A 6-year-old Boy with a Swollen Knee

Pediatric Pathways

A 6-year-old Boy with a Swollen Knee

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Pediatric Pathways from American Family Children's Hospital: Dr. Sheryl Henderson

Sheryl Henderson, MD, PhD


Pediatric Pathways from American Family Children's Hospital: J. Muse Davis

J. Muse Davis, MD, PhD

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Pediatric Infectious Diseases

After reading this article and answering the review questions the reader will be able to:

  1. Recognize common clinical presentations of Lyme disease in children.
  2. State when laboratory testing is indicated, which tests apply to the particular case, and how to interpret the results.
  3. Articulate the appropriate treatment regimens for children and adolescents with different presentations of Lyme disease.


A 6-year-old boy presents to an urgent care clinic in northern Wisconsin in late December with a swollen, painful right knee. The swelling started five days ago and seems to be getting bigger. There is no history of recent trauma to the site and he has never had joint complaints before. Physical examination shows a healthy, well-developed boy with a warm, tender swollen knee. The patella is mobile and a generous effusion is detectable beneath. There is no erythema of the skin and the rest of his exam is unremarkable. X ray of the knee shows no bony abnormalities. The effusion is tapped and has ~21,000 leukocytes/ml3, with a predominance of granulocytes.

The patient lives with his parents in Georgia and is visiting family in Wisconsin for the winter holidays. He had previously visited the North Woods of Wisconsin in early August for a family camping vacation. During the first week of school he developed fever and malaise with body aches. He had a five day history of a curious circular rash noted on his chest which started as a small red “spot” that expanded over the course of five days, developing a central clearing. It was flat and red, but not painful or itchy. His mother brings a picture of the rash (Figure 1). He was treated supportively, and his symptoms resolved within a week.

Figure 1. Rash on chest of 6-year-old boy.

Figure 1. Rash on chest of 6-year-old boy.

Lyme disease is rarely found in Georgia, however, his travel to an endemic area and febrile illness with a characteristic rash shortly after his summer visit to Wisconsin raises suspicion for Lyme arthritis. There is no recollection of a tick bite on the patient or his family members. A Lyme EIA (Enzyme Immunoassay) with reflex Western blot IgG was sent from his serum, and the knee joint fluid is sent for culture and nucleic acid testing (PCR) for Borrelia burgdorferi. He is empirically prescribed amoxicillin at 50 mg/kg/day divided in 3 doses/day for 28 days. The joint fluid bacterial culture and the PCR are negative but the total serum antibody is 3.0 LIV (positive is over 1.2). Given this result, a serum IgG immunoblot is performed, which is positive for 7 of the 10 diagnostic bands. His knee swelling begins to improve within a week of starting treatment.

Diagnosis: Lyme Arthritis—Late Lyme Disease


Lyme disease is caused by Borrelia burgdorferi, a spirochete transmitted by tick bites from Ixodes tick species. Wisconsin is one of the endemic areas for Lyme disease in the United States. The disease’s myriad presentations are categorized based on the site and timing of appearance after the tick bite (early localized, early disseminated or late disease). The classic and most common presentation of early Lyme disease is erythema migrans (EM), a unique circular rash as seen in this case. A very common presentation of late Lyme disease is arthritis of large joints, most commonly the knee. The arthritis can be monoarticular or oligoarticular. While early Lyme disease with its characteristic rash can often be diagnosed based on history and physical exam alone, late Lyme disease can be a difficult diagnosis. Here we will outline the lifecycle of B. burgdorferi, discuss the major manifestations of early and late Lyme disease, and review the current recommendations for treatment. We will also review the laboratory investigations of Lyme disease and their proper interpretations.


