with a number of other skin conditions — see Differential diagnosis.

The description and differential diagnosis of erythema migrans are derived from a US guideline [Wormser et al, 2006], a systematic review of the history and physical examination characteristics for the diagnosis of erythema migrans [Tibbles and Edlow, 2007], guidance from the UK Health Protection Agency [HPA, 2009e], narrative reviews [Edlow, 2002; Hengge et al, 2003; Stanek and Strle, 2003], and a standard textbook [Graham and Cox, 2004], with some modification from CKS expert reviewers.

• A systematic review reported that a history of a tick bite was present in only 64% (95% CI 52 to 74) of people with erythema migrans in a meta-analysis of eleven European studies, and in just 26% (95% CI 18 to 37) of people in nine US studies [Tibbles and Edlow, 2007].
• The locations for erythema migrans of around the waistband and under the breasts were suggested by a CKS expert reviewer.

• Tick bite hypersensitivity reaction
• An erythematous skin lesion presenting while the tick is still attached or which has developed within 48 hours of detachment is most likely to be a tick bite hypersensitivity reaction rather than erythema migrans.
• Tick bite hypersensitivity reactions are usually less than 5 cm in diameter, and itchy; they sometimes have an urticarial appearance, and typically begin to disappear within 24–48 hours.
• Hypersensitivity to an insect bite — develops rapidly, is often itchy, and is usually smaller than erythema migrans (see the CKS topic on Insect bites and stings).
• Other skin conditions to consider include:
• Adverse reaction to a drug — presents as a deep, violaceous plaque. There is no change in size, and it is itchy and often on hands, feet, face, or genitals.
• Bacterial cellulitis — usually occurs on a limb or at site of skin trauma. It presents as uniform erythema (redness), which is warm to touch and painful, and has a faster onset than erythema migrans (see the CKS topic on Cellulitis - acute). It may be present at the same time as erythema migrans.
• Contact dermatitis — the shape or location often suggests the diagnosis; it is often vesicular (see the CKS topic on Dermatitis - contact).
• Discoid eczema — is very itchy and scaly (see the CKS topic on Eczema - atopic).
• Erythema annulare centrifugum — a small, pink papule that slowly enlarges to form a ring with a central clearing. It may be solitary or (more often) multiple, is smooth or slightly scaly at the advancing edge, and is rarely vesicular.
• Erythema multiforme — appears as multiple target lesions (sometimes blisters). The lesions are small (less than 2 cm in diameter), diffuse, and symmetrical, with slow enlargement; palmar and mucosal involvement is common and there is often an obvious precipitant.
• Granuloma annulare — is usually smaller than erythema migrans. The periphery is usually papular, and it can have a central clearing.
• Pityriasis rosea — appears as multiple oval lesions, with peripheral scale and moderate itch; a herald patch on the trunk precedes other lesions by 7–14 days.
• Southern tick-associated rash illness (STARI) — is a similar rash to erythema migrans, and is seen in southern US.
• Spider bite (usually non-UK) — is often necrotic and very painful.
• Tinea (ringworm) — these lesions are characterized by scale and itch (see the CKS topic on Fungal skin infection - body and groin).
• Urticaria — the multiple raised lesions are nettle-like or blotchy, and very itchy; it usually resolves within 24–36 hours (see the CKS topic on Urticaria).

• For all people with suspected Lyme disease, consider seeking advice from a microbiologist, an infectious diseases specialist, or the Lyme Borreliosis Unit on the appropriateness, timing, and type of investigations.
• Testing is not generally considered to be necessary for people with erythema migrans and a history of a tick bite or possible exposure to ticks, as this presentation is sufficient to make a clinical diagnosis of Lyme disease.
• Testing in primary care can be considered for:
• People with a rash suggestive of erythema migrans but without a history of a tick bite or possible exposure to ticks and no other clinical features of Lyme disease.
• People with isolated, unilateral facial palsy (as seen with Bell's palsy) if it is thought that Lyme disease needs to be excluded because of a history of a tick bite or possible exposure to ticks.
• For people with other types of neurological symptoms, or with rheumatological or cardiac symptoms, testing should usually only be carried out in primary care following specialist advice. Many such people will require hospital admission or urgent specialist assessment.
• To test for Lyme disease, take a blood sample for antibodies to Borrelia burgdorferi.
• If the result is negative and the sample was taken within 2 weeks of the onset of symptoms, repeat the test 2 weeks later.
• If the initial result is borderline or positive (by enzyme immunoassay), the same sample will be retested by the laboratory, using immunoblot or Western blotting, to confirm the result.
• The enzyme immunoassay has low specificity (a high false positive rate) and can be positive with other conditions (including glandular fever, syphilis, rheumatoid arthritis, other autoimmune conditions, and some neurological conditions).

These recommendations are based on European and US guidelines on the diagnosis of Lyme disease [Brouqui et al, 2004; Wormser et al, 2006], guidance from the UK Health Protection Agency [HPA, 2009e], and on comments from CKS expert reviewers.

• The basis for recommendations on who to investigate is covered in the Basis for recommendation for How to manage suspected Lyme disease.
• Antibodies to Borrelia burgdorferi are not detectable in the first 2–4 weeks following infection.
• Second-stage immunoblots help to reduce false-positive reporting.