History

Fact Explanation
Age Lyme disease is a multi system disease caused by the spirochete Borrelia burgdorferi which is transmitted by ticks to the humans [1]. The deer ticks Ixodes scapularis & Ixodes pacificus are known to carry the bacterium and act as vectors for transmission. It takes about 3-30 days for the symptoms to appear after a tick bite [2], and three stages of infection are identified, namely early localized (stage 1), early disseminated (stage 2) and late stages (stage 3) [3]. The disease is most often found in the 5-9 years and 55-59 years age groups [4]. Thus asking about the age can give a clue to the diagnosis.
Occupation This is very important as mentioned above, the bacterium causing the lyme disease, Borrelia burgdorferi, is most commonly transmitted by the deer ticks Ixodes scapularis & Ixodes pacificus. Thus occupations that are likely to cause exposure to wild animals such as wild life officers /park rangers/ veterinary surgeons are at an increased risk of disease transmission [3].
Travel history Recent travel to country side/ wild life safari is important aspects of history as these findings can give a clue to the diagnosis.
Early localized stage :General ill symptoms The initial symptoms are fever, headache,malaise,chills, myalgia and fatigue similar to viral illness [3].
Early localized stage : Skin rash Patients may complaint of a single erythematous lesion on the skin which is the erythema migrans rash. It is important to ask about skin rash in the history as 80% of patients present with erythema migrans rash at the initial stage [2].
Early localized stage : Joint pain Transient arthralgia with swelling of the joints can occur at the early localized stage [2].
Early disseminated stage : Skin rash The rash of erythema migrans may proceed into the early disseminated stage causing multiple lesions, as opposed to single lesion in the early localized stage [3].
Early disseminated stage : Joint pain Arthralgia is a common in the early disseminated stage [3]. Note: Joint symptoms are the most common extracutaneous manifestations of the early disseminated disease [4].
Early disseminated stage : Facial asymmetry of recent onset Patients may present with this symptom at the early disseminated stage when the facial nerve is affected resulting in palsy [3]. Most often this is unilateral, and asking about the exposure to wild animals can give a clue to the cause of the palsy [1].
Early disseminated stage : Chest pain/ exertional dyspnea/ palpitations/syncope/fatigue These are all manifestations of cardiac involvement of the Lyme disease, causing Lyme carditis [2]. Atrio-ventricular block causes palpitations and syncope [4] . Other rare cardiac effects include bundle branch block, myopericarditis and heart failure [1]. Lyme disease should be suspected in patients coming from endemic areas complaining of these symptoms, and the symptoms occur within 1 to 2 months after infection [1].
Late stage: Headache & neck stiffness This occurs in about 15% of untreated patients at the late stage as a consequence of neurological involvement of the disease causing meningitis [1].
Late stage: Altered personality and difficulty in sleeping The patient or the family members may complaint of altered personality and insomnia, due to subacute encephalopathy or axonal polyneuropathy at the late stage of the disease [1].
Late stage: Weakness of limbs & sensory impairment This can be present at the late stage in about 15% of untreated patients, as a result of motor/sensory radiculoneuropathy and myelitis [1].
Late stage : arthritis Arthralgia in the early localized stage can progress into arthritis at the late stage in the untreated disease, with manifestation of clinical features about 6 months after the initial infection [6]. This occurs in 60% of untreated patients and common sites of chronic arthritis are knee & hip joints [3].
Post-Lyme disease syndrome: Fatigue / arthralgia / myalgia/ cognitive difficulties These symptoms may persist even after successful treatment of Lyme disease which is sometimes attributed to post-Lyme disease syndrome [1]. This is thought to be caused by an auto-immune reaction triggered by the association of Lyme disease and human leukocyte antigen haplotypes [1].
References
  1. STEERE AC. Lyme disease. N Engl J Med [online] 2001 Jul 12, 345(2):115-25 [viewed 18 September 2014] Available from: doi:10.1056/NEJM200107123450207
  2. DEPIETROPAOLO DL, POWERS JH, GILL JM, FOY AJ. Diagnosis of lyme disease. Am Fam Physician [online] 2005 Jul 15, 72(2):297-304 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16050454
  3. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880
  4. BACON RM, KUGELER KJ, MEAD PS, CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC). Surveillance for Lyme disease--United States, 1992-2006. MMWR Surveill Summ [online] 2008 Oct 3, 57(10):1-9 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/18830214
  5. WORMSER G. P., DATTWYLER R. J., SHAPIRO E. D., HALPERIN J. J., STEERE A. C., KLEMPNER M. S., KRAUSE P. J., BAKKEN J. S., STRLE F., STANEK G., BOCKENSTEDT L., FISH D., DUMLER J. S., NADELMAN R. B.. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases [online] 2006 November, 43(9):1089-1134 [viewed 18 September 2014] Available from: doi:10.1086/508667
  6. MARQUES AR. Lyme disease: a review. Curr Allergy Asthma Rep [online] 2010 Jan, 10(1):13-20 [viewed 18 September 2014] Available from: doi:10.1007/s11882-009-0077-3

