INFEKTTAG 2013 T · ๏ frühe und chronische Neuroborreliosen, Karditis: sehr selten Altpeter et...

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INFEKTTAG 2013 _ TRENDSOutdoor Infektionen _ Carol Strahm

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OUTDOOR INFEKTIONEN ...

... Trends ... zu den von Zecken übertragenen Krankheiten in der

Schweiz

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1. LYME BORRELIOSE

Alte und neue Trends

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LYME BORRELIOSE๏ häufigste zeckenübertragene Krankheit in der Schweiz

๏ 6000-12000 Fälle pro Jahr

๏ unbehandelt: chronischer Infekt mit verschiedenen typischen Stadien ๏ Stadium I früh lokalisiert (ECM)

๏ Stadium II früh disseminiert (Bannwarth, Lymphozytom, Carditis)

๏ Stadium III spät/ chronisch (Arthritis, ACA, Neuroborreliose)

๏ Erreger: Borrelia burgdorferi sensu lato

Altpeter et al., Swiss Med Wkly. 2013;143:0.

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180 | MARCH 2011 | VOLUME 7 www.nature.com/nrrheum

therapy. She confined herself to bed for 24 days because of the knee pain, weakness and a headache. One month later, she had some decrease in the left-knee swelling and resolution of the headache and weakness.

Following her self-confinement, the patient returned to the rheumatologist (Figure 1; second presentation). He reviewed the testing done 1 month previously by the acupuncturist, including the repeat Lyme-disease testing, for which she was positive (ELISA >5.00; Western Blot, negative for IgM, positive for IgG), and the erythrocyte sedimentation rate (121 mm/h). Physical examina tion by the rheumatologist revealed a 1+ effusion of her left knee.

The rheumatologist prescribed doxycycline therapy (100 mg, twice daily for 28 days) and the patient agreed to adhere to the treatment course. The left-knee swell-ing had gradually improved at 1 month of follow-up. Three days before the completion of doxycycline therapy, however, the left-knee effusion recurred and when examined by the rheumatologist the following week, the left knee had a 2+ effusion that persisted for an additional 9 days. The left-knee effusion subsequently resolved. The patient has had no further arthritis and remained well at 6 months of follow-up.

DiagnosisLyme disease was recognized in 1976 as an epidemic of oligoarthritis in children and adults in Lyme, Connecticut, USA.1 In a prospective study, recurrent episodes of monoarthritis or oligoarthritis, particularly involving the knee, were reported in 60% of patients with Lyme disease.1,2 The causative organism in North America, B. burgdorferi, was isolated from the tick vector, Ixodes scapularis, in 1982.3 In Europe, Lyme disease is caused not only by B. burgdorferi, but also by other closely related borrelial species, including B. afzelii, infec-tion with which is associated with acrodermatitis, and B. garinii, associated with encephalomyelitis (Figure 2a).4 Over the past 30 years, the geographic range of Lyme

disease has expanded and Lyme disease is now the most common vector-borne disease in both North America and Europe.5

Lyme disease has characteristic, well-recognized clini-cal features and is generally classified into early and late stages;6 early disease can be localized or disseminated (Figure 2b). Lyme disease typically begins with erythema migrans (EM) or other early-stage disease manifesta-tions.7 Such early disease can be localized to the skin or can involve hematogenous dissemination to other sites, including the skin (multiple EM lesions), the heart (Lyme carditis) or the nervous system (early neuro-logical disease).6 In general, Lyme disease is recognized early and with increasing accuracy in endemic areas, such as the coastal regions of Northeast USA. However, patients who are not treated for early disease (owing to a lack of early disease manifestations, a lack of detec-tion or inadequate treatment) are at risk for late-stage disease, particularly Lyme arthritis in North America. Lyme arthritis is more common in North America than in Europe, because infection in North America is almost exclusively caused by B. burgdorferi and not other, less arthritogenic, borrelial species.2,4 Antibiotic treatment of early disease is usually curative;8 progression from early disease to late-stage arthritis, therefore, has become less common. In addition, the initiation of antibiotic therapy in patients who develop Lyme arthritis alters the natural history of the disease and shortens the number and duration of arthritic episodes.9

Although Lyme disease has become endemic in certain areas and the geographical range of Lyme disease has expanded,10 early recognition and treatment has resulted in a reduction in cases of early disseminated disease or progression to Lyme arthritis. Indeed, the natural history of untreated Lyme arthritis is rarely observed. This Case Study describes an individual who chose, over a period of years, to decline antibiotic therapy to treat her Lyme disease. The natural history of her disease is consistent with previous reports.1,2

Rheumatologist

Tick biteErythematous rash

Mild headacheStiff neck

Homeopathic remediesNo antibioticsRash improved

Homeopathic remediesNo antibiotics

AcupunctureLeft-knee swelling

persisted

AcupunctureLeft-knee swelling

improved

Lyme arthritis diagnosedPatient declined

recommendation of doxycycline

Homeopath prescribed doxycycline for 14 days

Discontinued after no improvement

Headache and weakness con!ne patient to bed

First presentationLyme arthritis con!rmedAmoxicillin prescribed

for 30 days

Second presentationDoxycycline

administered for 30 days

Swelling improved

Right-elbow painRight-shoulder pain

Left-knee swelling

Swelling recurredfor 9 daysSwelling worsened

Pain in right kneeLeft-ankle painand swelling

Left-knee painand swelling

Patient had not taken amoxicillin

Symptoms improvedNo sign of arthritis

AcupuncturistHomeopath

1 year

Figure 1 | Timeline of the case illustrating the natural history of Lyme disease. Visits to the homeopath, acupuncturist and rheumatologist are color-coded and displayed below the timeline.

CASE STUDY

nrrheum_209_MAR11.indd 180 14/2/11 12:36:17

© 2011 Macmillan Publishers Limited. All rights reserved

KLINIK DER UNBEHANDELTEN LYME BORRELIOSE (USA)

Schoen, Nat Rev Rheumatol. 2011 Mar;7(3):179–84.

St. I St. II Stadium III

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BORRELIEN: AKTUELLE TRENDS (OST)SCHWEIZ

Sentinella Daten 2008-2012

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REGION 5 (AR, AI, GL, SG, SH,

TG, ZH, FL)Inzidenz CH 131/100000


303

156

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2/3

[email protected] Telefon: 031 323 87 06

Abbildung 1: Geschätzte Fälle von Arztbesuchen wegen Zeckenstich bzw. Lyme-Borreliose, sowie Fälle von FSME, Schweiz, 2010-2012

JAHRESTRENDS 2010-12www.bag.admin.ch

http://www.bag.admin.ch/themen/medizin/00682/00684/06330/index.html

http://www.bag.admin.ch/themen/medizin/00682/00684/06330/index.html

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SENTINELLA-RESULTATE

๏ 90% Erythema chronicum migrans (ECM)

๏ ～10% spätere Stadien - Stadium II/III

๏ 4-5%: Acrodermatitis chronica atrophicans (ACA), Lyme Arthritis, benignes Lymphozytom

๏ frühe und chronische Neuroborreliosen, Karditis: sehr selten


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FRAGE

Welches ist die optimale Behandlung eines Erythema chronicum migrans?

1. Clamoxyl 3x1000mg für 14 Tage

2. Doxycyclin 2x100mg für 21 Tage



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Stupica et al., CID 2012 May 21

M A J O R A R T I C L E

Treatment of Erythema Migrans WithDoxycycline for 10 Days Versus 15 Days

Da!a Stupica,1 Lara Lusa,2 Eva Ru"ic-Sabljic,3 Tja!a Cerar,3 and Franc Strle11Department of Infectious Diseases, University Medical Center Ljubljana, 2Institute for Biostatistics and Medical Informatics, Ljubljana, and 3Instituteof Microbiology and Immunology, Faculty of Medicine Ljubljana, Slovenia

Background. The efficacy of 10-day doxycycline treatment in patients with erythema migrans has been as-sessed in the United States but not in Europe. Experts disagree on the significance of post–Lyme borreliosis symp-toms.

Methods. In a noninferiority trial, the efficacies of 10 days and 15 days of oral doxycycline therapy wereevaluated in adult European patients with erythema migrans. The prevalence of nonspecific symptoms was com-pared between patients with erythema migrans and 81 control subjects without a history of Lyme borreliosis. Theefficacy of treatment, determined on the basis of clinical observations and microbiologic tests, was assessed at 14days and at 2, 6, and 12 months. Nonspecific symptoms in patients and controls were compared at 6 months afterenrollment.

Results. A total of 117 patients (52%) were treated with doxycycline for 15 days, and 108 (48%) receiveddoxycycline for 10 days. Twelve months after enrollment, 85 of 91 patients (93.4%) in the 15-day group and 79 of86 (91.9%) in the 10-day group had complete response (difference, 1.6 percentage points; upper limit of the 95%confidence interval, 9.1 percentage points). At 6 months, the frequency of nonspecific symptoms in the patientswas similar to that among controls.

Conclusions. The 10-day regimen of oral doxycycline was not inferior to the 15-day regimen among adultEuropean patients with solitary erythema migrans. Six months after treatment, the frequency of nonspecific symp-toms among erythema migrans patients was similar to that among control subjects.

Clinical Trials Registration. NCT00910715.

In several randomized studies assessing the efficacy oforal antibiotics for erythema migrans treatment thatwere performed in Europe and the United States, differ-ent antibiotics and dosing regimens have proved compa-rable and very effective. After antibiotic treatment,objective signs of Lyme borreliosis occurred in only rareinstances [1–13]; however, the proportion of patientswith subjective symptoms !6 months after treatmentranged considerably, from 0% to 40.8% in the United

States [1–8] and from 0% to 23.4% in European ran-domized clinical studies [9–13]. On the basis of thosestudies, the Infectious Diseases Society of America rec-ommended 14–21 days of oral antibiotics for treatmentof erythema migrans [14]. Results of more recent re-search suggest that 14 days of oral antibiotics suffice forexcellent treatment outcome [15–17]. The efficacy ofshorter, 10-day treatment with doxycycline has been es-timated in the United States [5] but not in Europe.