Lyme disease was first recognized in 1975 after an epidemiologic study of children in Lyme, Connecticut. Due to its distinct geographic and seasonal characteristics, Lyme was thought most likely to be associated with an arthropod vector. In 1982, the causative agent was identified as Borrelia burgdorferi, a Treponema-like bacterium discovered in the gastrointestinal tract of Ixodes scapularis (also known as the blacklegged or deer tick). This tick is limited geographically to the coastal northeast and the northern Midwest. In 2012, Wisconsin was one of 13 US states to report Lyme disease. Lyme is our most common tickborne disease with >23,000 documented cases in Wisconsin from 1980 to 2010. The majority of cases occur during the summer months when the deer tick is feeding. Practitioners should also be aware that in Wisconsin Ixodes scapularis hosts other human pathogens such as Babesia, Anaplasma phagocytophilum, Ehrlichia sp. and the Powassan virus. It is not uncommon for co-infections to occur.

B. burgdorferi relies on vertebrate (non-human) reservoir hosts as its primary home. In Wisconsin the most common reservoir is the white footed mouse. Reservoir hosts can tolerate relatively high numbers of bacteria without developing symptoms. The tick larva acquires B. burgdorferi by feeding on a reservoir host. It subsequently develops into a nymph. The nymph or adult tick is capable of transmitting B. burgdorferi to humans. When the tick attaches to the human, the bacteria multiply in the tick gut, enter the circulatory system and then the salivary glands. Bacteria are transmitted from the saliva of the tick to the human during a blood meal. In general, the tick must be attached for more than 36 hours for the bacterial transmission to occur. In 2012, an average of 22% of I. scapularis nymphs were infected with Borrelia; the majority were found in northern counties of the state.

The symptoms observed in Lyme disease are primarily the result of the host inflammatory response. Initial bacterial growth begins at the site of the bite, and is facilitated by several anti-inflammatory substances supplied in tick saliva. Bacterial factors also play a role in dampening the immune response. The classic EM rash occurs at the onset of the T-cell immune response to infection, 7 to 10 days after inoculation. Blood-borne dissemination begins with direct invasion of nearby capillaries, with subsequent extravasation at remote tissues.

Manifestations of early and late Lyme disease (see Table 1)

Table 1. Manifestations of different stages of Lyme disease

Lyme Disease



Early localized

  • Localized Erythema migrans rash at tick site

3 to 30 days after bite (mean 10 days)

Early Disseminated

  • Multiple EM lesions
  • Cranial nerve palsies
  • Keratitis, uveitis, conjunctivitis
  • Meningitis
  • Carditis—heart block

Within weeks of tick bite. Initial EM rash may or may not be present.


  • Arthritis
  • Peripheral neuropathy


Months after tick bite

Early manifestations: The hallmark EM rash at the site of the tick bite, usually developing 3 to 30 days after the bite, is the only finding required to make a diagnosis in the appropriate epidemiological setting. It is seen in 70-80% of documented cases. Only about one-third of diagnoses are associated with certain recollection of a tick bite. The initial lesion is generally a macule or papule, is round or oval, and expands evenly in diameter to >5cm in diameter. Central clearing usually develops, creating the classic “bull’s eye” rash. An erythematous lesion that appears during the bite or within 48 hours of tick detachment is more likely to represent a hypersensitivity reaction. EM is often accompanied by complaints such as fever, malaise and arthralgias. Lymphadenopathy may also be present. These symptoms, like the rash, are generally self-limited but may wax and wane over several weeks. When more than one EM lesion is present, it is thought that one site is the source and the others (usually smaller) arise by hematogenous spread of bacteria, representing early disseminated disease.

Neurologic symptoms may also represent early disseminated disease. Meningitis is the most common neurologic finding, presenting with stiff neck, headache, and occasional nausea and vomiting. Lumbar puncture is indicated in someone with meningeal symptoms or severe and persistent headaches; the fluid usually shows a lymphocytic predominance. Cranial neuropathies, especially seventh nerve palsy, are common. In endemic areas, Lyme disease is a common infectious cause of seventh cranial nerve palsy in children and may or may not be coincident with an EM rash. Other more rare manifestations include keratitis, uveitis or pseudotumor cerebri. The peripheral neuropathies and changes in behavior sometimes attributed to Lyme in adults are extremely rare in children. Cardiac effects are rare in children, but can vary from intermittent atrioventricular block to myopericarditis. These sequelae generally appear several weeks after the bite, and are usually accompanied by other system involvement.