Examination

Fact Explanation
Early localized stage: General examination: Skin rash Erythematous, oval to circular, with a median diameter of 16 cm, appearing as a single lesion is the classical erythema migrans rash seen in the Lyme disease. The common sites are the back, groin, popliteal fossa, abdomen & axilla [1]. More than one lesion may be seen in about 10-20% of patients [2].
Early disseminated stage: General examination: Skin rash Tha rash of erythema migrans is seen at multiple sites at the early disseminated stage [1].
Early disseminated stage: Cardio-vascular examination This is important in patients complaining of cardiac symptoms, to look for signs of heart failure, which is a rare complication [3].
Late stage: General examination: Neck stiffness/ meningism/positive kernig’s sign These signs are present when the patient is having meningitis, which can occur in about 15% of untreated patients at the late stage of the disease [3].
Late stage: Neurological examination: Altered mental status and cognitive impairment This can be present rarely when subacute encephalopathy or axonal polyneuropathy is present at the late stage. Altered mental status can also occur due to meningitis, which is another neurological manifestation [3].
Late stage: Neurological examination: Cranial nerve palsies This is also a sequel of neurological manifestations at the late stage of the disease. Thus in every patient presenting at the late stage, cranial nerve examination should be carried out [3]. Facial nerve is commonly affected and mostly unilateral [1].
Late stage: Neurological examination: Motor & sensory deficit Motor/sensory impairment can be present at the late stage due to radiculoneuropathy and myelitis [3].
References
  1. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880
  2. AUCOTT J, MORRISON C, MUNOZ B, ROWE PC, SCHWARZWALDER A, WEST SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infect Dis [online] 2009 Jun 1:79 [viewed 18 September 2014] Available from: doi:10.1186/1471-2334-9-79
  3. STEERE AC. Lyme disease. N Engl J Med [online] 2001 Jul 12, 345(2):115-25 [viewed 18 September 2014] Available from: doi:10.1056/NEJM200107123450207