The clinical course of erythema migrans in Europediffers somewhat from that in the United States[18, 19], and there has been no direct comparisonbetween the 2 continents on the efficacy of individu-al antibiotics for this condition. The primary objec-tive of this trial was to assess the noninferiority of10-day oral doxycycline treatment in comparisonwith 15-day treatment in European patients with ery-thema migrans. The primary efficacy outcome was

Received 22 November 2011; accepted 22 March 2012; electronically published20 April 2012.

Correspondence: Da!a Stupica, Department of Infectious Diseases, UniversityMedical Center Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia ([email protected]).

Clinical Infectious Diseases 2012;55(3):343–50© The Author 2012. Published by Oxford University Press on behalf of the InfectiousDiseases Society of America. All rights reserved. For Permissions, please e-mail:[email protected]: 10.1093/cid/cis402

Doxycycline Therapy for Erythema Migrans • CID 2012:55 (1 August) • 343

at Universitaet Zuerich on July 10, 2012

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Clinical outcomes for patients in the 2 treatment groups atfollow-up visits are summarized in Table 2. The large majorityof patients (86.7% in the 15-day group, and 84.6% in the 10-day group) had complete response from 2 months onward.None of the patients developed an objective manifestation ofLyme borreliosis or fulfilled any of the predefined failure crite-ria. The proportion of patients with NOIS was highest at thebaseline visit (69 of 225 [30.7%]) and steadily decreased over

the study period, to 13 of 177 (7.3%) at 12 months (Figure 2).The frequency of individual NOIS, except for dizziness, forget-fulness, and concentration difficulties, statistically significantlydecreased during follow-up (Supplementary Figure 1). Of the13 patients with NOIS at 12 months, none qualified as havingpost–Lyme disease syndrome because the reported symptomswere not severe enough to result in reduction of previous ac-tivity levels [14]. The proportion of patients who did not com-plete the 12-month visit and had incomplete response at thelast available visit (5 of 48 [10.4%]) was similar to the propor-tion of patients with incomplete response at the 12-monthvisit (13 of 177 [7.3%]). It is therefore unlikely that patientswho reported NOIS participated less often in the follow-up.

There were no significant differences between patients withand patients without NOIS at baseline with regard to age, sex,duration of erythema migrans, Borrelia seropositivity, skinculture positivity, or presence of comorbidities.

The multivariable logistic regression model for repeatedmeasurements indicated that the probability of reaching acomplete response increased with time from enrollment, mostmarkedly and with greatest statistical significance between 14days and the 2-month follow-up visit, and was higher formales and for patients without NOIS at baseline. Age, positiveresults of skin culture, and duration of treatment were not as-sociated with complete response (Table 3).

Microbiologic FindingsBorrelia antibody titers were positive in 31 of 224 serumsamples (13.8%) tested at enrollment. During follow-up, therewere no significant differences in the proportion of seroposi-tive patients at different time points or between the 2 treat-ment groups. B. burgdorferi sensu lato was isolated frompretreatment skin biopsy specimens obtained from 93 of 207

Table 2. Achievement of Complete Response, by Time AfterEnrollment, to 15-Day and 10-Day Regimens of DoxycyclineTreatment

Time 15-Day Group 10-Day GroupDifferencea

(95% CIb)

14 day 71/117 (60.7) 60/108 (55.6) 5.1 (16.8)2 months 98/113 (86.7) 88/104 (84.6) 2.1 (10.9)6 months 95/101 (94.1) 81/96 (84.4) 9.7 (17.9)12 months 85/91 (93.4) 79/86 (91.9) 1.6 (9.1)Last evaluablevisit

107/117 (91.5) 101/108 (93.5) !2.1 (4.6)

Data are No. of patients with complete response/no. receiving treatment(%), unless otherwise indicated.Abbreviation: CI, confidence interval.a Percentage-point difference in the proportion of patients in each group withcomplete response.b Upper limit of the CI.

Table 1. Characteristics of Patients With Erythema MigransTreated With Doxycycline for 15 or 10 Days

Characteristic 15 Days (n = 117) 10 Days (n = 108)

Age, years 51 (38–60) 54 (43.8–62)Male sex 54 (46.2) 46 (42.6)Comorbiditiesa 45 (38.5) 50 (46.3)Tick biteb 55 (47) 48 (44.4)Days from bite to onset of EM 17 (10–30) 14 (7–20.5)Days since EM first observed 12 (5–25) 14 (5–28.5)EM with central clearing 70 (60.3) 67 (62)Largest diameter of EM, cm 16 (10–23) 14 (10–23)Nonspecific symptoms (NOIS)c 35 (29.9) 34 (31.5)

Fatigue 13 (11.1) 18 (16.7)Malaise 6 (5.1) 4 (3.7)Arthralgias 5 (4.3) 6 (5.6)Headache 14 (12) 13 (12)Myalgias 9 (7.7) 10 (9.3)Paresthesias 4 (3.4) 3 (2.8)Dizziness 4 (3.4) 2 (1.9)Nausea 4 (3.4) 2 (1.9)Insomnia 0 1 (0.9)Sleepiness 5 (4.3) 1 (0.9)Forgetfulness 1 (0.9) 0Concentration difficulties 1 (0.9) 1 (0.9)Irritability 1 (0.9) 0Pain in the spine 3 (2.6) 2 (1.9)

No. of NOIS 0 (0–1) 0 (0–1)NOIS severity scored 0 (0–2) 0 (0–5)Seropositivee 14 (12.0) 17 (15.9)Culture positivef 48 (44.9) 45 (45.0)

Data are median (interquartile range) or No. (%) of patients, unless otherwiseindicated.Abbreviations: EM, erythema migrans; NOIS, new or increased symptoms.a Underlying chronic illness, such as arterial hypertension, hyperlipidemia,osteoporosis, diabetes mellitus, thyroid disease, cardiac rhythm abnormality,psychiatric illness, ischemic heart disease, osteoarthritis, and asthma.b Patients with a history of tick bite at the site of the EM skin lesion.c Some patients had >1 NOIS.d Data are mean value (range) calculated on the basis of a 10-cm visualanalog scale, with a score of 10 being the most severe.e Positive for Borrelia burgdorferi sensu lato immunoglobulin M and/orimmunoglobulin G at enrollment. Serologic testing was done for 117 patientsin the 15-day group and 107 in the 10-day group.f A total of 107 patients in the 15-day group and 100 in the 10-day groupconsented to skin biopsy.

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FRAGE

Kann man eine Neuroborreliose in der Praxis diagnostizieren und behandeln?

1. Ja, ich habe schon mehrere diagnostiziert und erfolgreich ambulant therapiert

2. Therapieren ja, diagnostizieren mach ich nicht selber

3. nein, ich weise Verdachtspatienten immer ins Spital ein

4. weiss nicht

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and the controls inappropriately chosen. Another studyfound no association between CD57+ and post-Lymedisease symptoms [78].

Recommendation. There is not enough evidence to rec-ommend examination for lymphocyte subpopulationsas a diagnostic tool.

Recommendations

Choice of laboratory methods1. Investigation of CSF/serum pair for Bb-specificantibodies, intrathecal antibody production and signsof CSF inflammation is obligatory for laboratorydiagnosis of LNB (level B).2. Culture and PCR may be corroborative in very earlyLNB (GPP).3. At present, no further methods are recommendable.

Diagnostic criteriaLyme neuroborreliosis poses a clinical diagnostic chal-lenge. In view of the variable presentations, diagnosticcriteria rooted in a combination of clinical and labo-ratory findings are necessary. Unfortunately, such cri-teria, based on international consensus, do not exist. InEurope, detection of intrathecal synthesis of Bb-specificantibodies – a positive Bb AI – is considered necessaryfor the diagnosis [79], but its sensitivity can be as low as55% [4,5,80–84]. American criteria do not require apositive Bb AI [85].

We recommend (GPP) the following criteria fordefinite and possible LNB (Table 2).

Definite LNB. The following three criteria are fulfilled:(I) neurological symptoms suggestive of LNB (withother causes excluded); (II) CSF pleocytosis; (III) Bb-specific antibodies in CSF (produced intrathecally).

Possible LNB. Two out of these three criteria are ful-filled. If criterion III is lacking; after a duration of6 weeks, there has to be found Bb-specific antibodies inthe serum.

These criteria apply to all subclasses of LNB exceptfor late LNB with polyneuropathy where the followingshould be fulfilled for definite diagnosis:(I) Peripheral neuropathy(II) Clinical diagnosis of ACA(III) Bb-Specific antibodies in serum.

Treatment

Early LNB

Early LNB with manifestations confined to the PNS andmeninges

Effective agents. In 1983, two class IV, small case seriesindicated the e!ect of high dose intravenous (IV) pen-icillin [86,87]. Several class III and IV studies have re-ported response to 10- to 28-day courses of IV penicillin(20 million U daily), IV ceftriaxone (2 or 4 g daily), IVcefotaxime (3 g · 2 g or 2 g · 3 g daily) and oraldoxycycline (200 mg daily for 2 days and 100 mg dailyfor 8 days) [14,88–91] (Table 3). IV ceftriaxone, cefo-taxime and penicillin seem to have similar e"cacy[88,90,91] (class III). First-generation cephalosporinswere ine!ective in vitro against Bb in an American study[92]. There are not enough data to support the use ofthe following: metronidazole, trimetoprim-sulfameth-oxazole, fluconazole, isoniazid, combinations of anti-biotics or steroids.

Oral versus intravenous administration of antibiotics.Oral doxycycline has a good CSF penetration and givesCSF concentrations above the minimum inhibitoryconcentration [93]. Several class III studies have shownthat oral doxycycline has similar short- and long-terme"cacy as have various parenteral regimens [89,94–98].A recent Norwegian class I study of 102 LNB patientsshowed that oral doxycycline (200 mg daily for14 days) was non-inferior if compared with IV ceftri-axone (2 g daily for 14 days) [11].

Duration of treatment. The occurrence of persistentresidual symptoms after standard antibiotic therapy hasled to speculations about surviving bacteria and aneventual need for longer treatment duration. There areno class I comparisons of di!erent treatment durations.In most European treatment studies, the duration ran-ged from 10 to 14 days (Table 3), and few studies for aslong as 28 days. A case series reported excellent or goodresponse in 90% of patients with disseminated Lyme

Table 2 Suggested case definitions for Lyme neuroborreliosis (LNB)

Definite neuroborreliosisa

All three criteria fulfilled

Possible neuroborreliosisb

Two criteria fulfilled

Neurological symptoms suggestive

of LNB without other obvious

reasons

Cerebrospinal fluid pleocytosis

Intrathecal Bb antibody production

aThese criteria apply to all subclasses of LNB except for late LNB with

polyneuropathy where the following should be fulfilled for definite

diagnosis: (I) peripheral neuropathy (II) acrodermatitis chronica

atrophicans (III) Bb-specific antibodies in serum.bIf criteria III is lacking; after a duration of 6 weeks, there have to be

found Bb-specific IgG antibodies in the serum.

