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Case Records of the Massachusetts General Hospital

Founded by RichardC. Cabot
EricS. Rosenberg, M.D., Editor
JoAnneO. Shepard, M.D., Associate Editor
SallyH. Ebeling, Assistant Editor

NancyLee Harris, M.D., Editor

AliceM. Cort, M.D., Associate Editor
EmilyK. McDonald, Assistant Editor

Case 24-2015: A 28-Year-Old Pregnant

Woman with Fever, Chills, Headache,
and Fatigue
LindenT. Hu, M.D., AtheM. Tsibris, M.D., and JohnA. Branda, M.D.

Pr e sen tat ion of C a se

From the Department of Geographical
Medicine and Infectious Disease, Tufts
Medical Center (L.T.H.), the Depart
ments of Medicine (A.M.T.) and Patholo
gy (J.A.B.), Massachusetts General Hos
pital, and the Departments of Medicine
(A.M.T.) and Pathology (J.A.B.), Harvard
Medical School all in Boston.
N Engl J Med 2015;373:468-75.
DOI: 10.1056/NEJMcpc1501763
Copyright 2015 Massachusetts Medical Society.

468

Dr. Brian C. Zanoni (Infectious Disease): A 28-year-old pregnant woman (gravida 3,

para 0020) was admitted to this hospital in the summer because of fever, chills,
headache, and fatigue.
The patient had been well until approximately 5 days before admission, at 28 weeks
of gestation, when she noted feeling warm, which she attributed to a malfunctioning air-conditioning system at work. Three days before admission, malaise and headaches occurred. The next day, she called her health care providers about her symptoms and reported Braxton Hicks contractions and frequent fetal movement, with
no fevers, vaginal bleeding, or leaking of fluid. She was advised to rest and increase her fluid intake. That night, she took diphenhydramine for sleep. The day
before admission, she came to the outpatient obstetrics clinic of this hospital because of a temperature of 37.4C. She reported decreased fetal movement at home,
which improved on arrival to the clinic. She was taking prenatal vitamins. She was
allergic to cephalexin and trimethoprimsulfamethoxazole, which caused a rash,
and to multiple fruits and vegetables, which caused anaphylaxis.
On examination, the temperature was 36.7C, the blood pressure 103/66 mm Hg,
and the pulse 72 beats per minute. The abdomen was soft and nontender, without
palpable uterine contractions. On a nonstress test, the average fetal heart rate was
125 beats per minute, with moderate variability and positive accelerations; these findings were interpreted as reassuring. On ultrasonography, fetal biometric measurements were consistent with a weight of 1244 g (51st percentile for 28 weeks 4 days
of gestation), and there was appropriate gradual growth since a previous scan had
been obtained, as well as a normal volume of amniotic fluid; the fetus was active.
Later that day, the patient traveled to a coastal area in Massachusetts that she visited
weekly. That evening, increased fatigue, diffuse body aches, low back pain, and an
earache occurred, and the temperature rose to 38.6C. The obstetrician who was on
call that evening recommended that the patient go to a local emergency department for evaluation; the examination was reportedly normal. There was a platelet
count of 125,000 per cubic millimeter, and a peripheral-blood smear showed no

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Case Records of the Massachuset ts Gener al Hospital

