Are
Various Babesia Species a Missed Cause for Hypereosinophilia?
A Follow-up on the First Reported Case of Imatinib Mesylate
for Idiopathic Hypereosinophilia
By
James L. Schaller, MD, MAR; Glenn A. Burkland, DMD; PJ Langhoff
Medscape General Medicine. 2007;9(1):38. ©2007 Medscape
Posted 02/27/2007
Background
When Drs. Schaller and Burkland were sent readers' responses
to their 2001 MedGenMed article "Rapid and Complete Control
of Idiopathic Hypereosinophilia With Imatinib Mesylate",
they submitted the following reply as an update.
Abstract
Introduction: In 2001 we reported the first
case of use of imatinib mesylate (Gleevec) for treatment of
idiopathic hypereosinophilia syndrome (HES). These findings
have been replicated in some patients with HES. After 1 year
of taking imatinib, the patient stopped this medication, and
during the last 5 years the patient has not experienced a relapse.
He has, however, recently been diagnosed with babesiosis. This
new diagnosis might relate to his HES.
Methods: After 6 years we decided to follow
up on this patient's treatment. We interviewed the patient,
his son, his aunt, and 2 consulting physicians and also reviewed
relevant laboratory results to determine whether his HES had
returned and whether his residual morbidity had changed.
Results: The patient has had no relapse of
HES and his eosinophil counts have remained low-normal. He was
recently diagnosed with babesiosis, and was prescribed atovaquone
and azithromycin with a significant decrease in morbidity. His
eosinophil cationic protein levels have also fallen to low-normal
since starting atovaquone and azithromycin.
Discussion: New Babesia species are emerging
as human infections. Most do not have available antibody or
polymerase chain reaction diagnostic testing at this time. Manual
differential examinations are of variable utility due to low
numbers of infected red blood cells, suboptimal technique, and
limited experience. Therefore, a diagnosis might need to be
empirical at times, and should be based on signs and symptoms.
Conclusion: The patient has not relapsed in
the 5 years that he has not been taking imatinib. Babesiosis
should be added to the many possible causes of HES. It is unknown
how often babesiosis causes HES as well as what percentage of
HES patients have babesiosis.
--------------------------------------------------------------------------------
Readers are encouraged to respond to the author at jschaller@swfla.rr.com
or to Paul Blumenthal, MD, Deputy Editor of MedGenMed, for the
editor's eyes only or for possible publication via email: pblumen@stanford.edu
Introduction
In 2001 we reported the first case of use of imatinib mesylate
(Gleevec) for treatment of idiopathic hypereosinophilia syndrome
(HES).[1]
After 5
years, new information is available about the patient's care.
Specifically, it is possible that an emerging complex protozoa
infection, babesiosis, is associated with his medical history.
On the basis of our experience with this patient, it appears
that a diagnosis of babesiosis is not always simple. For example,
the number of Babesia species that infect humans has grown from
4 to 10 or more during the last 15 years.[2]
Available laboratory testing does not offer species-specific
antibody and polymerase chain reaction (PCR) testing for these
emerging species. Diagnostic clues for active Babesia, such
as anemia, are not actually present in at least one aggressive
emerging species (B duncani)[3]
(P.A. Conrad, oral communication, October 2006). Some Babesia
experts caution that this intracellular parasite might be common.[4-6]
As a background,
the patient was diagnosed repeatedly with idiopathic HES, an
often fatal illness that can damage a wide range of possible
organs, including the heart, nervous system, lungs, liver, and
kidneys. It is often treated with interferon-alpha and hydroxyurea,
and we believe that these medications saved his life. For example,
a small cerebral infarction related to his idiopathic HES did
not recur over 6 years and his eosinophil counts were moderately
controlled (eg, 12% eosinophils) on this combination treatment.
However, his eosinophil cationic protein (ECP) was not controlled.
(His values were 30-140 ng/mL with < 24 as the reference
range.)
His interferon-alpha/hydroxyurea
treatment increased or did not remove a profound intractable
headache, severe fatigue, irritability, and concentration difficulties.
After years on hydroxyurea and interferon-alpha, the severity
of this morbidity or side effects motivated us to try a trial
of imatinib mesylate. Treatment involved compounded capsules
of 25 mg, used in doses between 75 and 100 mg per day, and was
followed by an abrupt remission of HES in a few weeks and a
normalization of his ECP. He experienced no significant side
effects. Over the course of a year, the patient's eosinophil
count remained low-normal, and the patient decided on a trial
of imatinib mesylate in 25-mg reductions over 3 months. He has
not experienced a relapse during the past 5 years.