12 A. Mygland et al.

! 2009 The Author(s)Journal compilation ! 2009 EFNS European Journal of Neurology 17, 8–16

Mygland et al., Eur. J. Neurol. 2010 Jan;17(1):8–16, e1–4.

Diagnose: es braucht immmer eine LPinkl Liquor/ Serum Antikörper für

Reiber-Quotient!

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and lines were wrapped by the nurses before the medication was administered. Although no systematic assessment was done, the blinding was deemed successful for the doctors because they did not take part in practical administration of the drugs, and successful for the patients because wrapping was complete and none of them reported identifi cation of their treatment. Nurses were instructed not to inform others if they unintentionally saw the yellow colour of ceftriaxone. The allocation scheme was not revealed until all patients were examined at 4 months after the start of treatment, apart from for one patient whose intravenous ceftriaxone treatment was extended by 1 week because of an increased CSF cell count at day 13 of treatment.

We examined CSF samples for Bb intrathecal antibody production with the IDEIA Lyme neuroborreliosis kit (DakoCytomation, Cambridgeshire, UK), using purifi ed native fl agella from the B afzelii DK1 strain as antigens. In this assay, corrections for impairment of the blood–brain barrier are unnecessary,14 and intrathecal production of antibodies is detected when, according to the manufacturer’s recommendation, the antibody index of ODCSF/ODserum multiplied by (ODCSF−ODserum) is 0·3 or more (where OD is optical density).

Statistical analysisBlinded analysis of results from the fi rst 16 patients suggested a mean clinical score reduction of 6 (SD 3). The participating clinicians agreed that detection of a mean group diff erence larger than 1·5 units in favour of ceftriaxone would be desirable, corresponding to a standardised diff erence (SD/mean) of 1·5/3=0·5. With a one-sided test and signifi cance level of 0·05, 50 patients in each group would be needed to reject a null hypothesis of inferiority with 80% power.15 To compensate for dropouts and potentially non-assessable patients, we aimed to enrol 120 patients.

For comparison of unpaired categorical data, we used Pearson’s χ² test. For continuous outcome variables, we used a linear model with treatment group and clinical presentation as factors, and baseline clinical score as a covariate. The non-parametric Mann-Whitney U test was used when the outcome variable was clearly not normal. For the main outcome, we report p values for the traditional tests of superiority in which p>0·05 indicates no diff erence, and for the reverse test in which

136 patients assessed for eligibility

18 not included9 did not meet inclusion criteria8 refused to participate1 forgot enrolment

118 randomised

59 assigned to intravenous ceftriaxone

59 assigned to oral doxycycline

1 did not receive allocated treatment owing to late delivery from pharmacy3 discontinued owing

to adverse events

55 received 14 days of intravenous ceftriaxone

1 lost to follow-up (refused)

6 excluded owing to new diagnosis

2 lost to follow-up (both refused)


48 analysed 54 analysed

59 received 14 days of oral doxycycline

Figure !: Trial profi le

Oral doxycycline (n=54)

Intravenous ceftriaxone (n=48)

Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)

Coexisting diseases 22 (41%) 14 (29%)

Tick bite 30 (56%) 26 (54%)

Erythema migrans 17 (31%) 5 (10%)

Neuroborreliosis diagnosis

Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)

Symptom duration >6 months 6 (11%) 4 (8%)

Mean duration of symptoms (weeks) 10 (19) 8 (13)

Mean CSF cell count (n) 194 (237) 178 (187)

Mean CSF protein (g/L) 1·2 (0·7) 1·3 (0·8)

Mean clinical score 8·2 (4·1) 8·9 (4·1)

Mean subjective score 4·3 (2·3) 5·1 (2·3)

Main objective fi ndings

Bannwarth’s syndrome* 18 (33%) 12 (25%)

Facial palsy 12 (22%) 9 (19%)

Other cranial neuropathies 2 (4%) 3 (6%)

Radiculopathy 13 (24%) 18 (38%)

Ataxia 2 (4%) 0 (0%)

Myelopathy 1 (2%) 0 (0%)

Cognitive defi ciency 0 (0%) 1 (2%)

Arm paresis 1 (2%) 1 (2%)

ACA and paraesthesias 1 (2%) 0 (0%)

Only subjective complaints 4 (7%) 4 (8%)

Data are mean (SD) or number of patients (%), unless otherwise stated. ACA=acrodermatitis chronicum atrophicans. *Includes lymphocytic CSF pleocytosis, cranial neuropathy, and radiculopathy.

Table !: Baseline demographic, clinical, and laboratory characteristics of patients

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118 randomised




to adverse events











Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)


Tick bite 30 (56%) 26 (54%)



Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)









Facial palsy 12 (22%) 9 (19%)



Ataxia 2 (4%) 0 (0%)








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118 randomised




to adverse events











Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)


Tick bite 30 (56%) 26 (54%)



Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)









Facial palsy 12 (22%) 9 (19%)



Ataxia 2 (4%) 0 (0%)








2x100mg 1x2g

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118 randomised




to adverse events











Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)


Tick bite 30 (56%) 26 (54%)



Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)









Facial palsy 12 (22%) 9 (19%)



Ataxia 2 (4%) 0 (0%)








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118 randomised




to adverse events











Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)


Tick bite 30 (56%) 26 (54%)



Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)









Facial palsy 12 (22%) 9 (19%)



Ataxia 2 (4%) 0 (0%)








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118 randomised




to adverse events











Mean age (years) 54 (13) 52 (13)

Sex (female) 26 (48%) 17 (35%)


Tick bite 30 (56%) 26 (54%)



Defi nite 37 (69%) 34 (71%)

Possible 17 (31%) 14 (29%)









Facial palsy 12 (22%) 9 (19%)



Ataxia 2 (4%) 0 (0%)








Outcome (LP, klinischer Score, Follow-up 4 Monate):kein signifikanter Unterschied!

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EFNS GUIDELINES (EUROPEAN FEDERATION OF

NEUROLOGICAL SOCIETIES)

Frühe Neuroborreliose (< 6 Monate)

๏ PNS (Bannwarth)/ Meningitis:

๏ Penicillin IV, Ceftriaxon 2g IV, Doxycyclin 2x100mg für 14 Tage,

๏ ZNS (Myelitis, cerebrale Vaskulitis, Enzephalitis)๏ Ceftriaxon 2g IV tgl für 14 Tage

Späte Neuroborreliose (> 6 Monate)

๏ 3 Wochen therapie (Ceftriaxon), Ausnahme ACA und PN


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EFNS GUIDELINES (EUROPEAN FEDERATION OF

NEUROLOGICAL SOCIETIES)

Frühe Neuroborreliose (< 6 Monate)

๏ PNS (Bannwarth)/ Meningitis:

๏ Penicillin IV, Ceftriaxon 2g IV, Doxycyclin 2x100mg für 14 Tage,

๏ ZNS (Myelitis, cerebrale Vaskulitis, Enzephalitis)๏ Ceftriaxon 2g IV tgl für 14 Tage

Späte Neuroborreliose (> 6 Monate)

๏ 3 Wochen therapie (Ceftriaxon), Ausnahme ACA und PN


i n f e k t t a g _ 2 0 1 3

SEROLOGIE

alte Trends

i n f e k t t a g _ 2 0 1 3

FRAGE

Wie hoch ist die Seroprävelnz der Borreliose bei der gesunden Bevölkerung?

1. ca 2%

2. ca 5%

3. ca 10%

4. >10%

i n f e k t t a g _ 2 0 1 3

SEROPRÄVALENZ SCHWEIZ (%)

0

10

20

30

40

35

26

10

WALDARBEITER OL LÄUFERBLUTSPENDER

Altpeter et al., Swiss Med Wkly. 2013;143:0. // Nadal et al., Eur J Clin Microbiol Infect Dis. 1989 Nov;8(11):992–5. // Altpeter et al. SMW. 1992 Jan 8;122(1-2):22–6. // Fahrer et al., JID 1991 Feb;163(2):305–10.

i n f e k t t a g _ 2 0 1 3

SEROLOGIE IN RISIKOGRUPPEN

Fahrer et al., JID 1991 Feb;163(2):305–10.

negativ74%

positiv26%

OL LÄUFER (950)

96%

4%

BLUTSPENDER >1000 MÜM (51)

94%

6%

FREIWILLIGE STADT BERN (50)

Baseline (248 positive Serologien)Anamnese positiv (1.9-3.1%)•18 hatten eine sichere LB•11 hatten eine mögliche

i n f e k t t a g _ 2 0 1 3

SEROLOGIE IN RISIKOGRUPPEN

Fahrer et al., JID 1991 Feb;163(2):305–10.

negativ74%

positiv26%

OL LÄUFER (950)

96%

4%

BLUTSPENDER >1000 MÜM (51)

94%

6%

FREIWILLIGE STADT BERN (50)

Halbjahresfollow-up:•Serokonversion: 8% (45/558)•nur eine symptomatische LB•klinische LB Inzidenz 0.8% (6/755)

Baseline (248 positive Serologien)Anamnese positiv (1.9-3.1%)•18 hatten eine sichere LB•11 hatten eine mögliche

i n f e k t t a g _ 2 0 1 3

782 • CID 2001:33 (15 September) • Kalish et al.

Table 1. Positive and indeterminate antibody responses to Borrelia burgdorferi, asdetermined by ELISA, Western blot, or both, in patients who had early Lyme disease orLyme arthritis.