evidence of babesia; other laboratory test results

were reportedly negative. Results of testing for
Lyme disease were pending. The patient returned
to her coastal vacation residence. Overnight, the
temperature rose to 38.8C. On the morning of
admission, the patient called her obstetricians
office at this hospital to report fever, with a current temperature of 37.4C. She was advised to
take acetaminophen, drink fluids, rest, and return
for evaluation if she began feeling worse. Later
that day, the temperature rose to 39.4C and nausea
developed. That evening, she presented to the labor
and delivery unit of this hospital.
On presentation, the patient reported mild
headache, neck stiffness, a left earache, intermittent contractions, and a possible erythematous
rash on her right shin; she had no joint symptoms, vomiting, ear drainage, hearing difficulty,
or upper respiratory, gastrointestinal, or genitourinary symptoms. She was gravida 3, had had
two previous spontaneous miscarriages, and had
received prenatal care, with testing that was positive for rubella-specific antibodies and negative
for syphilis, human immunodeficiency virus (HIV),
hepatitis C virus, and hepatitis B virus surface
antigen.
The patient had a history of thrombophilia and
gastroesophageal reflux disease associated with
aspirin use and was heterozygous for factor V
Leiden. She reported contact with an indoor cat
at home and with outdoor cats and dogs at the
home of relatives; she knew of bats in the vicinity
of her home and mice in the basement of her
coastal vacation residence. She had no known sick
contacts, insect bites, or consumption of unpasteurized dairy products. She had traveled to Western Europe, Central America, Mexico, and Asia
within the previous 3 years. She worked in an
office, had stopped smoking 5 years earlier, and
had stopped drinking alcohol when she became
pregnant.
On examination, the temperature was 36.3C,
the blood pressure 110/64 mm Hg, the pulse 98
beats per minute, and the respiratory rate 18 breaths
per minute. The abdomen was gravid, soft, and
nontender, and the fetal heart rate was 130 beats
per minute, with accelerations. There was a faint
area of lacy, blanching erythema (4 cm in diameter) on the right shin and no lymphadenopathy;
the remainder of the examination was normal. The
red-cell indexes and results of coagulation tests

were normal, as were blood levels of creatinine,

total protein, albumin, globulin, alkaline phosphatase, total and direct bilirubin, uric acid, and
haptoglobin. Thick and thin Giemsa-stained
smears of peripheral blood were negative for babesia; other test results are shown in Table1. Urinalysis was negative. Cultures of the blood were
obtained.
During the next 4.5 hours, the temperature rose
to 38.9C. Ceftriaxone and rifampin were administered. During the next 3 days, results of testing
for hepatitis A and B viruses were suggestive of
protective immunity, and results of testing for
EpsteinBarr virus were suggestive of past infection; testing was negative for cytomegalovirus
nucleic acids, HIV, heterophile antibodies, and
IgM and IgG antibodies to Borrelia burgdorferi,
Coxiella burnetii, ehrlichia, and anaplasma. The
patient became afebrile within 48 hours and her
headache resolved on the fourth hospital day.
On the fifth hospital day, a diagnostic test
result was received.

Differ en t i a l Di agnosis
Dr. Linden T. Hu: A 28-year-old pregnant woman
presented with an acute onset of fevers, myalgias,
headache, and neck stiffness during the summer
in Massachusetts. Summer fevers are a common
occurrence in many parts of the United States
(Table2). Infection-related summer fevers are not
commonly caused by the adenoviruses, rhinoviruses, and influenza that dominate during the
winter months in temperate areas; instead, enteroviruses (e.g., coxsackievirus) and infections resulting from outdoor exposure to environmental or
zoonotic reservoirs of disease are prevalent. In
Massachusetts, many of these agents are transmitted by mosquito or tick vectors.
Although this patient did not identify a specific tick or mosquito bite, these are recognized
in a minority of cases.1,2 She did have multiple
opportunities for exposure to these agents, given
her frequent travel to coastal Massachusetts and
her participation in outdoor activities. Differentiating between potential causes of summer fevers is often difficult because of the nonspecific
nature of the symptoms, particularly during the
early stages of infection. However, certain features
of this patients presentation including headache, rash, thrombocytopenia, and hepatitis

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Table 1. Laboratory Data.*

Reference Range,
Adults

Variable

On Admission,
This Hospital

4th Day,
This Hospital

Hematocrit (%)

36.046.0 (women)

34.1

30.4

Hemoglobin (g/dl)

12.016.0 (women)

12.1

11.0

450011,000

5900

6800

Neutrophils

4070

90.0

62.0

Lymphocytes

2244

6.1

29.0

Monocytes

411

3.0

7.0

Eosinophils

08

2.0

White-cell count (per

mm3)

Differential count (%)

Basophils

03

0.2

150,000400,000

81,000

122,000

Sodium (mmol/liter)

135145

134

Potassium (mmol/liter)

3.44.8

3.7

Platelet count (per mm3)