Late manifestations: Lyme disease that is untreated in the early stages can progress to symptoms occurring weeks to months after a tick bite. Arthritis is a common manifestation of late disease in children. It presents as monoarticular or oligoarticular disease, with swelling and pain without marked erythema or warmth. Ninety percent of cases involve the knee. The mean incubation period is 4 months, making it a common winter-time presentation of the disease. Arthritis may recur over many months, with complete resolution between attacks.

Laboratory Investigations

In an endemic area such as Wisconsin, the finding of EM and plausible tick exposure is diagnostic without any laboratory testing, and is the mode of diagnosis for most pediatric cases. Serum antibody testing may be negative during the early stages of the disease with the EM rash. Thus, the rash is an adequate diagnostic entity.

In Wisconsin, Lyme disease is reportable to the public health department within 72 hours of recognizing a case. Reporting requirements were updated in 2012. All cases of EM rash diagnosed by a medical professional as due to Lyme disease should be reported. However, reporting of cases considered to be Lyme disease without EM is optional unless required by the local health department. Laboratories continue to provide health departments with confirmed positive Lyme testing results.

Laboratory testing for Lyme disease can be complicated; misinterpretations can lead to undue anxiety for patients and physicians. It is important that testing is performed in FDA approved laboratories that follow national standards for testing, interpretation and quality control. This system only performs well in cases with a reasonable pretest probability. Therefore laboratory testing of any kind should be reserved for patients with a history and physical exam which is suggestive of the disease. Given that Wisconsin is an endemic region for Lyme, pretest probability is already high. If the patient described above did not have a history of travel to Wisconsin during late summer, testing would not be advisable due to the low pretest probability of Lyme disease in Georgia.

Once it is assured that someone has a significant risk of the disease, a two-step approach to antibody testing is necessary (see Figure 2).

Figure 2. Multi-tiered Approach to Lyme Disease Serologic Diagnosis

Figure 2. Multi-tiered Approach to Lyme Disease Serologic Diagnosis

* Serologic testing-not isolated EM **S/S = signs and symptoms

Adapted from CDC website: http://www.cdc.gov/lyme/healthcare/clinician_twotier.html

The first step is a screening measure of total antibody response, typically enzyme immune-assay (EIA). The EIA has good negative predictive value but false positives do occur due to nonspecific binding. Therefore equivocal or positive results from EIA testing must be confirmed with Western immunoblot testing. This test uses gel electrophoresis to separate individual antibodies to B. burgdorferi into a series of bands. Host response detected to enough of these characteristic bands indicates a positive result. In Western immunoblot testing, IgM (the early immune response) and IgG (the definitive immune response) are tested separately. A positive result requires very specific banding requirements. IgM antibody is most often present during the first month after a tick bite, therefore it is not recommended to perform this test after 30 days. A positive IgM immunoblot after this time period is more likely to be a false positive result. Just as EIA testing should not be done without a plausible exposure, immunoblot testing is not recommended with a negative EIA. Many laboratories offer a reflex immunoblot to be performed when the EIA is positive or equivocal. Nucleic acid testing may be performed on joint fluid or cerebrospinal fluid. However, the yield is low and false negatives do occur. Detection by this method likely indicates a high concentrations of bacteria.


Doxycycline is the first line choice for many situations, but has contraindications in children less than 8 years old. In early, localized disease with single EM, doxycycline at 4mg/kg/day divided twice daily (up to 200 mg/day) is prescribed for 14-21 days. Patients who cannot take doxycycline can be given amoxicillin at 50mg/kg/day divided three times daily (up to 1.5 gm/day), or cefuroxime axetil at 30mg/kg/day divided twice daily (up to 1.0 gm/day) for the same duration. It should be noted that first generation cephalosporins have no efficacy against Borrelia burgdorferi.

