VARHAISVAIHEEN BORRELIOOSI + IgM

[Bb]

Lähettäjä: Soijuv Lähetetty: 30.3.2005 8:35

Steeren kumppaneineen tekemässä tutkimuksessa osalla borrelioosin varhaisvaiheeseeen sairastuneista henkilöistä esiintyi systeemisiä oireita kuten kuume, vilunväreet, päänsärky, niskajäykkyys, tuntohäiriöt, kipuja lihaksissa/luissa, kurkkukipu, kuiva yskä. Henkilöillä ei ollut esiintynyt pureman jälkeistä ihomuutosta.

Positiivinen IgM yksinään ei artikkelin kirjoittajien mielestä kerro onko kyseessä borrelioosi vai jokin muu spirokeettojen tai virusten aiheuttama infektio. Positiivinen IgM saattaa tutkimuksen mukaan johtua myös ehrlichiasta tai jostakin viruksesta kuten Epstein Barr -viruksesta (Suom. huom. Punkit kuljettavat mukanaan myös näitä. Joka tapauksessa oireet aiheuttava mikrobi tulee selvittää ja hoitaa tilanne sen mukaisesti, eikä yksinomaan todeta IgM:n nousun voivan johtua muustakin kuin borreliabakteerista ja jättää tilanne siihen.)


American Journal of Medicine
Volume 114 * Number 1 * January 1, 2003
Copyright © 2003 Excerpta Medica

Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease

Allen C. Steere, MD a , *
Alpana Dhar, MD a
Jesus Hernandez, MD a
Peter A. Fischer, MD a
Vijay K. Sikand, MD a
Robert T. Schoen, MD b
John Nowakowski, MD c
Gail McHugh a
David H. Persing, MD, PhD d a Division of Rheumatology/Immunology
(ACS,AD,JH,PAF,VKS,GM)
Tufts University School of Medicine
New England Medical Center
Boston, Massachusetts, USA

b Department of Medicine (RTS)
Yale University School of Medicine
New Haven, Connecticut, USA

c Division of Infectious Diseases (JN)
New York Medical College
Valhalla, New York, USA

d Sections of Clinical Microbiology
Infectious Diseases,and Experimental Pathology (DHP)
Mayo Foundation
Rochester, Minnesota, USA


* Requests for reprints should be addressed to Allen C. Steere, MD, Massachusetts General Hospital, 149 Thirteenth Street, Room 8301, Charlestown, Massachusetts 02129, USA
Manuscript received January 5, 2002, accepted January 29, 2002

The study was supported in part by SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania, and by a grant (Cooperative agreement No. CCU110291) from the Centers for Disease Control and Prevention, Atlanta, Georgia. Dr. Dhar received support from the Lincoln Financial Group Foundation.
PII S0002-9343(02)01440-7

Patients with Lyme disease, which is caused by the tick-borne spirochete Borrelia burgdorferi [1] , may present during summer with systemic symptoms without the initial skin lesion erythema migrans [2] . The same tick may also transmit Anaplasma phagocytophila, which causes human granulocytic ehrlichiosis [3] [4] [5] , or Babesia microti, a red blood cell parasite [6] [7] . These organisms, as well as several viral infections, may cause nonspecific systemic symptoms.

Serologic support for the diagnosis of Lyme disease may also be problematic early in the infection. A positive immunoglobulin (Ig) M response to whole B. burgdorferi sonicate by enzyme-linked immunosorbent assay (ELISA) and Western blot may represent a false-positive response [8] [9] . For example, Ehrlichia infection may induce a false-positive IgM response to B. burgdorferi [10] , as may infection with certain viral agents, including Epstein-Barr virus [11] . Although the IgG criteria for Lyme disease have greater specificity, several weeks of infection are necessary before most patients develop IgG responses to five or more of the 10 designated spirochetal proteins [12] . A new ELISA has been developed that detects IgG reactivity with a peptide of the VlsE outer-surface lipoprotein of B. burgdorferi [13] . Because patients often have a response to this peptide before they have IgG reactivity with the
requisite number of bands by Western blot, this test may be useful in the diagnosis of early Lyme disease.

We therefore sought to describe patients in a Lyme disease vaccine trial [14] who presented with systemic symptoms without erythema migrans.

Patients and methods

In 1995, 10,936 people (aged 15 to 70 years) were enrolled in a Lyme disease vaccine trial that involved 31 different centers in 10 states where the infection is endemic [14] . During the 20-month study, which included two summer transmission seasons of Lyme disease, systemic or influenza-like symptoms accompanied by IgM or IgG seroconversion to B. burgdorferi were reported in 63 participants. The reporting study investigators, and often the patients, were contacted for additional clinical information using a standardized questionnaire. For this report, we included only the 42 patients who had systemic symptoms, without physician-diagnosed or self-reported erythema migrans.