Chloride (mmol/liter)

100108

99

Carbon dioxide (mmol/liter)

23.031.9

22.8

Plasma anion gap

315

12

Urea nitrogen (mg/dl)

825

Total

0.01.0

0.5

1.3

Direct

0.00.4

0.2

0.8

Aspartate aminotransferase (U/liter)

932

297

383

Alanine aminotransferase (U/liter)

733

329

468

110210

283

Bilirubin (mg/dl)

Lactate dehydrogenase (U/liter)

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for bilirubin to
micromoles per liter, multiply by 17.1.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical condi
tions that could affect the results. They may therefore not be appropriate for all patients.

may offer clues to the most likely diagnoses reported a mild headache, we cannot rule out these
(Table3).
diagnoses on the basis of the severity of this symptom, especially early during the course of the
Headache
illness.
Headache is a common, nonspecific finding asMeningitis with associated neck stiffness can
sociated with many febrile illnesses. Infections be consistent with infections such as Lyme disease,
with pathogens that are able to cross the blood human granulocytic anaplasmosis, Rocky Mounbrain barrier and directly infect cells of the cen- tain spotted fever, and enterovirus, but it affects
tral nervous system are typically manifested by a minority of patients and headaches can occur
severe headaches as a prominent early feature. in the absence of meningitis. Deer tick virus and
From our list of infections that cause summer eastern equine encephalitis typically cause severe
fever, Lyme disease, human granulocytic ana- meningoencephalitis and are not compatible with
plasmosis, Rocky Mountain spotted fever, lepto- this patients presentation.
spirosis, eastern equine encephalitis, West Nile
Borrelia miyamotoi, which was first identified
virus, deer tick virus, tularemia, and enterovirus all as a human pathogen in 2011, is now recognized
commonly cause headache. Although this patient as the fifth agent of human disease to be trans-

470

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Case Records of the Massachuset ts Gener al Hospital

mitted by the Ixodes scapularis tick in the northeastern United States.3 The organism is most closely
related to the borrelia species that causes relapsing fever. A limited amount of information about
the symptomatic disease associated with B. miyamotoi is currently available, but it may cause a
syndrome that is similar to relapsing fever, with
prominent headaches and meningitis (reported
in an immunocompromised patient), fevers, myalgias, and fatigue.4-6

Table 2. Causes of Summer Fever in the United States.

Tickborne
Lyme disease
Anaplasmosis
Ehrlichiosis
Babesiosis
Borrelia miyamotoi infection
Tularemia
Rocky Mountain spotted fever

Rash

Southern tickassociated rash illness

The presence of a rash can be a distinguishing

feature of a summer fever. Rocky Mountain spotted fever, tularemia, and Lyme disease are associated with characteristic rashes that can be diagnostic. This patients rash is described as a faint,
lacy erythema; these features are not consistent
with the rash associated with Rocky Mountain
spotted fever or ulceroglandular tularemia. Furthermore, the rash is not consistent with the
classic description of the erythema migrans rash of
Lyme disease. However, less than 50% of erythema
migrans rashes have target-shaped (bulls-eye)
lesions; the majority are homogeneous, erythematous, and usually round or oval in appearance.7
Nonspecific maculopapular or morbilliform rashes are associated with leptospirosis, West Nile
virus, and enterovirus and are occasionally reported in patients with human granulocytic anaplasmosis. Southern tickassociated rash illness, which
is transmitted by the Amblyomma americanum tick,
causes a rash that is indistinguishable from the
erythema migrans rash of Lyme disease. No infectious agent has been definitively linked with
southern tickassociated rash illness, and the disease appears to be very self-limited.8,9 An erythema migranslike rash was reported in two patients
from Japan with B. miyamotoi disease, but there
is not enough information to definitively determine that rash is a common manifestation of
this infection.10

Powassan virus

Hepatitis

At the time of admission to this hospital, this patient had clinically significant elevations in hepatic
aminotransferase levels that were indicative of
mild-to-moderate hepatitis. This is a common
finding in patients with human granulocytic anaplasmosis11 and has also been reported in patients
with Lyme disease, although this patients hepa-