Test, antibody, result

No. (%) of patients

With early Lyme disease(n p 40)

With Lyme arthritis(n p 39)

Duringactive infection At follow-up


ELISA

IgM

Positive 20 (50) 0 4 (10) 0

Indeterminate 17 (43) 9 (23) 22 (56) 13 (33)

IgG

Positive 17 (43) 11 (28) 39 (100) 28 (72)

Indeterminate 11 (28) 12 (30) 0 10 (26)

Western blot

IgM 35 (88) 7 (18) 21 (54) 9 (23)

IgG 20 (50) 10 (25) 39 (100) 24 (62)

ELISA and Western blot

IgM 33 (83) 4 (10) 15 (38) 6 (15)

IgG 19 (48) 10 (25) 39 (100) 24 (62)

IgM or IgG 35 (88) 14 (35) 39 (100) 26 (67)

proteins during active infection, including several bands notused in the diagnostic criteria. In the follow-up evaluation, thenumber of IgM and IgG bands had decreased, but at least 2diagnostic IgM bands were still apparent. Altogether, 14 patients(35%) were still seropositive by the 2-test approach 10–20 yearsafter having early Lyme disease.

During early disease, the median IgM response was 300 Uand the median IgG response was 400 U by ELISA (figure 1,left); 10–20 years later, the median IgG response was still 400U, and IgM reactivity was usually no longer detectable. Duringactive disease, Western blot frequently detected IgM or IgGreactivity with the 23-kDa outer surface protein C (OspC) andthe 41-kDa flagellar protein, sometimes with the 18-, 39-, 45-,58-, 66-, or 93-kDa proteins, but rarely with the 28-, 30-, or31-kDa (OspA) proteins or the 34-kDa (OspB) proteins (figure2, left). At long-term follow-up, IgM reactivity was found al-most exclusively with the 23- and 41-kDa proteins, whereasIgG responses to bands that had been present during activeinfection were often still apparent.

Serological results for patients with late Lyme disease.During active Lyme arthritis, 15 (38%) of the 39 patients hada positive IgM response to B. burgdorferi, and all had a positiveIgG response by the 2-test approach (table 1). At long-termfollow-up, 6 (15%) still had IgM reactivity with the spirochete( ), and 24 (62%) had a positive IgG response (P p .04 P !

). Altogether, 26 patients (67%) were still seropositive by.0001the 2-test approach 10–20 years after having active Lyme ar-thritis. Although most patients who remained seropositive at

long-term follow-up had a positive IgG antibody response, 2patients in this group (5%) had a positive IgM response only.During active infection, both of these patients had IgM andIgG responses to multiple spirochetal proteins. In the follow-up evaluation, the number of IgM and IgG bands had de-creased, but 2 diagnostic IgM bands were still apparent.

During active Lyme arthritis, the median IgM response byELISA was 100 U, and the median IgG response was 12,800 U(figure 1, right); 10–20 years later, the median IgG responsehad declined 6-fold, to 1600 U, and only a few patients stillhad low-level IgM reactivity with the spirochete. During activearthritis, the patients often had IgM reactivity to the 23- and41-kDa proteins and IgG responses to !10 spirochetal proteins,and about one-third had reactivity with the OspA and OspBproteins (figure 2, right). At long-term follow-up, IgM reactivityhad faded considerably, but IgG reactivity was usually still pre-sent, with bands most often present at 18, 39, 41, 58, and 93kDa.

Concordance of ELISA and Western blot results at long-term follow-up. The concordance of ELISA and Western blotresults was similar for patients with early disease and those withLyme arthritis, and therefore, data from both groups are pre-sented together here. All 18 patients with a negative IgG re-sponse by ELISA had a negative Western blot result, but 27(44%) of the 61 patients who had a positive or indeterminateIgG response by ELISA had fewer than the required minimumof 5 bands on Western blot ( ; CI, 0.21–0.52). Of thek p 0.3622 patients with a positive or indeterminate IgM response by

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782 • CID 2001:33 (15 September) • Kalish et al.

Table 1. Positive and indeterminate antibody responses to Borrelia burgdorferi, asdetermined by ELISA, Western blot, or both, in patients who had early Lyme disease orLyme arthritis.

Test, antibody, result

No. (%) of patients

With early Lyme disease(n p 40)

With Lyme arthritis(n p 39)



ELISA

IgM

Positive 20 (50) 0 4 (10) 0

Indeterminate 17 (43) 9 (23) 22 (56) 13 (33)

IgG

Positive 17 (43) 11 (28) 39 (100) 28 (72)

Indeterminate 11 (28) 12 (30) 0 10 (26)

Western blot

IgM 35 (88) 7 (18) 21 (54) 9 (23)

IgG 20 (50) 10 (25) 39 (100) 24 (62)

ELISA and Western blot

IgM 33 (83) 4 (10) 15 (38) 6 (15)

IgG 19 (48) 10 (25) 39 (100) 24 (62)

IgM or IgG 35 (88) 14 (35) 39 (100) 26 (67)

proteins during active infection, including several bands notused in the diagnostic criteria. In the follow-up evaluation, thenumber of IgM and IgG bands had decreased, but at least 2diagnostic IgM bands were still apparent. Altogether, 14 patients(35%) were still seropositive by the 2-test approach 10–20 yearsafter having early Lyme disease.

During early disease, the median IgM response was 300 Uand the median IgG response was 400 U by ELISA (figure 1,left); 10–20 years later, the median IgG response was still 400U, and IgM reactivity was usually no longer detectable. Duringactive disease, Western blot frequently detected IgM or IgGreactivity with the 23-kDa outer surface protein C (OspC) andthe 41-kDa flagellar protein, sometimes with the 18-, 39-, 45-,58-, 66-, or 93-kDa proteins, but rarely with the 28-, 30-, or31-kDa (OspA) proteins or the 34-kDa (OspB) proteins (figure2, left). At long-term follow-up, IgM reactivity was found al-most exclusively with the 23- and 41-kDa proteins, whereasIgG responses to bands that had been present during activeinfection were often still apparent.

Serological results for patients with late Lyme disease.During active Lyme arthritis, 15 (38%) of the 39 patients hada positive IgM response to B. burgdorferi, and all had a positiveIgG response by the 2-test approach (table 1). At long-termfollow-up, 6 (15%) still had IgM reactivity with the spirochete( ), and 24 (62%) had a positive IgG response (P p .04 P !

). Altogether, 26 patients (67%) were still seropositive by.0001the 2-test approach 10–20 years after having active Lyme ar-thritis. Although most patients who remained seropositive at

long-term follow-up had a positive IgG antibody response, 2patients in this group (5%) had a positive IgM response only.During active infection, both of these patients had IgM andIgG responses to multiple spirochetal proteins. In the follow-up evaluation, the number of IgM and IgG bands had de-creased, but 2 diagnostic IgM bands were still apparent.

During active Lyme arthritis, the median IgM response byELISA was 100 U, and the median IgG response was 12,800 U(figure 1, right); 10–20 years later, the median IgG responsehad declined 6-fold, to 1600 U, and only a few patients stillhad low-level IgM reactivity with the spirochete. During activearthritis, the patients often had IgM reactivity to the 23- and41-kDa proteins and IgG responses to !10 spirochetal proteins,and about one-third had reactivity with the OspA and OspBproteins (figure 2, right). At long-term follow-up, IgM reactivityhad faded considerably, but IgG reactivity was usually still pre-sent, with bands most often present at 18, 39, 41, 58, and 93kDa.

Concordance of ELISA and Western blot results at long-term follow-up. The concordance of ELISA and Western blotresults was similar for patients with early disease and those withLyme arthritis, and therefore, data from both groups are pre-sented together here. All 18 patients with a negative IgG re-sponse by ELISA had a negative Western blot result, but 27(44%) of the 61 patients who had a positive or indeterminateIgG response by ELISA had fewer than the required minimumof 5 bands on Western blot ( ; CI, 0.21–0.52). Of thek p 0.3622 patients with a positive or indeterminate IgM response by

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Kalish et al., CID. 2001 Sep 15;33(6):780–5.

i n f e k t t a g _ 2 0 1 3

SCHLUSSFOLGERUNG๏ hohe Seroprävalenz in der Schweiz (4-30% je nach Risiko

und Alter)๏ positive Serologie ohne Klinik nicht verwertbar

๏ viele asymptomatische Infektionen

๏ Serologie unspezifisch (Screening-Test) ⇒ immer Bestätigung mittels Western-Blot

๏ Stadium I: Serologie oft negativ

๏ Serologie kann nicht als Verlauf verwertet werden

i n f e k t t a g _ 2 0 1 3

TELEFONKONSIL

Ein Landwirt hatte bereits vor 3 Jahren ein erfolgreich behandeltes Erythema migrans (EM) und kommt nun mit einem erneutem EM an anderer Stelle.

1. Rezidiv?

2. Reinfektion?

3. Immunität?

i n f e k t t a g _ 2 0 1 3

IMMUNITÄT DER BORRELIOSE

๏ früher: keine antibiotische Therapie, schubweiser Verlauf mit teilweise wiederholten EM war häufig

๏ heute: Erreger bekannt, EM wird meist behandelt

๏ Immunität: ๏ frühe Lymeborreliose (Stadium I/II): ungenügende Immunität

๏ keine Serokonversion nach EM-Therapie: keine Immunität

๏ späte Borreliose: protektive Immunität ((Sub)Speziesspezifisch)

Huegli et al., Ticks Tick Borne Dis. 2011 Sep;2(3):129–36. // Steere. N Engl J Med. 2012 Nov 15;367(20):1950–1. // Nadelman et al., CID. 2007 Oct 15;45(8):1032–8.

i n f e k t t a g _ 2 0 1 3

Nadelman et al., NEJM. 2012 Nov 15;367(20):1883–90.

n engl j med 367;20 nejm.org november 15, 2012 1883

The new england journal of medicineestablished in 1812 november 15, 2012 vol. 367 no. 20

Differentiation of Reinfection from Relapse in Recurrent Lyme Disease

Robert B. Nadelman, M.D., Klára Hanincová, Ph.D., Priyanka Mukherjee, B.S., Dionysios Liveris, Ph.D., John Nowakowski, M.D., Donna McKenna, A.N.P., Dustin Brisson, Ph.D., Denise Cooper, B.S., Susan Bittker, M.S.,

Gul Madison, M.D., Diane Holmgren, R.N., Ira Schwartz, Ph.D., and Gary P. Wormser, M.D.