Differential Diagnoses

Fact Explanation
Erythema multiforme This also causes erythematous target like lesions and can be confused with erythema migrans. However, it causes multiple lesions and involves mucous membranes which can aid in making the diagnosis [1].
Granuloma annulare This also causes erythematous lesions with central clearing. The scaling nature and the site of the lesion which is feet and hands helps in making the diagnosis [1].
Nummular eczema Causes coin shaped erythematous lesions similar to erythema migrans. However, the lesions are much smaller in diameter (2-10 cm) and are located in the back and the hands [1]. Also, itching may be present with a positive personal/family history of atopy [2].
Tinea infection of skin This also causes annular/ring lesions, but the centre is clear and the margins are raised as opposed to erythema migrans [3]. Note: Although these conditions can be confused with erythema migrans, rapid and prolonged expansion of the rash is unique to erythema migrans [1]. Proper identification of erythema migrans is of vast importance as it is the only clinical manifestation that is able to make the diagnosis of Lyme disease in the absence of laboratory confirmation [4].
Rheumatoid arthritis These also cause joint symptoms with inflammation. In rheumatoid arthritis, small joints including proximal interphalangeal joints are involved mostly and the most distinguishing feature is the presence of morning stiffness [5].
Osteoarthritis Osteoarthritis involves the knee joint most commonly similar to Lyme disease, but the patient will complaint the pain is exacerbated by movement and minimal at rest, whereas the pain is likely to be constant in Lyme disease [6].
Ischemic heart disease (IHD) Chest pain, exertional dyspnea and fatigue found in the cardiac involvement of the Lyme disease are present in ischemic heart disease as well. Presence of dyslipidemia and ischemic changes in exercise electrocardiograph favor in the diagnosis of IHD [7].
Anemia Exertional dyspnea, fatigue and palpitations can suggest anemia that can be due to various reasons such as chronic disease, reduced dietary intake of nutrients or a hemolytic disorder. Full blood count and blood picture are useful in making a diagnosis [8].
Meningitis caused by other bacteria / viruses As the clinical features of meningitis are similar, looking for the characteristic findings in the cerebro spinal fluid examination is important in identifying the causative organism of meningitis [9].
Psychiatric illness Bipolar affective disoreder/ personality disorder/ dementia can cause change in personality that can be confused with the neurological features of Lyme disease [10,11,12]. Careful evaluation for the presence of other features of Lyme disease along with mental state examination can help in making the correct diagnosis.
Cauda equine syndrome/ transverse myelitis/ Guillan Barre syndrome All these condition can cause radiculopathy, giving rise to motor & sensory impairment similar to Lyme disease. Careful neurological examination with evaluation of bladder & bowel symptoms and imaging of the spine can aid in making the diagnosis [13,14].
Bell’s palsy This also causes facial nerve palsy, mostly unilateral similar to Lyme disease and Lyme disease should be excluded before making the diagnosis of Bell’s palsy, specially in patients coming from the endemic areas of Lyme disease [15].
References
  1. AUCOTT J, MORRISON C, MUNOZ B, ROWE PC, SCHWARZWALDER A, WEST SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infect Dis [online] 2009 Jun 1:79 [viewed 18 September 2014] Available from: doi:10.1186/1471-2334-9-79
  2. BERKE R, SINGH A, GURALNICK M. Atopic dermatitis: an overview. Am Fam Physician [online] 2012 Jul 1, 86(1):35-42 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962911
  3. NOBLE SL, FORBES RC, STAMM PL. Diagnosis and management of common tinea infections. Am Fam Physician [online] 1998 Jul, 58(1):163-74, 177-8 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9672436
  4. WORMSER G. P., DATTWYLER R. J., SHAPIRO E. D., HALPERIN J. J., STEERE A. C., KLEMPNER M. S., KRAUSE P. J., BAKKEN J. S., STRLE F., STANEK G., BOCKENSTEDT L., FISH D., DUMLER J. S., NADELMAN R. B.. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases [online] 2006 November, 43(9):1089-1134 [viewed 18 September 2014] Available from: doi:10.1086/508667
  5. WASSERMAN AM. Diagnosis and management of rheumatoid arthritis. Am Fam Physician [online] 2011 Dec 1, 84(11):1245-52 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22150658
  6. SINUSAS K. Osteoarthritis: diagnosis and treatment. Am Fam Physician [online] 2012 Jan 1, 85(1):49-56 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22230308
  7. FLETCHER GF, MILLS WC, TAYLOR WC. Update on exercise stress testing. Am Fam Physician [online] 2006 Nov 15, 74(10):1749-54 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/17137006
  8. SHORT MW, DOMAGALSKI JE. Iron deficiency anemia: evaluation and management. Am Fam Physician [online] 2013 Jan 15, 87(2):98-104 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23317073
  9. BAMBERGER DM. Diagnosis, initial management, and prevention of meningitis. Am Fam Physician [online] 2010 Dec 15, 82(12):1491-8 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/21166369
  10. PRICE AL, MARZANI-NISSEN GR. Bipolar disorders: a review. Am Fam Physician [online] 2012 Mar 1, 85(5):483-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22534227
  11. WARD RK. Assessment and management of personality disorders. Am Fam Physician [online] 2004 Oct 15, 70(8):1505-12 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15526737
  12. SIMMONS BB, HARTMANN B, DEJOSEPH D. Evaluation of suspected dementia. Am Fam Physician [online] 2011 Oct 15, 84(8):895-902 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22010769
  13. WALLING AD, DICKSON G. Guillain-Barré syndrome. Am Fam Physician [online] 2013 Feb 1, 87(3):191-7 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23418763
  14. CASAZZA BA. Diagnosis and treatment of acute low back pain. Am Fam Physician [online] 2012 Feb 15, 85(4):343-50 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22335313
  15. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880