Deer tick virus

Mosquito-borne
West Nile virus
Eastern equine encephalitis
Jamestown Canyon virus
Nonvectored
Enterovirus
Tularemia
Leptospirosis
Hantavirus

titis was more severe than would be expected with

Lyme disease. Many of the initial descriptions of
abnormal aminotransferase levels associated with
Lyme disease were reported before the recognition of coinfection with anaplasma; therefore, it
is unclear how commonly hepatitis is associated
with B. burgdorferi infection alone. Mild-to-moderate elevation in aminotransferase levels (as in
this patient) has also been reported in patients
with B. miyamotoi infection, but the frequency of
this finding is not well established. Hepatitis and
splenomegaly can be seen in patients with tularemia or Rocky Mountain spotted fever but usually
appear during fulminant evolution of the disease.
Babesiosis is more commonly associated with rises
in the bilirubin level due to hemolysis of red cells
than with hepatocyte injury.
Thrombocytopenia

The other main distinguishing feature of this

patients presentation is thrombocytopenia that
worsened early in the course of her illness and
then appeared to improve by the fourth hospital
day. Mild thrombocytopenia that resolves quickly,

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Table 3. Clinical Features Associated with Summer Fever.

Cause of Fever

Headache

Rash

Thrombocytopenia

Hepatitis

Lyme disease

Common

Very common

Uncommon

Somewhat common

Human granulocytic anaplasmosis

Common

Uncommon

Common

Common

Somewhat common

Uncommon

Uncommon

Uncommon

Common

Uncertain

Common

Common

Babesiosis
Borrelia miyamotoi infection
Deer tick virus

Very common

Uncommon

Uncommon

Uncommon

Rocky Mountain spotted fever

Very common

Very common

Common

Somewhat common
Somewhat common

Tularemia

Somewhat common

Common

Common

Southern tickassociated rash illness

Somewhat common

Very common

Uncommon

Uncommon

Common

Common

Somewhat common

Uncommon

West Nile virus

Eastern equine encephalitis

Very common

Uncommon

Uncommon

Uncommon

Enterovirus

Very common

Somewhat common

Uncommon

Somewhat common

Leptospirosis

Very common

Somewhat common

Common

Common

either spontaneously or with treatment, is most

notably seen in patients with human granulocytic
anaplasmosis or B. miyamotoi disease. Thrombocytopenia is often accompanied by leukopenia,
which this patient did not have. It can also occur
in patients with leptospirosis, tularemia, and
Rocky Mountain spotted fever, but such patients
are typically critically ill by the time this feature
is observed.
This patient had many negative serologic tests
for specific infectious agents. Although her workup was extensive, it is difficult to put much weight
on these results because the sensitivity of serologic
testing early in the disease course is generally
poor. The negative smears for babesia are informative because the sensitivity of blood smears is
relatively high (approximately 80%).12 On the basis
of this patients clinical syndrome and negative
smears for babesia, babesiosis could confidently
be ruled out. Examination of buffy-coat preparations of whole blood for morulae of anaplasma
may provide a rapid diagnosis but is more difficult than examination of red cells for babesia,
and sensitivity is variable and highly dependent
on the skill of the microscopist. Therefore, a negative buffy-coat examination for anaplasma cannot be reliably used to rule out human granulocytic anaplasmosis.
This patients condition improved after she
received ceftriaxone and rifampin. This regimen
would have activity against the most likely diagnoses in this case, although it is difficult to say

472

whether improvement would have occurred even

without therapy. In a nonpregnant patient, doxycycline would probably have been substituted for
rifampin.
Pregnancy