Three serum samples were obtained from each patient: a baseline sample at study entry, an acute-phase sample when the patient had systemic symptoms, and a convalescent sample 3 to 4 weeks later. A positive result required seroconversion between baseline and acute or convalescent samples. Serologic testing for IgM and IgG antibodies to B. burgdorferi sonicate was done using Western blotting; the results were interpreted according to the criteria of the Centers for Disease Control and Prevention and the Association of State and Territorial Public Health Laboratory Directors [8] . Serum samples were tested for IgG reactivity with the 26-mer peptide (IR6) of the VlsE lipoprotein of B. burgdorferi using ELISA [13] , and for reactivity with A. phagocytophila and B. microti using indirect immunofluorescence assays [4] [15] . Blood samples, which were obtained during the acute phase of the illness, were anticoagulated with ethylenediaminetetraacetic acid and tested by polymerase chain reaction (PCR) for deoxyribonucleic acid (DNA) from B. burgdorferi, A. phagocytophila, or B. microti [4] [16] .

Results

Of the 1917 participants who were evaluated for suspected Lyme disease during the study [14] , 269 met prospectively defined criteria for definite, possible, or asymptomatic Lyme disease. Forty-two of these patients (16%) had systemic symptoms without erythema migrans, accompanied by IgM or IgG seroconversion to whole B. burgdorferi sonicate, which was defined in the original study as possible Lyme disease. For this post hoc analysis in which the more sensitive and specific VlsE peptide ELISA was available, the 28 patients with IgG seroconversion to the VlsE peptide or B. burgdorferi sonicate, or with a positive blood PCR test for B. burgdorferi DNA, were redefined as having definite Lyme disease (Table 1 ). The 14 patients who only had IgM seroconversion to the spirochete were still classified as having possible Lyme disease. Each of these groups was subdivided by whether the patients had PCR or serologic evidence of Ehrlichia or Babesia infection. Because the clinical symptoms were similar in vaccine or placebo recipients during the study, we did not stratify the patients by treatment group or year of disease onset.

Table 1. Polymerase Chain Reaction and Serologic Test Results in Patients with Definite or Possible Lyme Disease
* Twenty-two patients had IgG responses to the VlsE peptide; 19 had IgM responses and 11 had IgG responses to whole B. burgdorferi sonicate, and 4 had a positive blood PCR test for B. burgdorferi DNA. Of the remaining 2 patients, 1 had IgM and IgG reactivity with B. burgdorferi sonicate, and 1 had a positive blood PCR test to B. burgdorferi DNA and IgM reactivity with B. burgdorferi sonicate. Two patients had IgG seroconversion to both Ehrlichia and Babesia organisms. DNA = deoxyribonucleic acid; ELISA = enzyme-linked immunosorbent assay; Ig = immunoglobulin; PCR = polymerase chain reaction.


Definite Lyme Disease
Possible Lyme Disease
Alone* (n = 24) With Ehrlichiaor Babesia Infection (n = 4) Alone (n =
7) With Ehrlichiaor Babesia Infection(n = 7)
Borrelia burgdorferi
IgG seroconversion
VlsE peptide ELISA 22 3 0 0
Sonicate Western blot 12 2 0 0
IgM seroconversion
Sonicate Western blot 21 3 7 7
Positive blood PCR test 5 0 0 0
Ehrlichia organisms
IgG seroconversion - 3Ý - 5
Positive blood PCR test - 0 - 5
Babesia organisms
IgG seroconversion - 3Ý - 2
Positive blood PCR test - 0 - 1


Among the 24 patients who only had definite Lyme disease, oligoarticular or migratory arthralgias, primarily in the large joints, were common (Table 2 ). These patients also experienced severe headache frequently, often in the back of the head, accompanied by mild neck stiffness. Of these patients, 7 (29%) had paresthesias in a localized distribution in the face, arm, or leg. Although two thirds of the patients described chills or fever, these symptoms were not usually dominant or sustained. No one reported upper respiratory or gastrointestinal symptoms. Among the 4 patients who had definite Lyme disease and infection with Ehrlichia or Babesia or both organisms, the clinical picture was similar to that in the
patients with definite Lyme disease alone, except that these 4 patients tended to have more symptoms (median, six vs. four symptoms), and all had fever and chills (Table 2 ). Fever, chills, and malaise were common in the 14 patients with possible Lyme disease, including the 7 patients who also had evidence of ehrlichiosis or babesiosis. Although these 14 patients had headache or neck stiffness occasionally, none had neurologic abnormalities, and arthralgias were uncommon.