Investigations - for Diagnosis

Fact Explanation
Full blood count (FBC) FBC may show elavated white cell count with neutrophilic leukocytosis due to bacterial infection. Note: a normal FBC does not exclude the diagnosis of Lyme disease as some patients may have normal results in the FBC [1].
Erythrocyte sedimentation rate (ESR) ESR may be elevated in some infected patients and therefore is a useful test to be done initially.
Culture of the organism Culture is done on skin biopsy of patients with single lesions of erythema migrans and on the serum of patients with multiple lesions. The disadvantages are that it cannot be used among those without erythema migrans and not routinely available [2,3].
Serological tests This is the preferred diagnostic test [4]. Testing by enzyme linked immune sorbent assay (ELIZA) followed by western blot to confirm the initial results is recommended [5].
C6 peptide assay This is a IgG ELIZA test that has shown a promising result in confirmin the diagnosis but need further evaluation [6].
Polymerase chain reaction (PCR) PCR in the synovial fluid and cerebro spinal fluid (CSF) in patients with chronic arthritis and neurological Lyme disease respectively is recommended in patients with late Lyme arthritis [4].
Intrathecal antibody testing in the CSF sample This is the investigation of choice to diagnose neurological Lyme disease [4].
Testing for the antigen in urine This is usually not recommended as it has high false-positive rate [7].
Brain imaging (CT/ MRI) and analysis of cerebro-spinal fluid These can be useful at the late stage when neurological symptoms are present or to exclude other neurological differential diagnoses such as bacterial meningitis.
References
  1. COULTER P, LEMA C, FLAYHART D, LINHARDT AS, AUCOTT JN, AUWAERTER PG, DUMLER JS. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol [online] 2005 Oct, 43(10):5080-4 [viewed 18 September 2014] Available from: doi:10.1128/JCM.43.10.5080-5084.2005
  2. NOWAKOWSKI J, MCKENNA D, NADELMAN RB, BITTKER S, COOPER D, PAVIA C, HOLMGREN D, VISINTAINER P, WORMSER GP. Blood cultures for patients with extracutaneous manifestations of Lyme disease in the United States. Clin Infect Dis [online] 2009 Dec 1, 49(11):1733-5 [viewed 18 September 2014] Available from: doi:10.1086/648076
  3. KRAUSE PETER J., MCKAY KATHLEEN, THOMPSON CHARLES A., SIKAND VIJAY K., LENTZ RONALD, LEPORE TIMOTHY, CLOSTER LINDA, CHRISTIANSON DIANE, TELFORD SAM R., PERSING DAVID, RADOLF JUSTIN D., SPIELMAN ANDREW. Disease‐Specific Diagnosis of Coinfecting Tickborne Zoonoses: Babesiosis, Human Granulocytic Ehrlichiosis, and Lyme Disease. CLIN INFECT DIS [online] 2002 May, 34(9):1184-1191 [viewed 20 September 2014] Available from: doi:10.1086/339813
  4. WORMSER G. P., DATTWYLER R. J., SHAPIRO E. D., HALPERIN J. J., STEERE A. C., KLEMPNER M. S., KRAUSE P. J., BAKKEN J. S., STRLE F., STANEK G., BOCKENSTEDT L., FISH D., DUMLER J. S., NADELMAN R. B.. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases [online] 2006 November, 43(9):1089-1134 [viewed 18 September 2014] Available from: doi:10.1086/508667
  5. CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC). Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep [online] 1995 Aug 11, 44(31):590-1 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7623762
  6. STEERE AC, MCHUGH G, DAMLE N, SIKAND VK. Prospective study of serologic tests for lyme disease. Clin Infect Dis [online] 2008 Jul 15, 47(2):188-95 [viewed 18 September 2014] Available from: doi:10.1086/589242
  7. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880

Investigations - Followup

Fact Explanation
Recommendation for follow-up Follow-up of the chronic disease and evaluating the response to treatment with repeated serological testing is not currently recommended as persistently elevated antibody levels may be present in both cured and chronically ill patients [1].
References
  1. WORMSER G. P., DATTWYLER R. J., SHAPIRO E. D., HALPERIN J. J., STEERE A. C., KLEMPNER M. S., KRAUSE P. J., BAKKEN J. S., STRLE F., STANEK G., BOCKENSTEDT L., FISH D., DUMLER J. S., NADELMAN R. B.. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases [online] 2006 November, 43(9):1089-1134 [viewed 18 September 2014] Available from: doi:10.1086/508667