How did this patients pregnancy factor into the

differential diagnosis? Given the acuteness of the
disease onset and subsequent resolution of her
fevers, she almost certainly had an infection and
not a process related to her pregnancy. None of
the other infections under consideration occur
more commonly during pregnancy.
Given the patients travel to coastal Massachusetts, the two most likely causes of her illness are
human granulocytic anaplasmosis and B. miyamotoi infection. Of the two diseases, human granulocytic anaplasmosis is currently more commonly
reported; however, this may be due to availability
of testing. Also, there is growing evidence that
B. miyamotoi infection is more common than had
been previously thought.13,14 It is not possible to
distinguish between these diseases on the basis
of clinical presentation, routine laboratory tests,
or epidemiology. In this case, B. miyamotoi may
be slightly more likely than human granulocytic
anaplasmosis, if the patients neck stiffness represented meningitis and the reports of an association with an erythema migranslike rash prove
to be true. However, in Massachusetts, coinfection
with multiple pathogens occurs in up to 15% of
persons with infections transmitted by ixodes

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Case Records of the Massachuset ts Gener al Hospital

species, and coinfection with B. burgdorferi could

explain the rash. Lyme disease is unlikely to be
the sole cause of the patients symptoms. I suspect
that a polymerase-chain-reaction (PCR) assay of
this patients blood for human granulocytic anaplasmosis and B. miyamotoi infection was performed in this case. Serologic or PCR testing for
the glpQ (glycerophosphodiester phosphodiesterase) gene of B. miyamotoi can distinguish this
organism from B. burgdorferi.
Dr. Eric S. Rosenberg (Pathology): Dr. Tsibris,
what was your impression when you initially
evaluated this patient?
Dr. Athe M. Tsibris: We thought a tickborne illness, due to either Anaplasma phagocytophilum or
the newly recognized human pathogen B. miyamotoi, was the most likely cause in this case. We
also considered infections that might result from
the patients exposure to mice and pets. Leptospirosis was unlikely in the absence of active urinary
sediment. Patients with lymphocytic choriomeningitis virus infection typically present with an
influenza-like illness, and toxoplasmosis can resemble infectious mononucleosis; the patients
pregnancy led us to test for both of these diseases.

Cl inic a l Di agnosis
Anaplasmosis or Borrelia miyamotoi infection.

Dr . L inden T. Hus Di agnosis

Tickborne illness due to Borrelia miyamotoi or Anaplasma phagocytophilum.
Pathological Discussion

Dr. John A. Branda: A real-time PCR assay targeting

the 23S ribosomal RNA gene of borrelia species,15
which was performed on a blood sample at a reference laboratory, was positive. Additional PCR assays targeting the glpQ gene16 and the flagellin
gene,17 which can distinguish between B. burgdorferi and B. miyamotoi, revealed that the infectious agent was B. miyamotoi.
PCR assays specific for A. phagocytophilum and
Babesia microti that were performed on the same
specimen were negative. Indirect enzyme-linked
immunosorbent assay (ELISA) was initially negative for IgM and IgG antibodies to the glpQ antigen of B. miyamotoi.13 However, 1 week later, ELISA
was positive for the IgM antibodies but negative

for the IgG antibodies, findings that are consistent with recent B. miyamotoi infection. The glpQ
antigen is present in borreliae that cause relapsing fever (including B. miyamotoi) but is absent in
borreliae that cause Lyme disease; thus, ELISA for
antibodies to the glpQ antigen helps to distinguish between these categories of borrelia infection.18 In contrast, reactivity to serologic assays
for Lyme disease that were designed for use in
Europe3 and North America13 has been reported
in patients with B. miyamotoi infection.
In this patient, ELISA was negative for B. burgdorferi on the day after admission to this hospital, but 5 days later, a repeat test was positive. A
supplemental Western immunoblot assay was positive for IgM antibodies to B. burgdorferi, with all
three relevant IgM bands detected (p23, p39, and
p41), and was negative for IgG antibodies, with
no bands detected. Although the serologic findings for B. burgdorferi could represent cross-reactivity from B. miyamotoi infection, they are also
consistent with early Lyme borreliosis. Thus, the
microbiologic diagnosis in this case was B. miyamotoi infection with a possible B. burgdorferi coinfection.
Dr. Rosenberg: Dr. Tsibris, would you tell us
how you treated this patient?
Dr. Tsibris: The patient had marked improvement during the first 24 hours of receiving antibiotic therapy, and a lumbar puncture was deferred. The high probability of anaplasmosis led
us to recommend an empirical 7-day course of
oral rifampin, which was complicated by elevated
hepatic aminotransferase levels that were eight
to nine times as high as the upper limit of the
normal range.
The ideal treatment for B. miyamotoi infection
and the risk of transplacental fetal infection are
unknown. We elected to treat the patient with
intravenous ceftriaxone for 4 weeks. Persistent
elevation of bile-salt levels resulted in a diagnosis of intrahepatic cholestasis of pregnancy that
improved with the administration of ursodiol.
Labor was induced at 37 weeks of gestation, and
the patient had a vaginal delivery of a boy with
normal Apgar scores. At his 1-month and 4-month
checkups, the infant and his mother were noted
to be doing well.
Dr. Rosenberg: Since this is a relatively newly
recognized infection, can you give us guidance on
when it is appropriate to test for B. miyamotoi?

