To the Editor: In central Europe, Anaplasma phagocytophilum and Borrelia burgdorferi
are transmitted by the hard tick Ixodes ricinus (
1
). Acute human granulocytic ehrlichiosis (HGE) caused by A. phagocytophilum has rarely
been documented in Europe (
2
). Typical symptoms include fever, headache, myalgia, leukopenia, thrombocytopenia,
and abnormal liver function test results. The serologic prevalence ranges from 1.9%
to 14% in Germany (
1
), while clinically apparent infections of HGE have not been reported.
Acute Lyme borreliosis in Europe is associated with erythema migrans (
3
), recognized in up to 90% of patients (
4
). Erythema migrans may be accompanied by systemic symptoms such as fever, fatigue,
myalgia, arthralgia, headache, or stiff neck (
3
,
4
). In southern Germany, an incidence of 111 per 100,000 inhabitants has been reported
(
4
).
A 60-year-old woman from northern Germany was admitted with temperature of <40°C,
headache, myalgia, and generalized weakness that had begun 6 days earlier. She had
noticed an erythema migrans on her right thigh 4 days before she sought treatment.
At admission, a tender, 5 × 8 cm rash and a central papule were seen, but without
central clearing. The clinical examination was otherwise normal. Three weeks earlier
she had been on a trekking tour in Austria and Slovenia but had not been aware of
any tick bites.
The leukocyte count was 3,030/μL (normal 4,000–9,000), with 65% neutrophils, 24% lymphocytes,
10% monocytes, and 1% lymphoid cells. The following results were observed: platelets
127,000/μL (normal 150,000–450,000), aspartate aminotransferase 108 U/L (normal <31),
alanine aminotransferase 154 U/L (normal <34), gamma-glutamyl transferase 98 U/L (normal
<38), lactate dehydrogenase 317 U/L (normal <247), alkaline phosphatase 314 U/L (normal
<237), direct bilirubin 4.7 μmol/L (normal <3.4), C-reactive protein 132 mg/L (normal
<5), and neopterin 30 nmol/L (normal <10). All other routine laboratory parameters
were normal.
May-Grünwald-Giemsa (Fluke, Neu Ulm, Germany)–stained whole-blood smears did not show
Anaplasma initially and during follow-up. On admission serum antibody tests were negative
for A. phagocytophilum, B. burgdorferi, hepatitis A, B, and C, human herpes virus
6, herpes simplex virus 1 and 2, Epstein-Barr virus, cytomegalovirus, and tickborne
encephalitis virus. Because Lyme borreliosis and possible HGE were suspected, the
patient was treated with oral doxycycline 200 mg once daily for 3 weeks. Within 4
days after initiation of treatment, the patient recovered completely; thrombocytes
and leukocytes had normalized. Liver enzyme levels were still elevated but had normalized
at a follow-up examination 28 days later.
Four days after the initial examination, results for Borrelia-specific immunoglobulin
M (IgM) antibodies were positive, while results for IgG antibodies remained negative
(Table). Four weeks after the onset of symptoms, a test for A. phagocytophilum–specific
IgM antibodies was positive and IgG was negative thereafter (Table). An initial EDTA
blood sample that was stored frozen and examined retrospectively as well as follow-up
EDTA blood samples were negative for A. phagocytophilum in a polymerase chain reaction
(PCR) assay.
Table
Results of serologic tests at diagnosis and during follow-up*
Time (d) after onset of symptoms
Anaplasma (Ehrlichia) phagocytophilum (IFA)†
Borrelia burgdorferi (ELISA)‡
Borrelia burgdorferi (Immunoblot)§
IgM
IgG
IgM
IgG
IgM
IgG
6
Negative (<1:20)
Negative (<1:32)
Negative
Negative
Negative
Negative
10
ND
ND
Positive
Negative
ND
ND
28
Positive (1:40)
Negative (1:32)
Positive
Negative
Positive
Negative
107
Positive (1:20)
Negative (<1:32)
Positive
Negative
Positive
Negative
380
Negative (<1:20)
Negative (<1:32)
Equivocal
Negative
Positive
Negative
*Symptoms (fever, headache, myalgia) started 6 days before presentation. IFA, immunofluorescent
assay; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; ND, not done.
†Genzyme
Virotech, Germany. Positive titers: IgM >1:20, IgG >1:64.
‡Behring, Germany.
§In-house
Immunoblot, Max von Pettenkofer-Institut, Munich, Germany.
One year after initial examination, results for Borrelia-specific IgM antibodies were
positive and results for A. phagocytophilum-specific antibodies were negative (Table).
Although HGE has not been reported in Germany, a coinfection with B. burgdorferi and
A. phagocytophilum should be considered in patients with erythema migrans and atypical
changes for Lyme borreliosis such as fever, leukopenia, thrombocytopenia, and elevated
liver function test results.
The patient had traveled to an area where both tickborne pathogens, A. phagocytophilum
and B. burgdorferi, were endemic. Erythema migrans and antibody follow up suggested
Lyme borreliosis. High fever, leukopenia, thrombocytopenia, and elevated liver enzyme
levels indicated HGE. Anaplasma PCR was negative, possibly because blood samples were
tested retrospectively after 3 months of storage at –20°C. However, a commercially
available indirect fluorescent antibody assay was able to demonstrate seroconversion
of HGE-specific IgM antibodies 1 month after the initial onset of symptoms. According
to manufacturer's information, specificity ranged from 97.5% to 100%; sensitivity
was 71.4% at 60 days after A. phagocytophilum infection. A. phagocytophilum IgG antibodies
were not detected during follow-up, likely because of prompt treatment with doxycycline.
Wormser et al. (
5
) suggested that Borrelia-specific antibodies might indicate false-positive results
in patients with HGE infection. Our case, however, meets criteria of a newly acquired
infection with B. burgdorferi sensu lato, with an erythema migrans and seroconversion
of Borrelia-specific IgM antibodies.