Top Tips: Lyme Disease

Dr Roger Henderson Shares Seven Top Tips on the Identification and Management of this Tick-Borne Infection in Primary Care

Lyme disease is an infection caused by spirochaete bacteria belonging to the Borrelia genus, which includes Borrelia burgdorferi.¹ The condition is similar to syphilis in that it is caused by spirochaete bacteria and exhibits staged clinical presentations.² It is named after the town of Lyme in Connecticut, where a group of patients with the disease were investigated in the 1970s.^2,3 The infectious disease was determined to be transmitted to humans through the bites of infected ticks.³ 

Current Guidance on Lyme Disease

NICE published NICE Guideline (NG) 95, Lyme disease, in April 2018.⁴ The guideline aims to facilitate earlier diagnosis of the condition, and ensure its timely treatment with the appropriate antibiotic.⁴ Because of variation in the definitions of chronic Lyme disease and post-Lyme disease around the world, NG95 concentrates on diagnosis and management according to symptoms rather than classifications.⁴ Prior to the publication of NG95, variation in these definitions was compounded by conflicting guidelines on the condition from the Infectious Diseases Society of America and the International Lyme and Associated Diseases Society.^2,5,6 The situation was further complicated by the fact that different strains of Borrelia cause different clinical manifestations—in the US, B. burgdorferi is the main strain and is predominantly associated with arthritis, whereas in Eurasia, the strain B. garinii more often causes neurological symptoms.⁷

The Rising Incidence of Lyme Disease

Data from the UK Health Security Agency (UKHSA) show that the incidence of Lyme disease has risen steadily in England and Wales since the 1980s, but has decreased slightly since 2018, possibly as a result of changes in human behaviour or diagnostics associated with the COVID-19 pandemic.¹ Lyme disease is not a notifiable disease in the UK but—since October 2010, under the Health Protection (Notification) Regulations 2010⁸—every microbiology laboratory in England (including those in the private sector) is required to notify the UKHSA of all laboratory diagnoses of Lyme disease.¹ Given that diagnoses made on clinical grounds alone are not included, this means that case numbers may be an underestimate.⁴ However, the condition remains relatively rare, with cases peaking in the summer months and mainly affecting two age groups: those aged 45–64 years, followed by those aged 25–44 years.¹ The condition affects men and women equally.¹

This article provides seven top tips on the assessment and management of Lyme disease in primary care.

1. Identify the Clinical Signs and Stages of Lyme Disease

In the UK, Lyme disease is classified as early (stage 1 or localised), disseminated (stage 2), or late (stage 3).² The symptoms of Lyme disease depend on the disease stage—there is a wide range of symptoms for each stage, perhaps reflecting the challenge of diagnosing the condition, although some people remain asymptomatic.² 

Early Disease (Stage 1)

The classical presentation of early Lyme disease is a rash, termed erythema migrans (see Figure 1), and this may be the only presenting feature.¹ Found in 65–80% of infected people in Europe,⁹ this has the characteristic appearance of a circular rash that radiates from the bite, which usually becomes visible 1–4 weeks (but can appear between 3 days and 3 months) after a tick bite.^4,10–12 The rash is typically pinkish in appearance, is not usually itchy, hot, or painful, and can have a characteristic ‘target’ or ‘bullseye’ appearance of central erythema with a clearing around it and a diameter greater than 5 cm.⁹ In non-European countries, this target appearance may be less likely to occur, creating a greater diagnostic challenge.⁹ The rash usually resolves, and there may be associated nonspecific flu-like symptoms,⁹ as well as cognitive impairment (sometimes described as ‘brain fog’) and fatigue.⁴

Figure 1: Erythema migrans

Disseminated Disease (Stage 2) 

The second disease stage can occur weeks to months after being bitten, and is characterised by multiple lesions, usually smaller than 5 cm in diameter, generated as a result of haematogenous dissemination of infection.^9,13 However, this is still considered a feature of a relatively early infection.² A flu-like illness may be present (this is more common in the US).⁹ In Europe, the second most common group of presentations after erythema migrans is neurological problems (neuroborreliosis).² These may include facial nerve palsies,¹¹ meningitis,¹¹ mild encephalitis,² and mononeuritis multiplex.² Myocarditis may also occur, but this is rare.²