A bs tr ac t

From the Division of Infectious Diseases, Department of Medicine (R.B.N., J.N., D.M., D.C., S.B., G.M., D.H., G.P.W.), and the Department of Microbiology and Im-munology (K.H., P.M., D.L., I.S.), New York Medical College, Valhalla; and the Department of Biology, University of Pennsylvania, Philadelphia (D.B.). Ad-dress reprint requests to Dr. Nadelman at the Division of Infectious Diseases, New York Medical College, Munger Pavil-ion, Rm. 245, Valhalla, NY 10595, or at [email protected].

N Engl J Med 2012;367:1883-90. DOI: 10.1056/NEJMoa1114362Copyright © 2012 Massachusetts Medical Society.

BackgroundErythema migrans is the most common manifestation of Lyme disease. Recurrences are not uncommon, and although they are usually attributed to reinfection rather than relapse of the original infection, this remains somewhat controversial. We used molecular typing of Borrelia burgdorferi isolates obtained from patients with culture-confirmed episodes of erythema migrans to distinguish between relapse and reinfection.

MethodsWe determined the genotype of the gene encoding outer-surface protein C (ospC) of B. burgdorferi strains detected in cultures of skin or blood specimens obtained from patients with consecutive episodes of erythema migrans. After polymerase-chain-reaction amplification, ospC genotyping was performed by means of reverse line-blot analysis or DNA sequencing of the nearly full-length gene. Most strains were further analyzed by determining the genotype according to the 16S–23S ribosomal RNA intergenic spacer type, multilocus sequence typing, or both. Patients received standard courses of antibiotics for erythema migrans.

ResultsB. burgdorferi isolates obtained from 17 patients who received a diagnosis of ery-thema migrans between 1991 and 2011 and who had 22 paired episodes of this lesion (initial and second episodes) were available for testing. The ospC genotype was found to be different at each initial and second episode. Apparently identical genotypes were identified on more than one occasion in only one patient, at the first and third episodes, 5 years apart, but different genotypes were identified at the second and fourth episodes.

ConclusionsNone of the 22 paired consecutive episodes of erythema migrans were associated with the same strain of B. burgdorferi on culture. Our data show that repeat episodes of erythema migrans in appropriately treated patients were due to reinfection and not relapse. (Funded by the National Institutes of Health and the William and Sylvia Silberstein Foundation.)

The New England Journal of Medicine Downloaded from nejm.org by CAROL STRAHM on November 14, 2012. For personal use only. No other uses without permission.

Copyright © 2012 Massachusetts Medical Society. All rights reserved.

i n f e k t t a g _ 2 0 1 3

Nadelman et al., NEJM. 2012 Nov 15;367(20):1883–90.

n engl j med 367;20 nejm.org november 15, 2012 1883

The new england journal of medicineestablished in 1812 november 15, 2012 vol. 367 no. 20

Differentiation of Reinfection from Relapse in Recurrent Lyme Disease

Robert B. Nadelman, M.D., Klára Hanincová, Ph.D., Priyanka Mukherjee, B.S., Dionysios Liveris, Ph.D., John Nowakowski, M.D., Donna McKenna, A.N.P., Dustin Brisson, Ph.D., Denise Cooper, B.S., Susan Bittker, M.S.,

Gul Madison, M.D., Diane Holmgren, R.N., Ira Schwartz, Ph.D., and Gary P. Wormser, M.D.

A bs tr ac t

From the Division of Infectious Diseases, Department of Medicine (R.B.N., J.N., D.M., D.C., S.B., G.M., D.H., G.P.W.), and the Department of Microbiology and Im-munology (K.H., P.M., D.L., I.S.), New York Medical College, Valhalla; and the Department of Biology, University of Pennsylvania, Philadelphia (D.B.). Ad-dress reprint requests to Dr. Nadelman at the Division of Infectious Diseases, New York Medical College, Munger Pavil-ion, Rm. 245, Valhalla, NY 10595, or at [email protected].

N Engl J Med 2012;367:1883-90. DOI: 10.1056/NEJMoa1114362Copyright © 2012 Massachusetts Medical Society.

BackgroundErythema migrans is the most common manifestation of Lyme disease. Recurrences are not uncommon, and although they are usually attributed to reinfection rather than relapse of the original infection, this remains somewhat controversial. We used molecular typing of Borrelia burgdorferi isolates obtained from patients with culture-confirmed episodes of erythema migrans to distinguish between relapse and reinfection.

MethodsWe determined the genotype of the gene encoding outer-surface protein C (ospC) of B. burgdorferi strains detected in cultures of skin or blood specimens obtained from patients with consecutive episodes of erythema migrans. After polymerase-chain-reaction amplification, ospC genotyping was performed by means of reverse line-blot analysis or DNA sequencing of the nearly full-length gene. Most strains were further analyzed by determining the genotype according to the 16S–23S ribosomal RNA intergenic spacer type, multilocus sequence typing, or both. Patients received standard courses of antibiotics for erythema migrans.

ResultsB. burgdorferi isolates obtained from 17 patients who received a diagnosis of ery-thema migrans between 1991 and 2011 and who had 22 paired episodes of this lesion (initial and second episodes) were available for testing. The ospC genotype was found to be different at each initial and second episode. Apparently identical genotypes were identified on more than one occasion in only one patient, at the first and third episodes, 5 years apart, but different genotypes were identified at the second and fourth episodes.

ConclusionsNone of the 22 paired consecutive episodes of erythema migrans were associated with the same strain of B. burgdorferi on culture. Our data show that repeat episodes of erythema migrans in appropriately treated patients were due to reinfection and not relapse. (Funded by the National Institutes of Health and the William and Sylvia Silberstein Foundation.)

The New England Journal of Medicine Downloaded from nejm.org by CAROL STRAHM on November 14, 2012. For personal use only. No other uses without permission.


๏ in keinem von 22 konsekutiven Episoden (17 Patienten) von Erythema migrans wurde kulturell derselbe Borrelien-Stamm nachgewiesen

๏ es handelte sich um Reinfektionen

i n f e k t t a g _ 2 0 1 3

Huegli et al., Ticks Tick Borne Dis. 2011 Sep;2(3):129–36.

RISIKO EINES ZECKENSTICHS...

i n f e k t t a g _ 2 0 1 3



EM5.2%

kein Sy94.8%

EM NACH ZECKENSTICH (14/259)

i n f e k t t a g _ 2 0 1 3



EM5.2%

kein Sy94.8%


Serokonversion3.5%

keine Konversion96.5%

ASYMPTOMATISCHE SEROKONVERSION (9/255)

i n f e k t t a g _ 2 0 1 3



EM5.2%

kein Sy94.8%


Serokonversion3.5%

keine Konversion96.5%

ASYMPTOMATISCHE SEROKONVERSION (9/255)

33%

67%

BORRELIENINFIZIERTE ZECKEN

B. burg. ss1

B. garinii2

B. valasiana3

B.afzelii25

i n f e k t t a g _ 2 0 1 3

Feder et al., NEJM. 2007 Oct 4;357(14):1422–30. // Stupica et al., CID 2012 May 21

,CHRONIC LYME DISEASE‘T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 357;14 www.nejm.org october 4, 20071426

additional antibiotic treatment for patients who have long-standing subjective symptoms after ap-propriate initial treatment for an episode of Lyme disease.32-34

One of these trials enrolled 78 patients who were seropositive for antibodies against B. burgdor-feri at trial entry; a second trial enrolled 51 patients who were seronegative.32 All patients had anteced-ent objective signs of Lyme disease, most often physician-diagnosed erythema migrans. Patients were treated either with a 1-month course of cef-triaxone administered intravenously, followed by 2 months of doxycycline given orally, or with iden-tical-appearing intravenous and then oral place-bos. Patients were assessed at enrollment and 3 months after completion of treatment with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). There were no significant differences in the scores between the patients in the antibiotic and placebo groups.

In a single-center trial conducted by Krupp et al., 55 patients with severe fatigue (as measured by an 11-item questionnaire) after treatment of well-documented Lyme disease underwent ran-domization to receive ceftriaxone or an identical-appearing placebo for 28 days.33 The investigators reported a reduction in scores for fatigue severity in the ceftriaxone group that exceeded the reduc-tion in the placebo group by 13 percentage points (i.e., a reduction of 22% vs. 9%; P = 0.01) but no significant improvement in cognitive function. There was no significant difference between the groups with regard to the degree of improvement in reported health status on the basis of the SF-36 score. Patients in the ceftriaxone group were sig-nificantly more likely than those in the placebo group to identify their treatment assignment cor-rectly at the end of therapy, raising a concern that masking was compromised and that a placebo ef-fect may explain the greater improvement in scores for fatigue severity in the treated group.33

Antibiotic therapy can cause considerable harm to patients treated for chronic Lyme disease or post–Lyme disease symptoms.2 Life-threatening anaphylaxis33 and biliary complications requiring cholecystectomy35 have occurred after ceftriaxone administration. Candidemia from infection of an intravenous catheter has resulted in death.36 In an unpublished study in which 37 patients underwent randomization to receive 10 weeks of treatment with either ceftriaxone or placebo, about one fifth of the patients had serious adverse events, the ma-jority of which were related to intravenous cath-eters.37 In light of the risk of serious adverse events in their study, Krupp et al. concluded that “re-peated courses of antibiotic treatment are not indi-cated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction.”33

Eligibility criteria for two controlled trials stip-ulated that symptoms must be severe enough to interfere with the patient’s ability to function.32 Thus, the physical health status of the patients enrolled in these two studies was equivalent to that of patients with congestive heart failure or osteoarthritis.32 This finding was preordained by the study design, but it has been incorrectly inter-preted by some to indicate that patients with post–Lyme disease symptoms typically are severely disabled.

The investigators who conducted the controlled treatment trials had great difficulty finding pa-tients who met the criteria for entry, despite inten-sive efforts that included both the notification and involvement of Lyme disease support groups and associations.32,33 For two of the three studies, ad-ditional sites had to be engaged,32 and the enroll-ment period had to be extended for all three stud-ies.32,33 To enroll 55 patients in one of the studies, investigators had to screen more than 500 people, most of whom were excluded because of the ab-sence of a substantiated history of Lyme disease.33

33p9

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REG F

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Category 1 Category 2 Category 3 Category 4Symptoms of unknowncause, with no evidence

of Borrelia burgdorferiinfection

A well-defined illnessunrelated to B. burgdorferi

infection

Symptoms of unknowncause, with antibodies

against B. burgdorferi butno history of objective

clinical findings that areconsistent with Lyme disease

Post–Lyme disease syndrome

Figure 1. The Four Predominant Categories of Disease Associated with Chronic Lyme Disease.