Table 2. Characteristics of Systemic Symptoms in Patients with Early Lyme Disease

Definite Lyme Disease
Possible Lyme Disease
Alone (n = 24) With Ehrlichia or Babesia Infection (n = 4) Alone (n =
7) With Ehrlichia or Babesia Infection (n = 7)
Number (%) or Median (Range)
Age 53 (27-72) 44 (35-57) 48 (37-62) 45 (33-68 )
Male sex 14 (58 ) 4 (100) 5 (72) 5 (72)
Fever 15 (63) 4 (100) 7 (100) 7 (100)
Chills 12 (50) 4 (100) 4 (57) 6 (86)
Malaise 17 (71) 4 (100) 7 (100) 6 (86)
Headache 13 (54) 2 (50) 6 (86) 4 (57)
Stiff neck 10 (42) 1 (25) 2 (29) 3 (43)
Paresthesia 7 (29) 1 (25) 0 0
Arthralgia 17 (71) 3 (75) 2 (29) 2 (29)
Myalgia 11 (46) 4 (100) 5 (71) 3 (43)
Sore throat 2 (8 ) 0 0 0
Dry cough 1 (4) 0 0 1 (14)
Number of symptoms per patient 4 (1-7) 6 (5-6) 5 (4-7) 6 (2-7)

Antibiotic treatment and outcome

Of the 42 patients without erythema migrans, 34 were treated with doxycycline (100 mg twice daily for 3 to 4 weeks), 6 received amoxicillin (250 or 500 mg three times daily for 3 to 4 weeks), and 2 declined treatment. Although information about Ehrlichia or Babesia infection was not available until after decisions about treatment were made, 7 of the 8 patients who had ehrlichiosis received doxycycline and 1 was given amoxicillin, whereas 3 of the 5 patients with babesiosis were treated with clindamycin and quinine. In all groups (definite or possible Lyme disease, alone or with coinfection), symptoms resolved within a median of 3 to 7 days. However, 7 patients, 5 of whom had definite Lyme disease alone, had arthralgias or fatigue persisting for weeks to months after treatment. None of the 42 patients developed later manifestations of Lyme disease, such as arthritis or neurologic abnormalities, during the study.

Discussion

Among the patients with definite Lyme disease, oligoarticular or migratory arthralgias and pain in the back of the head with mild neck stiffness were common symptoms. This clinical picture, which may be suggestive of meningitis, is often seen in patients with erythema migrans during the early, disseminated phase of Lyme disease [17] . In a previous report [18] , 8 of 12 patients who had such symptoms associated with erythema migrans had a positive test for B. burgdorferi DNA in cerebrospinal fluid, but none had a spinal fluid pleocytosis. In our study, 4 (14%) of the patients with definite Lyme disease had coinfection with Ehrlichia or Babesia organisms. Consistent with previous experience [19] , these 4 patients tended to have more symptoms than did those with B. burgdorferi infection alone.

The 14 patients with possible Lyme disease had a more nonspecific picture, with prominent fever, chills, and malaise; 7 had evidence of infection with Ehrlichia or Babesia organisms. We cannot exclude the possibility that these 7 patients had coinfection, but we favor the interpretation that most had infection only with Ehrlichia or Babesia organisms, usually documented by both PCR testing and IgG seroconversion, accompanied by a false-positive IgM response to B. burgdorferi. Several of the other 7 patients may have had a self-limited viral infection instead of coinfection.

In this report, the IgG VlsE peptide ELISA, which was not available in the vaccine study, was useful in identifying patients with definite Lyme disease. The accuracy of this test is supported by a post-hoc assessment of vaccine efficacy, which was 45% in the 16 patients with definite Lyme disease who acquired the infection in the first year of the study and 100% in the 12 patients who acquired it in the second year, rates that were similar to those in patients in the vaccine study with culture-proven erythema migrans [14] . In contrast, no vaccine efficacy was observed in the 14 patients with possible Lyme disease who had only IgM seroconversion to the spirochete.

Similar to previous reports of treating patients with erythema migrans [20] [21] [22] [23] [24] , most of our patients had resolution of symptoms within days after treatment with oral doxycycline or amoxicillin, whereas a small number had occasional arthralgias or persistent fatigue for weeks or months after treatment. Both ehrlichiosis and babesiosis are often asymptomatic and may not require treatment. Nevertheless, early Lyme disease and ehrlichiosis may be treated successfully with doxycycline [25]. For severe cases of babesiosis, intravenous clindamycin and oral quinine, or oral atovaquone and azithromycin [26] , may be effective.

Physicians in endemic areas should be aware that systemic symptoms during summer, especially when headache or arthralgia but no upper respiratory or gastrointestinal symptoms is reported, may be a presentation of Lyme disease. Serologic testing may show a positive IgM or IgG response to B. burgdorferi, but a positive IgM response alone does not distinguish clearly between Lyme disease and other tick-borne or viral infections.

Acknowledgement

The authors thank Dr. David S. Krause at GlaxoSmithKline, Pharmaceuticals and Dr. Dennis L. Parenti at American Home Products for guidance and support and the members of the Lyme Disease Vaccine Study Group for providing information and observations.

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