Table 2.

Data collection and measurements for all patients with confirmed Lyme borreliosis

	Baseline	10 days	2 weeks	6 weeks	3 months	6 months	9 months	12 months
Written information and informed consent	X
Baseline characteristics	X
Physical examination	Xa				Xac	Xac	Xac	Xac
Recording Lyme manifestation, treatment and concomitant medication	X		Xb		X	X	X	X
Recording adverse events	X		Xb		X	X		Xa
Questionnaires
Primary outcome: CIS (subscale fatigue), SF-36 (subscale pain), CFQ	X				X1	X	X1	X
Clinical parameters: PHQ-15, SF-36 (subscale physical functioning and subscale social functioning), TiC-P (health-care use and absenteeism of work)	X				X	X	X	X
Cognitive-behavioral parameters: brief IPQ, CBRSQ, HADS, SES-F, PCS, IPAQ	X				X	X
Comorbidities: TiC-P (co-morbidity list)	X							X
Comorbidities: PREDIS	X
Laboratory measurements
B. burgdorferi s.l. serology	X	Xac		X	Xac
Serology other TBPs3	X2			X2
PCR B. burgdorferi s.l. and other TBPs3 (blood)	X			X
Genome wide association studies	X4
Cytokine measurements in cell culture supernatants	X			X
Gene expression micro-arrays on ex vivo stimulated PBMCs	X5			X5
Skin biopsies: culture, MLST, PCR B. burgdorferi s.l. and other TBPs, gene-expression profiling	X6

^aPatients included through the clinical expert centers for Lyme borreliosis only

^bPatients included through the website www.tekenradar.nl only

^cThese visits and laboratory measurements can be left out if patients are not able or not willing to. This is regarded as an allowed deviation from the protocol

¹CIS questionnaire only short version, to limit the burden for patients

²In cases (patients with persistent symptoms) and twice as much controls (patients without persistent symptoms), starting with the 6 weeks sample. If borderline or positive, the baseline sample will be tested as well

³Serology on Babesia spp., Rickettsia conorii, Anaplasma phagocytophilum (commercially available) and Borrelia miyamotoi (experimental). Quantitative PCR including Babesia spp., Rickettsia spp., Anaplasma phagocytophilum, Neoehrlichia mikurensis, as well as a pan relapsing fever Borrelia qPCR (if positive, a specific Borrelia miyamotoi qPCR will be performed)

⁴In the first consecutive included 600 patients with erythema migrans

⁵In a selection of patients, included through the clinical expert centers for Lyme borreliosis

⁶In patients with a skin manifestation included through the clinical expert centers for Lyme borreliosis (only after additional consent). Both the affected and contra-lateral side will be investigated

Abbreviations: (q)PCR (quantitative) polymerase chain reaction, TBPs tick-borne pathogens, PBMCs peripheral blood mononuclear cells, MLST Multilocus sequence typing. For the abbreviations of the various questionnaires, see the main text