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Dr. Hu: So little is known about B. miyamotoi

that it is difficult to make recommendations. Some
patients have a very severe presentation, similar
to that of relapsing fever, but the majority of patients probably have self-limited disease and will
get better without treatment. At this point, we do
not know whether routine testing should be recommended. My suspicion is that testing for B. miyamotoi will be part of the standard panel for
tickborne diseases, in contrast to deer tick virus,
which is rare and should be tested for only when
suspicion is high.
From a practical point of view, had this patient not been pregnant, she would have been
treated with doxycycline, which would have been
active against both B. miyamotoi and anaplasma
infection. Since both diseases are fairly easily
treated with doxycycline, diagnostic testing for
these pathogens may not be necessary.
Dr. Hasan Bazari (Medicine): Since serologic testing is unreliable early during the course of infection, should we use PCR-based tests to diagnose
these illnesses?
Dr. Branda: For that exact reason, the test of
choice for the diagnosis of anaplasmosis or B. miyamotoi infection is PCR assay of the blood. However, PCR assays of the blood (at least the currently available assays) are not sensitive for Lyme
disease during any stage, and therefore serologic
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testing is still the test of choice for supporting

the diagnosis of Lyme disease.
Dr. Rosenberg: How should we advise our patients
to minimize their risk of acquiring tickborne infections?
Dr. Hu: I recommend interventions that require minimal adherence. In addition to wearing
clothing that provides full coverage during potential exposures, showering after potential exposures has been proven to be effective. Clothing
that is embedded with permethrin, which can last
through many washes, also decreases the chance
of tick and mosquito bites. Nightly tick checks,
to remove the ticks before substantial feeding has
occurred, is effective for preventing Lyme disease
but difficult to do.

Fina l Di agnosis
Borrelia miyamotoi infection and possible Borrelia
burgdorferi infection.
Presented at Medical Grand Rounds.
Dr. Hu reports receiving consulting fees from Abzyme and
grant support to his institution from FoodSource Lure; Dr. Tsibris, consulting and editing fees from DynaMed/EBSCO; and Dr.
Branda, consulting fees from AdvanDx and grant support to his
institution from bioMerieux, Immunetics, Alere, and DiaSorin.
No other potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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Case Records of the Massachuset ts Gener al Hospital

sensu lato in field-collected Ixodes

nymphs in North America. J Med Entomol 2005;42:1057-62.
17. Scoles GA, Papero M, Beati L, Fish D.
A relapsing fever group spirochete trans-

mitted by Ixodes scapularis ticks. Vector

Borne Zoonotic Dis 2001;1:21-34.
18. Schwan TG, Schrumpf ME, Hinnebusch BJ, Anderson DE Jr, Konkel ME.
GlpQ: an antigen for serological dis-

crimination between relapsing fever and

Lyme borreliosis. J Clin Microbiol 1996;
34:2483-92.
Copyright 2015 Massachusetts Medical Society.

Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences
Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference
material is now eligible to receive a complete set of PowerPoint slides, including digital images, with identifying legends,
shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners.org.

n engl j med 373;5nejm.org July 30, 2015

The New England Journal of Medicine

Downloaded from nejm.org on August 23, 2015. For personal use only. No other uses without permission.
Copyright 2015 Massachusetts Medical Society. All rights reserved.

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