For early, disseminated EM (multiple rashes) the oral regimen is the same but the duration is 21 days. Isolated facial palsy or asymptomatic first degree heart block may be treated with an oral regimen for 14 to 21 days. Treatment for facial palsy is given to prevent progression to disseminated disease, not to decrease the duration of symptoms. Arthritis may be treated with an oral regimen but for 28 days. For more serious infections, such as symptomatic heart block, meningitis or recurrent arthritis, intravenous antibiotics are usually indicated, (ceftriaxone, cefotaxime or penicillin). Consultation with a pediatric infectious disease specialist is highly recommended in such cases.

It is important to note that in some children who receive a full course of treatment for Lyme disease, symptoms may linger for months after completing treatment. These cases likely represent ongoing immune-mediated responses. Studies in adults indicate that repeated courses of antibiotics do not decrease the duration of symptoms and therefore, repeated antibiotic courses are not recommended. Some experts do recommend one repeat of antibiotic treatment for recurrence or persistence of Lyme arthritis beyond 2 months.


The first step to prevention of Lyme disease is avoidance of tick bites. Practical measures such as wearing clothing to minimize skin exposure (long sleeved shirts and long pants), avoiding dense brush that might harbor ticks and using insect repellents (permethrin and DEET) are recommended. Daily or more frequent skin inspections to identify and promptly remove any ticks from someone who has spent time outdoors will minimize the possibility that a tick attaches for more than 36 hours. Transmission of B. burgdorferi is thus reduced. The Wisconsin Department of Health and the U.S. Centers for Disease Control provide further detailed information on prevention and control of tick bites. See links at the following website: http://www.dhs.wisconsin.gov/communicable/Tickborne/TickPrevCtrl.htm.


Lyme disease is quite common in Wisconsin during the summer months. Infection is transmitted by the nymphal and sometimes adult phases of species of I. scapularis ticks. The vast majority of cases are diagnosed based on the history of likely tick exposure and the finding of erythema migrans. Laboratory testing is not required for a diagnosis in such settings. Late manifestations such as arthritis occur weeks after the initial exposure, so the clinician must consider Lyme even through the colder months, long after ticks have stopped biting. A two-tiered approach for serologic testing for antibody is recommended and must only be performed on patients with a history compatible with tick exposure in the right time and place. A positive screening EIA is not diagnostic, and must be confirmed by Western immunoblot testing. Serologic immunoblot testing can only be reliably used if performed and interpreted by the current standards of the Centers for Disease Control. Treatment of most cases involves 14-21 days of oral doxycycline or amoxicillin. Disseminated infection always requires at least 21 days of treatment, and serious infections such as meningitis and symptomatic heart block require parenteral treatment and consultation with an infectious disease specialist.

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CME Questions

References and Resources

  1. Sood, S.K. and Krause, P.J., Borrelia In Cherry JD, Harrison GJ, Hotez PJ, Kaplan SL, Steinbach WJ (Eds): Feigin and Cherry’s Textbook of Pediatric Infectious Disease, 7th edition, Elsevier, Philadelphia, 2014.
  2. Radolf, J.D., et al., Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol, 2012. 10(2): p. 87-99.
  3. Wormser, G.P., et al., 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, 2006. 43(9): p. 1089-134.
  4. Lyme Disease (Lyme Borreliosis, Borrelia burgdorferi Infection), in Red Book: 2012 Report of the Committee on Infectious Diseases. 2012, American Academy of Pediatrics: Elk Grove Village, IL. p. 474-479
  5. Centers for Disease Control and Prevention. Lyme Disease: What you need to know. http://www.cdc.gov/lyme/resources/brochure/lymediseasebrochure.pdf
  6. Wisconsin Department of Health. Borrelia. http://www.dhs.wisconsin.gov/communicable/Tickborne/Lyme/Index.htm