Clinical characteristics and serological profiles of Lyme disease in children: a 15-year retrospective cohort study in Switzerland

Abstract

Background: Lyme disease (LD) is caused by Borrelia burgdorferi and is the most common tickborne disease in the northern hemisphere. Although classical characteristics of LD are well-known, the diagnosis and treatment are often delayed. Laboratory diagnosis by serological testing is recommended for most LD manifestations. The objective of this study was to describe clinical characteristics and associated serological profiles in children with LD.

Methods: This retrospective cohort study included children aged 0-18 years, diagnosed with LD according to current guidelines at University Children's Hospital Zurich between January 1, 2006 and December 31, 2020. Two-tier serological testing with the recomWell enzyme-linked immunosorbent assay and recomLine Western blot (MIKROGEN Diagnostik, MIKROGEN GmbH, Neuried, Germany) was performed at the Institute of Medical Microbiology, University of Zurich.

Findings: In total, 469 children diagnosed with LD were included (median age, 7.9 years); 190 patients (40.5%) with Lyme neuroborreliosis (LNB), 171 (36.5%) patients with skin manifestations (erythema migrans, n = 121; multiple erythema migrans, n = 11; borrelial lymphocytoma, n = 37; and acrodermatitis chronica atrophicans, n = 2), and 108 (23.0%) patients with Lyme arthritis. We observed seasonal variations for patients with skin manifestations and LNB, with high prevalence in May-October, but not for patients with Lyme arthritis. Significant differences between LD manifestation groups were found for age, inflammatory parameters, and specificity and concentration of B. burgdorferi-specific serum antibody responses. We observed distinct patterns of pronounced serum antibody responses against B. burgdorferi antigens in LNB (IgM against VlsE, p41, and OspC) and Lyme arthritis (IgG against p100, VlsE, p58, p41, p39, and p18).

Interpretation: Our study is one of the largest and most detailed for children with LD. We present unique findings regarding the differences in clinical characteristics and immune responses between various manifestations of LD in children.

Funding: No specific funding to disclose for this study.

Keywords: Borrelia burgdorferi; Erythema migrans; Facial nerve palsy; Lyme arthritis; Meningitis; Neuroborreliosis.

Fig. 1

Study flow.^a) Search terms (in alphabetical order): “acrodermatitis chronica atrophicans”, “Bannwarth's syndrome”, “Borrelia burgdorferi”, “borreliosis”, “carditis”, “erythema migrans”, “erythemata migrantia”, “facial palsy”, “facial nerve palsy”, “Lyme”, “lymphadenosis benigna cutis”, “Lyme arthritis”, “Lyme borreliosis”, “Lyme disease”, “lymphocytoma”, “meningoradiculitis”, “neuroborreliosis”, and “radiculitis”. ^b) Inclusion criteria according to current guidelines for the diagnosis of LD^,: (1) skin manifestations, including EM (clinical diagnosis); lymphocytoma (clinical diagnosis WITH/WITHOUT positive two-tier serology); and acrodermatitis chronica atrophicans (clinical diagnosis AND positive two-tier serology); (2) Lyme neuroborreliosis (LNB), i.e., LNB (presence of neurological symptoms and signs AND positive two-tier serology [serum and/or CSF] AND/OR IAP); and isolated peripheral facial nerve palsy (FP) (FP without any other medical symptoms and signs [e.g., headache, fever, nuchal rigidity, etc.]¹⁸); (3) Lyme arthritis (clinical diagnosis AND positive two-tier serology). All serological tests were performed at the Institute of Medical Microbiology, University of Zurich. Patients were categorized according to the organ system involved. Patients fulfilling the diagnostic criteria for LNB were considered to have LNB, regardless of whether skin manifestations such as EM were also observed. Abbreviations: EM, erythema migrans; IAP, intrathecal antibody production; LD, Lyme disease; LNB, Lyme neuroborreliosis.

Fig. 2

Epidemiology and age distribution according to different manifestations of Lyme disease. A: Cases per year. The black line illustrates annual cases normalized to total emergency department visits (%). B: Seasonal changes per month. Total number of cases over the 15-year study period per month. C: Age differences. The median is shown as a black line across the box that represents the lower and upper quartiles. Whiskers extend to the maximum and minimum values within 1.5 times the interquartile range above and below the third and first quartiles, respectively. Abbreviations: ED, emergency department; LNB, Lyme neuroborreliosis.

Fig. 3

Representative pictures of patients with erythema migrans and lymphocytoma. A: Erythema migrans (EM). B: Multiple EM. C: Lymphocytoma.

Fig. 4

Serum antibody responses to individual Borrelia burgdorferi antigens in different manifestations of Lyme disease. Diagnostic bands for the eight antigens (p100, VlsE, p58, p41, p39, OspA, OspC, and p18) from the Western blot (recomLine Borrelia IgM and IgG; MIKROGEN Diagnostik) were assessed for color reaction and intensity after adding diluted patient serum and peroxidase conjugated anti-human antibodies (IgG or IgM). The intensity was graded as follows: 0 (no reaction, equal to the intensity of the cutoff for the control), 1+, 2+, 3+, and 4+. Intensities of at least 1+ were considered positive.A: Percentage of positive IgM and IgG bands. B: Heatmap representing the intensity of IgM and IgG bands. Each column represents one patient. Western blot results for all eight antigens were available as follows: skin manifestation: IgM, n = 19, IgG, n = 30 (erythema migrans: IgM, n = 5, IgG, n = 7; lymphocytoma: IgM, n = 12, IgG, n = 21; acrodermatitis chronica atrophicans: IgM, n = 2, IgG, n = 2); Lyme neuroborreliosis (LNB): IgM, n = 142, IgG, n = 136; and Lyme arthritis: IgM, n = 33, IgG, n = 80. Abbreviations: Ig, immunoglobulin; LNB, Lyme neuroborreliosis.