Since our
initial publication, our findings have been repeatedly replicated.[7-13]
In summary, these publications report many patients with HES
have a dramatic positive response with imatinib treatment. Yet
not all patients with HES respond to imatinib mesylate and not
all retain positive responses. The cause of HES is unclear and
heterogeneous. Causes for HES include dysregulation of interleukin
5, interleukin 3, and granulocyte-macrophage colony-stimulating
factor. Of these cytokines, interleukin 5 appears to have the
greatest role in the regulation of eosinophil maturation.[14]
The positive effect of imatinib mesylate on HES has been attributed
to many mechanisms. These include activated kinase such as Abl,
platelet-derived growth factor receptor (PDGFR), KIT, and the
novel fusion tyrosine kinase FIP1L1-PDGFRalpha, which is a consequence
of an interstitial chromosomal deletion. All of these are inhibited
by imatinib.[15]
However, no single mechanism seems to explain all patients'
positive response.[16]
Follow-up
Methods
After 6 years we decided to follow up on this patient's treatment.
We interviewed the patient, his son, aunt, and 2 consulting
physicians and also reviewed relevant sample laboratory results
to determine whether his HES had returned and whether his residual
morbidity while on imatinib had changed.
Results
After the patient was weaned off imatinib approximately 5 years
ago, he had serial complete blood counts (CBCs), every 2-4 weeks
for a year, due to a serious concern over a relapse. Eosinophils
remained in the low-normal range, and ECP never surpassed the
high-normal range.
Off imatinib,
the patient was able to work a 50-hour week successfully, but
did have ongoing medical and neuropsychiatric symptoms that
began with the onset of his HES. The most significant was an
intractable headache, paresthesia of the calves and feet, mild
fatigue (requiring 9 hours of sleep per night), mild irritability,
mild cognitive rigidity, a mild decrease in interpersonal relational
skills, mild depression, and middle-age onset of an obsessive
personality disorder, according to a board-certified psychiatrist
and neuropsychologist.
Although
imatinib caused some transient relief from his severe headache,
the benefit was lost and 2-week trials of 150 mg, 200 mg, 250
mg, and 300 mg did not regain any relief. The patient failed
to receive headache relief despite full and complete trials
with all major prophylactic and abortive medications over 12
years by 8 different neurologists. In 2006, a research-oriented,
board-certified neurologist felt that the patient had failed
all available headache medications. Other treatments for his
remaining morbidities (eg, antidepressants from 5 medication
classes and many mood stabilizers) had no clear benefit.
In late
2006, the patient's son was slowly unable to function in school
due to profound fatigue. Evaluations by specialists in endocrinology,
infectious disease, oncology, and pediatric psychiatry yielded
no clear diagnosis. Then the child was tested for Babesia by
the family pediatrician after she read that Ixodes ticks can
carry these protozoa. The family requested broad laboratory
testing, and the results included a positive PCR for B microti.
The pediatrician chose to ignore the negative IgG and IgM B
microti titers and began an unspecified treatment for 3 weeks
for presumed babesiosis infection; there was no clear benefit.
The child is pursuing other medical consultations and is receiving
home instruction due to ongoing profound fatigue and occasional
sweats.
Also in
late 2006, an aunt living in the same household began experiencing
"signs of menopause" which she described as "waves
of warmth, chills, and sweats." Her gynecologist, however,
was not convinced on the basis of a menses history and laboratory
results, and referred her back to her internist who thought
her symptoms could just as easily be fever, chills, and sweats
related to an infection. Her temperature was 99.0-99.8 °F
during 2 weeks of daily afternoon checks. The aunt's internist
heard about the patient's son and ordered B microti IgG, IgM,
PCR, and sedimentation rate tests as well as manual CBC. After
all returned negative, a relative who worked in pathology asked
for the manual differential to be repeated. He called and discussed
his limited experience and recent reading on Babesia with the
pathologist, including the need for red blood cell (RBC) examination
to be done at a power 1000x with oil, with instructions to look
for specific Babesia intracellular RBC inclusions. The full
recommendations to increase the capacity of the manual RBC examination
are unavailable. Surprisingly, the repeat manual yielded a positive
finding of a Babesia-like infectious agent in the woman's RBCs.
In this
context, the same testing was run on our recovered HES patient,
but no Babesia was found.