Only patients with category 4 disease have post–Lyme disease symptoms.

The New England Journal of Medicine Downloaded from nejm.org on February 21, 2013. For personal use only. No other uses without permission.


i n f e k t t a g _ 2 0 1 3

Feder et al., NEJM. 2007 Oct 4;357(14):1422–30. // Stupica et al., CID 2012 May 21

,CHRONIC LYME DISEASE‘T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 357;14 www.nejm.org october 4, 20071426

additional antibiotic treatment for patients who have long-standing subjective symptoms after ap-propriate initial treatment for an episode of Lyme disease.32-34

One of these trials enrolled 78 patients who were seropositive for antibodies against B. burgdor-feri at trial entry; a second trial enrolled 51 patients who were seronegative.32 All patients had anteced-ent objective signs of Lyme disease, most often physician-diagnosed erythema migrans. Patients were treated either with a 1-month course of cef-triaxone administered intravenously, followed by 2 months of doxycycline given orally, or with iden-tical-appearing intravenous and then oral place-bos. Patients were assessed at enrollment and 3 months after completion of treatment with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). There were no significant differences in the scores between the patients in the antibiotic and placebo groups.

In a single-center trial conducted by Krupp et al., 55 patients with severe fatigue (as measured by an 11-item questionnaire) after treatment of well-documented Lyme disease underwent ran-domization to receive ceftriaxone or an identical-appearing placebo for 28 days.33 The investigators reported a reduction in scores for fatigue severity in the ceftriaxone group that exceeded the reduc-tion in the placebo group by 13 percentage points (i.e., a reduction of 22% vs. 9%; P = 0.01) but no significant improvement in cognitive function. There was no significant difference between the groups with regard to the degree of improvement in reported health status on the basis of the SF-36 score. Patients in the ceftriaxone group were sig-nificantly more likely than those in the placebo group to identify their treatment assignment cor-rectly at the end of therapy, raising a concern that masking was compromised and that a placebo ef-fect may explain the greater improvement in scores for fatigue severity in the treated group.33

Antibiotic therapy can cause considerable harm to patients treated for chronic Lyme disease or post–Lyme disease symptoms.2 Life-threatening anaphylaxis33 and biliary complications requiring cholecystectomy35 have occurred after ceftriaxone administration. Candidemia from infection of an intravenous catheter has resulted in death.36 In an unpublished study in which 37 patients underwent randomization to receive 10 weeks of treatment with either ceftriaxone or placebo, about one fifth of the patients had serious adverse events, the ma-jority of which were related to intravenous cath-eters.37 In light of the risk of serious adverse events in their study, Krupp et al. concluded that “re-peated courses of antibiotic treatment are not indi-cated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction.”33

Eligibility criteria for two controlled trials stip-ulated that symptoms must be severe enough to interfere with the patient’s ability to function.32 Thus, the physical health status of the patients enrolled in these two studies was equivalent to that of patients with congestive heart failure or osteoarthritis.32 This finding was preordained by the study design, but it has been incorrectly inter-preted by some to indicate that patients with post–Lyme disease symptoms typically are severely disabled.

The investigators who conducted the controlled treatment trials had great difficulty finding pa-tients who met the criteria for entry, despite inten-sive efforts that included both the notification and involvement of Lyme disease support groups and associations.32,33 For two of the three studies, ad-ditional sites had to be engaged,32 and the enroll-ment period had to be extended for all three stud-ies.32,33 To enroll 55 patients in one of the studies, investigators had to screen more than 500 people, most of whom were excluded because of the ab-sence of a substantiated history of Lyme disease.33

33p9

AUTHOR:

FIGURE:

JOB: ISSUE:

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AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.

Please check carefully.

REG F

Enon

1st2nd3rd

Agger (Wormser)

1 of 1

10-04-07

ARTIST: ts

35715

Category 1 Category 2 Category 3 Category 4Symptoms of unknowncause, with no evidence

of Borrelia burgdorferiinfection

A well-defined illnessunrelated to B. burgdorferi

infection

Symptoms of unknowncause, with antibodies

against B. burgdorferi butno history of objective

clinical findings that areconsistent with Lyme disease

Post–Lyme disease syndrome

Figure 1. The Four Predominant Categories of Disease Associated with Chronic Lyme Disease.

Only patients with category 4 disease have post–Lyme disease symptoms.

The New England Journal of Medicine Downloaded from nejm.org on February 21, 2013. For personal use only. No other uses without permission.


Studien Kategorie 4:

๏ Drei randomisierte Studien: keine Benefit von zusätzlicher Antibiotikatherapie

๏ prospektive Kontrollgruppe CID-Studie von Stupica: nach 6 Mt kein signifikanter Unterschied)

i n f e k t t a g _ 2 0 1 3

Scandinavia [30]. The present study in European patients witherythema migrans shows that treatment with doxycycline 100mg twice daily for 10 days is not less effective than the 15-daytreatment. Regardless of treatment assignment, the outcomewas excellent. We found no evidence of objective manifesta-tions of the disease during the 12-month follow-up period.Only 13 of 177 patients (7.3%) examined at 12 months report-ed NOIS, and none of them qualified as having post–Lymedisease syndrome [14]. The large majority of patients hadcomplete response from 2 months onward. Improvement waspredominantly due to alleviation of fatigue, headache, arthral-gia, and myalgia; the frequencies of the other 10 NOIS fluctu-ated mildly (Supplementary Figure 1).

In our study, 3.1% of patients reported phototoxic adverseevents, which is in accordance with previous reports of theincidence of phototoxic cutaneous reactions to doxycycline asbeing <5% [31]. We observed phototoxicity in the 15-daygroup only. This could have been a coincidence, because thephototoxicity of doxycycline has been suggested to be depen-dent on the dose of doxycycline and the ultraviolet A intensity

[32], but according to some reports it is not related to durationof therapy [33].

The multivariable logistic regression model for repeatedmeasurements indicated that reaching a complete response in-creased with time from enrollment and that it was higher formales and patients without NOIS at baseline, whereas age,positive results of skin culture, and duration of treatment werenot significantly associated with complete response (Table 3).We do not have a reliable explanation for the higher rate ofcomplete response in males. Other findings, which are inaccordance with previous results, suggest that subjective long-term sequelae of Lyme borreliosis correlate with greater sever-ity of illness (ie, presence of NOIS) at presentation but notwith the duration of the initial antibiotic treatment (when thechoice of antibiotic and duration of treatment accord withrecommendations) [34]. Our previous study [35] found thatpatients with positive results of skin cultures had a lowerprobability of reaching complete response than patients whohad negative results of culture (OR, 0.39 [95% CI, .17–.88];P = .02), whereas in the present study this association was notstatistically significant, although the direction of association,albeit weak, was preserved (Table 3).

The proportions of patients with complete response weresimilar in the 2 treatment groups. With the exception of the14-day time point, when 26.2% of patients had still visible ery-thema migrans, at all later time points no objective manifesta-tions were found, and those with incomplete response hadrelatively benign subjective symptoms without functional com-promise. The upper limits of the 1-sided 95% CIs for differ-ences in complete response rates between the 2 treatmentgroups at 14 days, 2 months, 6 months, 12 months, and thelast available visit were 16.8, 10.9, 17.9, 9.1, and 4.6 percentagepoints, respectively. These results indicate that 15 days of treat-ment could have been associated with only a small improve-ment in outcome, at most, 4.6–17.9 percentage points(Table 2). Such small potential differences in efficacy are con-sistent with results of other antibiotic trials involving patientswith erythema migrans in which treatment regimens were con-sidered equivalent [3, 6, 7]. Furthermore, when our patientsand control subjects were asked whether they had had any of14 nonspecific symptoms during the week preceding the 6-month visit (when the percentage-point difference in completeresponse rate between the 15- and 10-day groups was largest),there were no significant differences between patients and con-trols with regard to frequency, number, and severity of non-specific symptoms. This finding accords with results of ourprevious trial, in which patients treated for erythema migranswere no more likely than those in an uninfected control groupto have subjective symptoms after 12 months [15].

There are several limitations to our study. First, we includedonly patients with solitary erythema migrans rather than those

Table 4. Demographic Characteristics and Frequency and Se-verity of 14 Nonspecific Symptoms in Patients in the 15-Day and10-Day Treatment Groups and in Controls at 6 Months AfterEnrollment

Characteristic15 Days(n = 101)

10 Days(n = 96)

Controls(n = 81) Pa

Age 52 (39–60) 56 (44.8–62) 51 (34–63) .19Male sex 46 (45.5) 39 (40.6) 38 (46.9) .66Comorbidities 40 (39.6) 45 (49.5) 36 (44.4) .58Nonspecific symptoms at 6 monthsAny 72 (71.3) 79 (82.3) 60 (74.1) .18Fatigue 57 (56.4) 55 (57.3) 44 (54.3) .92Malaise 40 (39.6) 40 (41.7) 37 (45.7) .71Arthralgias 42 (41.6) 47 (49.0) 34 (42.0) .52Headache 44 (43.6) 44 (45.8) 33 (40.7) .79Myalgias 36 (35.6) 39 (40.6) 30 (37.0) .76Paresthesias 37 (36.6) 39 (40.6) 25 (30.9) .40Dizziness 30 (29.7) 33 (34.4) 13 (16.1) .02Nausea 21 (20.8) 19 (19.8) 16 (19.8) .98Insomnia 36 (35.6) 42 (43.8) 29 (35.8) .42Sleepiness 42 (41.6) 44 (45.8) 38 (46.9) .74Forgetfulness 38 (37.6) 43 (44.8) 28 (34.6) .35Concentrationdifficulties

36 (35.6) 42 (43.8) 29 (35.8) .42

Irritability 37 (36.6) 44 (45.8) 42 (51.9) .11Pain in spine 57 (56.4) 53 (55.2) 45 (55.6) .98

No. of symptoms 5 (0–9) 6 (1–10.3) 6 (0–9) .51Symptom severity score 10 (0–25) 11 (4–30.8) 10 (0–30) .61

Data are median (interquartile range), or number (%) of patients.a Determined by the !2 test (for categorical variables) or by the Kruskal-Wallistest (for numerical variables).