Late Disease (Stage 3)

Late manifestations may include arthritis in the larger joints,¹⁴ vertigo,¹⁵ uveitis,⁴ pericarditis,⁴ polyneuropathies,¹³ and symptoms similar to fibromyalgia or chronic fatigue syndrome, known as ‘post-Lyme syndrome’–although this remains a point of much debate.²

2. Consider Alternative Diagnoses for Erythema Migrans

When examining an erythema migrans rash, primary care practitioners should consider possible differential diagnoses. In the UK, these typically include:¹⁶

• tick bite hypersensitivity
• hypersensitivity to an insect bite 
• cellulitis
• erythema multiforme
• granuloma annulare
• nummular (discoid) eczema 
• tinea (ringworm)
• urticaria
• conditions usually acquired when travelling outside of the UK, such as tick-borne encephalitis, spider bite, or Southern tick-associated rash illness.

3. Know When to Perform Diagnostic Testing

NICE Quality Standard 186

Often, making a firm diagnosis presents the greatest challenge; because of this, NICE has published a quality standard on Lyme disease.¹⁷ The guidance contains two quality statements that relate to diagnosis (see Box 1).¹⁷

The rationale for statement 2 is that there is a possibility of an initial false-negative test result. Test results may also be falsely negative if there is a reduced immune response, such as may occur if the patient is taking immunosuppressant medication.^4,17

The NICE-Recommended Testing Pathway

Testing for Lyme disease—including when to do so—remains contentious,¹⁸ depending on which global guidelines are followed. The NICE-recommended pathway is shown in Figure 2.¹⁹ 

Figure 2: Lyme Disease—Laboratory Investigations and Diagnosis¹⁹

In short, if a patient has tested negative within 4 weeks of the onset of their symptoms and Lyme disease is still suspected, the enzyme-linked immunosorbent assay (ELISA) test should be repeated 4–6 weeks after the first test.^10,20 If a person has suspected Lyme disease symptoms for 12 weeks or more, an immunoblot test should be undertaken.¹⁰ If the immunoblot is positive, then it is safe to diagnose Lyme disease and start antibiotic treatment.¹⁰ If the immunoblot is negative but symptoms persist, clinicians should consider a discussion with, or referral to, a specialist (regardless of the ELISA result) to review whether further tests are required or consider alternative diagnoses.¹⁰ If the immunoblot result is negative and symptoms have resolved, no treatment is required.¹⁰

NICE recommends that clinicians should always be cautious about diagnosing Lyme disease in people without a supportive history or positive serological test result because of the risk of missing an alternative diagnosis or providing inappropriate treatment.¹⁰

UKHSA guidance advises that anyone who has had a positive test result for Lyme disease in a non-NHS laboratory setting should have it repeated in an NHS laboratory.²⁰ 

4. Understand the Importance of Timely Antibiotic Treatment

If patients are diagnosed and treated properly with the appropriate therapy, Lyme disease is usually curable and is rarely fatal,² even though there is no ‘test of cure’ or vaccine against the condition.^4,12 Initial treatment should be with antibiotics, with the dose, duration, and type determined by the symptoms.¹⁷ 

For people diagnosed with Lyme disease (or with a high suspicion of Lyme disease awaiting test results), without focal symptoms but with erythema migrans and/or nonfocal symptoms, NICE recommends prescribing oral antibiotics as follows:⁴

• for adults and children (aged 12 years or older) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in Table 1 (note that for Lyme disease suspected during pregnancy, use appropriate antibiotics for the stage of pregnancy [see the recommendation in NG95 on assessing and diagnosing Lyme disease in the section on management for women with Lyme disease during pregnancy and their babies])
• for children (under 12) diagnosed with Lyme disease, offer antibiotic treatment according to their symptoms as described in Table 2 (note that management of Lyme disease in children and young people should be discussed with a specialist in line with recommendation 1.3.2 in NG95).