Management - General Measures

Fact Explanation
Assess the risk of transmission The duration of the deer tick on the human and whether it is engorged are the factors that determine the risk of transmission. The tick should be attached for at least 36 hours for transmission of Borrelia burgdorferi to occur as it takes about that time to reach the tick’s salivary glands from the gut [1]. This knowledge influences on treatment decisions as removal of the tick within 24 hours of attachment can prevent transmission [2].
Take measures for prevention of the disease Health education regarding prevention is an important aspect in the management, particularly in those living in endemic areas. Advice to avoid grassy/ wooded areas that are rich in deer population is very important as it it the the most effective preventive measure [3]. Also, advice to wear light colored clothing and frequent check-ups to easily detect ticks and bathing following outdoor activities are useful measures of prevention. Use of tick repellents also can be effective, as well as environmental modifications including mowing of grass, deer exclusion fencing and cleaning the leaf litters. Fine-tipped forceps are recommended to remove the attached ticks [2].
References
  1. LO RE V 3RD, OCCI JL, MACGREGOR RR. Identifying the vector of Lyme disease. Am Fam Physician [online] 2004 Apr 15, 69(8):1935-7 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15117014
  2. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880
  3. CLARK RP, HU LT. Prevention of lyme disease and other tick-borne infections. Infect Dis Clin North Am [online] 2008 Sep, 22(3):381-96, vii [viewed 18 September 2014] Available from: doi:10.1016/j.idc.2008.03.007

Management - Specific Treatments

Fact Explanation
Antibiotic treatment : Doxycyclin Oral doxycycline is the preferred drug of choice for early localized & disseminated disease with erythema migrans. It can also be used for cardiac disease and for arthritis at the late stage [1]. Doxycycline is a tetracycline that has broad spectrum activity. It exerts its bacteriostatic effect by inhibiting protein synthesis of bacteria [2]. It has added benefit as well, as it acts against other tick-borne illnesses such as human granulocytic anaplasmosis, that can co-exist with the Lyme disease in 10% of patients [1]. the recommended dosage is 100mg twice daily for adults for 10 to 21 days for early localized stage, 10 to 21 days for early disseminated days and 28 days for late stage [1]. Important: Doxycycline is contraindicated in breast feeding and pregnant women and chldren less than 8 years [3].
Antibiotic treatment : Amoxycillin Can be given 500mg three times daily for 14 to 21 days in early localized stage and for 28 days in the late stage [1].
Antibiotic treatment : Macrolides Azithromycin, erythromycin and clarythromycin can be used. The recommended dosages are for azithromycin: 500mg daily for 7 to 10 days; erythromycin: 500mg for 14 to 21 days; clarithromycin; 500mg twice daily for 14 to 21 days in early localized stage and for 28 days in arthritis [1]. Note: as macrolides are less effective than other drugs, they should be reserved for those who are intolerant to doxycycline/amoxycillin and cefuroxime acetil [1].
Antibiotic treatment : cephalosporins Intravenous cefotaxime & cephtriaxine are used for cardiac and neurologic Lyme disease and refractory Lyme arthritis [3]. The recommended dosing for cefotaxime is 2g 8 hourly while for cephtriaxone is 2g daily for 14 to 28 days [1]. important: As cephtraixone is not superior to oral antibiotics and has more adverse effects, it is not recommended to use in early Lyme disease unless the patient is having cardiac or neurologic symptoms [1] . Note: prolonged antibiotic therapy for chronic Lyme disease/ post-Lyme disease syndrome is currently not recommended as there is no scientific evidence of proven benefit [1].
Post-exposure prophylaxis This is recommended for engorged ticks that have been attached for 36 hours or more in an area of at least 20% rate of tick infection. A single 200mg dose of oral doxycycline is the drug of choice and should be given within 72 hours of tick removal [1].
References
  1. WORMSER G. P., DATTWYLER R. J., SHAPIRO E. D., HALPERIN J. J., STEERE A. C., KLEMPNER M. S., KRAUSE P. J., BAKKEN J. S., STRLE F., STANEK G., BOCKENSTEDT L., FISH D., DUMLER J. S., NADELMAN R. B.. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases [online] 2006 November, 43(9):1089-1134 [viewed 18 September 2014] Available from: doi:10.1086/508667
  2. BERNARDINO ANDREA L. F., KAUSHAL DEEPAK, PHILIPP MARIO T.. The Antibiotics Doxycycline and Minocycline Inhibit the Inflammatory Responses to the Lyme Disease Spirochete . J INFECT DIS [online] 2009 May, 199(9):1379-1388 [viewed 20 September 2014] Available from: doi:10.1086/597807
  3. WRIGHT WF, RIEDEL DJ, TALWANI R, GILLIAM BL. Diagnosis and management of Lyme disease. Am Fam Physician [online] 2012 Jun 1, 85(11):1086-93 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22962880