348 • CID 2012:55 (1 August) • Stupica et al



ownloaded from

SYMPTOME 6 MT NACH THERAPIE DES ERYTHEMA

MIGRANS„Patients were asked to refer their spouse, another family member, or a friend whose age was +/−5 years of the patient’s age and who had no history of Lyme borreliosis to

serve as a control“

Stupica et al., CID 2012 May 21

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2. FRÜHSOMMER-MENINGO-ENZEPHALITIS (FSME)

neue Trends?

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FRÜHSOMMER-MENINGO-ENZEPHALITIS

๏ zweithäufigste zeckenübertagene Erkrankung in der Schweiz

๏ ca 100-250 Fälle jedes Jahr

๏ Erreger: Flavivirus

๏ Symptome: asymptomatisch - grippale Symptome - Meningitis/ Enzephalitis - Tod


i n f e k t t a g _ 2 0 1 3

FSME - INZIDENZ IN DER OSTSCHWEIZ

2.9


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Das Risiko einer Infektion mit Zecken-Hirnhautentzündung nimmt zu „Nach einer starken Zunahme im 2005 (206 Fälle) und 2006 (246) haben die gemeldeten Fälle von Frühsommer-Meningoenzephalitis (FSME) im letzten Jahr wieder deutlich abgenommen (111 Fälle). Die Zahl der Fälle ist damit aber immer noch höher als der jährliche Durchschnitt der Jahre 2000-2004 (99 Fälle)“ schreibt das Bundesamt für Gesundheit (zitiert aus Bull BAG 2008; Nr. 7: 124-127). Die rückläufige Zahl der registrierten FSME-Fälle in der Schweiz im Jahr 2007 darf nicht mit einem Rückgang der FSME-verseuchten Zeckenpopulation gleichgesetzt werden. Das Risiko einer Infektion bleibt hoch oder ist weiter angestiegen. Der Rückgang der Anzahl registrierter FSME-Infektionen kann mit verschiedenen Faktoren zusammenhängen: risikobewussteres Verhalten infolge der schweizweiten Kampagne, vermehrte Impfung der exponierte Personen (FSME-Risikogruppen), aber auch die jährlichen Fluktuation der Entwicklung der Zeckenpopulation infolge der Witterungsverhältnisse. Wie sich die mit FSME verseuchte Zeckenpopulation - und damit das Infektionsrisiko mit FSME - weiter entwickelt, könnte nur mit einer periodischen flächendeckenden und stichprobenweisen Untersuchung von Zecken aufgezeigt werden. Solche systematischen Untersuchungen werden – leider nur für beschränkte Regionen - vom zoologischen Institut der Universität Neuenburg durchgeführt.

(Graphik aus Bull BAG 2008; Nr. 7: 124-127)

2008 2009 2010 2011 2012

122 115 98 172 82

2.9 3.0 2.0 3.6

TRENDS- INZIDENZ FSMEAltpeter et al., Swiss Med Wkly. 2013;143:0. // www.bag.admin.ch

2006

http://www.bag.admin.ch


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NEUSTE TRENDS FMSE (2008-11)

๏ 79% der Patienten waren hospitalisiert

๏ 1% Mortalität

๏ 50-60% zweigipfliger Verlauf mit initial Grippe-Symptomen

๏ 19% Meningitis - 59% Meningoenzephalitis - 9% keine Neurologie

๏ Verdachtsdiagnose meist klinisch - 20% Zeckenstich

๏ Diagnose: meist Serologie - 3% Liquor


i n f e k t t a g _ 2 0 1 3

Ganzer nördlicher Kantonsteil (unteres Toggenburg bis unteres Rheintal), Jona/Wagen, Mels/Sargans/Vilters

2011Wil/Jonschwil/Zuzwil/Niederhelfenschwil, Mörschwil, St. Magrethen/Balgach, Jona/Wagen, Mels/Sargans/Vilters

2010

Eidgenössisches Departement des Innern EDI

Bundesamt für Gesundheit BAG Direktionsbereich Öffentliche Gesundheit

FSME-Regionen (Die Liste ist nicht vollständig! Die aufgeführten Orte umschreiben nur grob die auf der Karte dargestellten Endemiegebiete. Neue Regionen sind unterstrichen.):

Aargau: Rheinfelden/Möhlin/Wallbach, Oberfrick/Bezirk Laufenburg, Koblenz/Döttingen/Zurzach, Birr/Brugg/Würenlingen, Baden/Wettingen, Rothrist/Zofingen/Brittnau, Gon-tenschwil/Schöftland/Muhen/Gränichen

Baselland: Liesberg

Bern: Gampelen/Erlach, Grosses Moos, Lyss/Jens/Port, Moutier, Vallon de Saint-Imier, Mühle-berg/Gurbrü/Kriechenwil/Laupen, Belp/Münsingen/Steffisburg, Thun/Spiez/Frutigen, Erlen-bach/vorderes Simmental, Interlaken/Leissigen

Fribourg: Salvenach/Ulmiz/Kerzers, Portalban/Autavaux, Franex/Nuvilly/Villeneuve, Bösingen/Wünnewil

Graubünden: Malans/Fläsch/Luziensteig, Grüsch/Seewis, Region Chur

Luzern: Reiden/Langnau/Dagmersellen/Nebikon/Egolzwil/Kottwil/Sursee/Knutwil, Reussbühl/Luzern/Ebikon, Beromünster/Neudorf/Rain

Nidwalden Stans/Buochs/Bürgenstock, Stanserhorn

Obwalden Kerns/Stanserhorn

Schaffhausen: Hallau, Osterfingen, Neuhausen/Beringen/Schaffhausen, Stein am Rhein, Bezirk Reiat

Schwyz: Gersau, Freienbach

Solothurn: Bellach/Lommiswil/Langendorf, Oensingen/Balsthal

St. Gallen: Ganzer nördlicher Kantonsteil (unteres Toggenburg bis unteres Rheintal), Jona/Wagen, Mels/Sargans/Vilters

Thurgau: Ganzer Kanton

Uri: Unteres Reusstal, Seelisberg

Waadt: Cudrefin/Salavaux/Chabrey, plaine de l'Orbe und Umgebung (Jurasüdfuss)

Wallis: Sierre/Salgesch, Raron/Turtig/Visp

Zug: Steinhausen

Zürich: Ganzer Kanton

Fürstentum Balzers/Vaduz/Nendeln Liechtenstein:

Zeckenenzephalitis (FSME) - SchweizBekannte Endemiegebiete (Naturherde)

BAG: Stand Dezember 2011

2006

Eidgenössisches Departement des Innern EDI

Bundesamt für Gesundheit BAG Direktionsbereich Öffentliche Gesundheit

Zeckenenzephalitis (FSME) - SchweizBekannte Endemiegebiete (Naturherde)

BAG: Stand Mai 2010

FSME-Regionen (Die Liste ist nicht vollständig! Die aufgeführten Orte umschreiben nur grob die auf der Karte dargestellten Endemiegebiete. Neue Regionen sind unterstrichen.):

Aargau: Rheinfelden/Möhlin/Wallbach, Oberfrick/Bezirk Laufenburg, Koblenz/Döttingen/Zurzach, Birr/Brugg/Würenlingen, Baden/Wettingen, Rothrist/Zofingen/Brittnau, Gon-tenschwil/Schöftland/Muhen/Gränichen

Baselland: Liesberg

Bern: Gampelen/Erlach, Grosses Moos, Lyss/Jens/Port, Moutier, Vallon de Saint-Imier, Mühle-berg/Gurbrü/Kriechenwil/Laupen, Belp/Münsingen/Steffisburg, Thun/Spiez/Frutigen, Erlen-bach/vorderes Simmental

Fribourg: Salvenach/Ulmiz/Kerzers, Portalban/Autavaux, Franex/Nuvilly/Villeneuve

Graubünden: Malans/Fläsch/Luziensteig, Grüsch/Seewis, Region Chur

Luzern: Reiden/Langnau/Dagmersellen/Nebikon/Egolzwil/Kottwil/Sursee/Knutwil, Reussbühl/Luzern/Ebikon, Beromünster/Neudorf/Rain

Nidwalden Stans/Buochs/Bürgenstock, Stanserhorn

Obwalden Kerns/Stanserhorn

Schaffhausen: Hallau, Osterfingen, Neuhausen/Beringen/Schaffhausen, Stein am Rhein, Bezirk Reiat

Schwyz: Gersau, Freienbach

Solothurn: Bellach/Lommiswil/Langendorf, Oensingen

St. Gallen: Wil/Jonschwil/Zuzwil/Niederhelfenschwil, Mörschwil, St. Magrethen/Balgach, Jona/Wagen, Mels/Sargans/Vilters

Thurgau: Ganzer Kanton

Uri: Unteres Reusstal, Seelisberg

Waadt Cudrefin/Salavaux/Chabrey, plaine de l'Orbe und Umgebung (Jurasüdfuss)

Zug: Steinhausen

Zürich: Ganzer Kanton

Fürstentum Balzers/Vaduz/Nendeln Liechtenstein:

SG - FSME VERBREITUNG

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Zeckenenzephalitis

Impfung gegen Zeckenenzephalitis (FSME): empfohlen für Risikogruppen.

MASSNAHMEN: PRÄVENTION...

๏ „Alle erwachsenen Personen sowie Kinder im Allgemeinen ab 6 Jahren, welche in Endemiegebieten wohnen oder sich dort zeitweise aufhalten, sollten sich gegen FSME impfen lassen.“

๏ Impfschutz nach 3 Dosen: 96-99%

๏ Geschlossene Kleidung, geschlossene Schuhe und Repellentien reduzieren das Risiko

www.bag.admin.ch



i n f e k t t a g _ 2 0 1 3

NEUE KRANKHEITNEO-

EHRLICHIOSEein neuer Trend?

Blick am Abend 31.10.12

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TREND... NEOEHRLICHIOSE

๏ 1999 Ehrlichia-like “Schotti variant”: Nachweis in Zecken in den Niederlanden, 2004 „Candidatus Neoehrlichia mikurensis“

๏ 2009/ 2010 6 Infektionen bei Menschen in Europa

๏ 2012 6.4% der Zecken infiziert (Westschweiz), 3.5-8% (ZH)

๏ 2012 2 Infektionen in Zürich und Nachweis in Zecken in der Umgebung

Maurer et al., JCM. 2012 Oct 31. // Fehr et al. 2010. Emerg. Infect. Dis. 16:1127–1129. // Lommano et al., Appl Environ Microbiol. 2012 Jul;78(13):4606–12.