Table 1: Antibiotic Treatment for Lyme Disease in Adults and Young People (Aged 12 and Over) According to Symptoms⁴

Table 2: Antibiotic Treatment for Lyme Disease in Children (Under 12) According to Symptoms^4,[A]

Jarisch–Herxheimer Reaction

A Jarisch–Herxheimer reaction can occur in as many as 15% of individuals within the initial 24 hours of starting antibiotic treatment for Lyme disease.^4,10 This systemic reaction is thought to be caused by the release of cytokines when antibiotics kill large numbers of bacteria.¹⁰ Symptoms of this reaction include fever, chills, muscle pains, and headache, and can sometimes be mistaken for an allergic reaction to the antibiotic.¹⁰ The reaction can start between 1–12 hours after antibiotic therapy is started, but can also occur later, and can last for a few hours or 1–2 days.¹⁰ Fortunately, this reaction is self-limiting, and typically resolves within 24–48 hours.¹⁰ Provided that the symptoms are not severe and there is no evidence of an allergic reaction (such as urticaria), the person should be advised to continue the antibiotic.^4,10 If a patient has ongoing symptoms of Lyme disease following two completed courses of antibiotics, it is no longer recommended that further antibiotics are routinely offered.^4,10

5. Advise on the Prevention and Removal of Ticks

When advising patients about avoiding tick bites, remind them that the most effective strategies include:^10,12

• wearing protective clothing such as long trousers and long-sleeved shirts
• using tick repellents
• keeping to paths and away from long grass or overgrown vegetation
• showering or bathing after returning from a tick-infested area
• checking skin periodically for attached ticks—these should be removed with tweezers or fine-pointed forceps, grasping the tick as closely as possible to the skin, pulling gently upwards, and trying not to break off the mouth parts
• when checking for ticks, paying particular attention to skin folds, as ticks seek out more humid areas for attachment—the head (including the scalp and hairline) and neck area of young children should also be checked carefully, as tick bites are relatively more common at these sites in this age group.

Patients should be advised not to burn the tick off (for example, using a lit cigarette or match head), or apply any substances to the tick (for example, petroleum jelly, alcohol, or nail varnish remover).¹⁰ These actions could cause the tick to regurgitate potentially infected material into the skin.¹⁰ After removal, patients should be encouraged to clean the skin with soap and water or skin disinfectant, and wash their hands.¹⁰

6. Be Aware of the Long-Term Effects of Lyme Disease

A small proportion of patients with Lyme disease may report subjective symptoms (such as fatigue, musculoskeletal pain, and neurocognitive symptoms) for months or—in some cases—years after appropriate antibiotic therapy, without any evidence of ongoing infection.^2,6,18,21 To date, no studies have demonstrated that these symptoms are more prevalent among individuals with Lyme disease compared with noninfected patients.¹⁸ Nevertheless, a proportion of patients experience symptoms that they attribute to the long-term effects of Lyme disease, and these patients may benefit from the advice of an infectious disease specialist.¹⁰

7. Recognise When to Refer

When referring a patient with Lyme disease for specialist advice, clinicians should choose the appropriate specialist for the person's history or symptoms. Consider referral for the following clinical scenarios:⁴

• emergency referral for symptoms suggesting:
  • central nervous system infection
  • uveitis or cardiac complications
• specialist advice for:
  • children and young people under 18 years with Lyme disease (unless there is a single erythema migrans lesion and no other symptoms)
  • adults with focal symptoms—seek advice or consider referral, without delaying treatment
• further advice with a national reference laboratory or referral to a specialist if a person has persistent symptoms despite negative results on an immunoblot test 
• patients who have symptoms related to Lyme disease that may need assessment and management, including:
  • chronic pain
  • depression
  • anxiety
  • fatigue
  • sleep disturbance
• management during pregnancy:
  • women who had Lyme disease during pregnancy and if there are concerns about their baby. Discuss history with a paediatric infectious disease specialist and seek advice on what investigations to perform
  • if the baby has Immunoglobulin M antibodies specific for Lyme disease or there is any suspicion the baby may be infected.

Summary

Lyme disease presents a number of particular difficulties in primary care, usually linked to clinical findings and the availability and timing of testing. The condition exhibits three stages—early, disseminated, and late—and can usually be diagnosed clinically if erythema migrans is present. If the rash is not present, or if there is a question about the diagnosis, then acute and convalescent serological testing is helpful. Treatment with antibiotics is highly effective, and the prognosis is usually good.