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NEOEHRLICHIOSE: ZH FÄLLE

๏ Fall 1: 68-jähriger Mann, CLL, kommt mit FUO, Risiko: regelmässige Spaziergänge im Wald mit dem Hund

๏ Fall 2: 58-jähriger Mann, Lymphom, R-CHOP, kommt mit FUO, Risiko: regelmässige Spaziergämge im Wald

๏ Diagnose: PCR im Blut und Knochenmark

๏ Verlauf: rasche Entfieberung unter Doxycyclin

Maurer et al., JCM. 2012 Oct 31.

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zum Schluss...

4. NEUER TREND: TULARÄMIE

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WAS IST TULARÄMIE๏ Infektion mit Francisella tularensis (Reservoir unbekannt)

๏ Übertragung: Direkter Kontakt mit infizierten Tieren (Hasenpest), Zecken, Aerosole

๏ Inkubationszeit 3-5 Tage (range 1-14d)

๏ Initialsymptome: Fieber, Schüttelfrost, Kopfschmerzen, Myalgien, im Verlauf Adynamie, Malaise

๏ Lymphknotenschwellung +++

๏ Eintrittsstelle (Eschar!) wird oft übersehen oder ist schon abgeheilt (glanduläre Formen)

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ÜBERRASCHUNG IM JAHRE 2000!

429

Table 1 Geographic origin and developmental stages of 6071Ixodes ricinus ticks

Region Nymphs Adult males Adult females(no. of ticks) (np5336) (np396) (np339)

Brugg (710) 596 60 54Kloten/Bülach (3717) 3201 320 196Neuenburg (89) 80 3 6Thun/Spiez (1099) 1009 10 80Ticino (456) 450 3 3Total 5336 396 339

Table 2 Total rates of tick infections

Pathogen Prevalence

Percent Positive pools/total pools

Francisella tularensis 0.12 7/607Ehrlichia phagocytophilaa 1.18 68/607Borrelia burgdorferi sensu lato 26.54 563/590TBEV 0.32 19/607

a TaqMan PCR specific for members of theEhrlichia phagocyto-phila genogroup

TBEV, tick-borne encephalitis virus

Table 3 Results of TaqMan PCR for 6071 Ixodes ricinus ticks by geographic origin and developmental stage

Developmental stage Prevalence

Francisella tularensis Ehrlichiaphagocytophilab

Borrelia burgdorferi TBEV

Nymphs 0.14 (7/521)a 0.94 (47/521) 25.9 (495/521) 0.27 (14/521)Adult males 0 (0/43) 2.61 (10/43) 21.1 (39/43) 0.97 (4/43)Adult females 0 (0/38) 3.72 (12/38) 20.16 (34/38) 0.27 (1/38)Adult males and females 0 (0(81) 2.95 (22/81) 20.66 (73/81) 0.6 (5/81)

a Data expression: x (y/N), where x is the percentage of positiveticks, y is the actual number of positive pooled samples, and N isthe total number of pools analyzed

b TaqMan PCR specific for members of the Ehrlichia phagocyto-phila genogroup

Results

Optimization of the Francisella Polymerase Chain Reac-tion System. The Francisella TaqMan PCR assaydetected ten molecules of the standard plasmid.Amplification of a standard plasmid dilution over eightorders of magnitude showed linearity over the wholerange. The assay proved to be specific for Francisellatularensis. The ATCC strain, the two field isolates, andthe vaccine strain generated fluorescence signals, butthe other bacterial DNA tested, including Francisellaphilomiragia, did not. Specificity was also verified bysequencing two cloned PCR products obtained byamplification of the ATCC strain. The TaqMan systemsthat detected Francisella tularensis, Borrelia burgdor-feri, and Ehrlichia phagocytophila had the same sensi-tivity of ten molecules per assay [17, 22]. In addition,the sensitivity of the TBEV RT-PCR was ten copies ofan in vitro transcribed RNA.

Prevalence According to the Sample Structure. Thesample structure of the 6071 ticks collected was asfollows: 5336 nymphs, 390 adult males, and 338 adultfemales (Table 1). Of the 6071 ticks examined, sevenpools (0.12%) were positive in the Francisella TaqManPCR, all of which contained nymphs. Sixty-eight(1.18%) of the 607 pools were positive in the Ehrlichiaphagocytophila genogroup TaqMan PCR and consistedof 47 (0.94%) nymph pools, 10 (2.61%) adult malepools, and 12 (3.72%) adult female pools. In theBorrelia burgdorferi TaqMan PCR, 563 (26.54%) poolsgave a positive reaction: 495 (25.9%) nymph pools, 39(21.1%) male pools, and 34 (20.16%) female pools. Inthe TBEV-specific TaqMan RT-PCR, 19 (0.32%) ofthe 607 tick pools tested positive. They consisted of 14(0.27%) nymph pools, four (0.97%) adult male pools,and one (0.27%) adult female pool (Tables 2 and 3).

Prevalence According to Tick Stage Development. Theprevalence of infected ticks varied with the stage ofdevelopment and the geographical origin (Table 3).Francisella was found in nymphs (0.14%) but not inadult ticks. Members of the Ehrlichia phagocytophilagenogroup were found more frequently in adult ticks(2.95%) than in nymphs (0.94%). In the chi-square test,

this difference was significant (P~0.001). Borrelia wasfound almost evenly distributed among the tick devel-opmental stages, and TBEV was more frequent in adultmales than in adult females and nymphs, but this wasnot statistically significant (Table 3). Ehrlichia andBorrelia were found in all five regions, whereas Franci-sella tularensis could be found in four of five regionsand TBEV in two of four regions. The highest preva-lence of members of the Ehrlichia phagocytophilagenogroup, Francisella tularensis, and Borrelia wasfound in Neuchatel, with an absence of TBEV in thisregion. TBEV was found in Thun/Spiez and in Kloten/Bülach.

Discussion

The goals of the present study were as follows: (i) toapply a new instrumentation to detect pathogens in

Wicki et al., Eur J Clin Microbiol Infect Dis. 2000 Jun 1;19(6):427–32

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TULARÄMIE IN DER SCHWEIZ: 2004-2012

20042005

20062007

20082009

20102011

20122013

0

10

20

30

40

year

num

ber

of p

atie

nts

©Urs Karrer, Kantonsspital Winterthur

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FÄLLE 2004 BIS 2012©Urs Karrer, Kantonsspital Winterthur

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total (n=98) 2012 (n=37)

Lokal

ulzeroglandulär

glandulär

okuloglandulär

oropharyngeal

Systemisch

typhoidal

pneumonisch

abdominal

keine Information

55 % 61 %

32 33

19 25

3 3

1 0

32 % 38 %

4 5

25 30

3 3

12 3


i n f e k t t a g _ 2 0 1 3

total (n=98) 2012 (n=37)

Lokal

ulzeroglandulär

glandulär

okuloglandulär

oropharyngeal

Systemisch

typhoidal

pneumonisch

abdominal

keine Information

55 % 61 %

32 33

19 25

3 3

1 0

32 % 38 %

4 5

25 30

3 3

12 3


i n f e k t t a g _ 2 0 1 3

TextText

TextText

TextText

!

©Peter Graber, Kantonsspital Liestal

i n f e k t t a g _ 2 0 1 3

Hospitalisation, Therapie mit Augmentin IV und Tobramycin mit rascher Besserung, Diagnose: ulzeroglanduläre Tularämie mittels FNP und Kultur

Tag 13Plötzlich Fieber, Schüttelfrost, Kopfschmerzen und zervikale Lymphknotenschwellung, keine Besserung auf Augmentin und NSAR

Tag 4-7Ein Jogger wurde bei einer Mäusebussard-Attcke am Kopf verletzt


Tag 0

i n f e k t t a g _ 2 0 1 3

IST AUCH IN ST. GALLEN ANGEKOMMEN...

i n f e k t t a g _ 2 0 1 3

Wachstum von Francisella tularensis susp holarctica. Diagnose: Pulmonale Tularämie

BlutkulturKeine Besserung unter Therapie mit Augmentin und Klacid

VerlaufTrockener Husten, ausgeprägte Müdigkeit und Schwäche mit Synkope

Eintritt

Feldman et al., NEJM. 2001 Nov 29;345(22):1601–6. // Poster SGINF 2012

Risikofaktor: Rasenmähen!

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TULARÄMIE: 2 FORMENTyp A Infektion (USA):

๏ Fulminant, geht bis septischer Schock

๏ Früher Mortalität 5-10%, seit AB 1-2%

๏ Pulmonale Form: 30-60%, nun 3-13%

Typ B Infektion (Europa):

๏ „Type B tularaemia is virtually nonlethal in humans, even when appropriate treatment is not inserted“

Tärnvik and Berglund. Eur Respir J. 2003

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DIAGNOSTIK

๏ Kultur (bei Verdacht: nur in Speziallaboratorien durchführen (Bio Safty))!

๏ PCR aus Ulcusmaterial der Eintrittspforte oder aus Biopsiematerial des Lymphknotens

๏ Serologie (Ende 2. Krankheitswoche positiv)


i n f e k t t a g _ 2 0 1 3

THERAPIE

๏ Streptomycin 97% Heilung, kein Relaps ๏ Ds. 10mg /kg i.m. alle 12 h für 10 Tage

๏ Gentamicin 86% Heilung, 6% Relaps๏ Ds. 3-5 mg/kg in drei Dosen / d i.m. oder iv.

๏ Tetrazyklin / Doxycyclin 88% Heilung, 12% Relaps๏ Ds. Vibramycin 2 x 100 mg /d für 14 Tage


i n f e k t t a g _ 2 0 1 3

- OUTDOOR AKTIVITÄT

- LOKALE LYMPHADENOPATHIE

- SYSTEMISCHE ENTZÜNDUNG

- KEIN ANSPRECHEN AUF BETALAKTAME

AN TULARÄMIE DENKEN!!

Fazit

i n f e k t t a g _ 2 0 1 3

FRAGEN UND DISKUSSION

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