Over the
following weeks, this academically advanced and motivated family
began to discuss their experience with neighbors and others
in their small community, an area characterized as having a
very high deer population and also a presumed high Ixodes tick
concentration. Some individuals reported having various Ixodes
infections, including babesiosis. At this time, the aunt found
an article on the WA-1 strain of Babesia on PubMed; it described
5 patients in a West Coast neighborhood as infected with a form
never tested for in our HES recovered patient.[17]
The patient
with HES in remission was then also tested for WA-1, newly named
Babesia duncani,[3]
which yielded negative results on IgM, IgG, and PCR.
Our HES
patient decided that Babesia should still be considered in his
case. He did gardening and nature walking as hobbies, and believed
that he was at higher risk than anyone in his household for
Ixodes tick attachments. He reasoned with his doctors that his
son had a positive PCR, had less outdoor contact than him, and
that a repeated manual CBC only caught the aunt's Babesia after
special communication with the pathologist.
Two consultants
agreed on a 4-week babesiosis treatment trial to determine whether
the patient's headache and other morbidity improved. He was
placed on atovaquone (Mepron) 750 mg twice daily with fatty
food to enhance absorption, and azithromycin (Zithromax) 250
mg 3 times daily. Babesiosis treatments may also be used to
treat malaria; this makes some sense because Babesia and malaria
are partially similar-appearing intracellular RBC parasites.
The patient also treated himself with a derivative of Artemisia
annua, a Chinese herb considered by the World Health Organization
and the United Nations Children's Fund to be the first-line
treatment for malaria if combined with a standard synthetic
antimalarial agent.[18-25]
The patient
has begun to improve with these treatments and therefore they
are being extended a month. Specifically, the paresthesias of
the calves and feet have markedly decreased and his fatigue
has improved. His sleep has decreased from 9 hours a night to
7.5-8 hours a night. His mood has significantly improved and
his cognitive rigidity, relational skills, and obsessive personality
problems have improved approximately 75%. His ECP has gone from
high-normal to low-normal levels. He has experienced a 50% overall
improvement in his headache pain. He is not at baseline, but
his mu agonist/antagonist pain treatment, a buprenorphine/naloxone
combination (Suboxone) which was the only treatment besides
oxycodone to relieve his pain, was able to be reduced from 2
mg every 8 hours to a mere 1 mg per day. (Buprenorphine for
pain is typically dosed at 3-4 times daily and rarely relieves
pain at this low dose.)[26]
Currently,
his physicians believe that his HES might have been due to an
undiagnosed infectious agent, ie, Babesia. They feel that his
residual morbidity is responding to babesiosis and malaria medications.
Because the patient had been a gardener and nature walker for
years before his HES, they believe that it is possible that
he had Ixodes exposures via his brush- and woods-lined home
and while hiking. Various family members, pets, and neighbors
have had clear Ixodes tick attachments with rare highly variable
rashes. The patient is not sure whether a few scalp "bumps"
when grooming his hair were tick attachments.
Discussion
As of January 2007, many new species of Babesia have been identified
and many have no specific human testing available in routine
national laboratories.[2] The manual CBC used to identify Babesia
and also a similar-appearing RBC parasite, malaria, is unreliable;
malaria in allopathic centers is often missed, especially if
the numbers of intracellular parasites are low.[27-29]
The patient in this case had 2 close relatives in the same home
with likely babesiosis diagnosed by some common symptoms and
lab results. While treatments should not fully diagnose an illness,
his positive response to 3 malaria medications used in babesiosis
treatment is noteworthy.
Spontaneous
unexplained remissions have been reported in HES patients with
different treatments in the past, eg, interferon-alpha.[30]
Because this patient has been free of HES lab findings for 5
years, we feel that he is probably outside the range of possible
"cyclic eosinophil oscillations."[16]
Could interferon-alpha
and imatinib control a Babesia-induced idiopathic HES? We do
not know. However, low doses of natural human interferon alpha
significantly inhibit the development of B microti infection
in mice.[31]
Further,
another partially related interferon, IFN-gamma, has antiparasitic
benefits, including against Babesia.[32,33]
Imatinib
has many mechanisms, and its ability to treat parasitic agents
is not known. The tyrosine kinase system, however, is one target
for the medication. Babesia contains a highly active protein
kinase.[34]
Viruses, bacteria, and parasites manipulate tyrosine kinase
and related pathways of their hosts to achieve efficient entry,
replication, and exit during their infectious cycles.[27]
Conclusion
The patient, the patient's physicians, and his family feel that
Babesia is a possible cause for both his HES and other ongoing
problems that have significantly remitted. We simply agree that
it should be included in the differential diagnosis of HES before
a diagnosis of HES is given; it is not on a list that is quite
full and useful.[35]
This emerging protozoa parasite should be considered in any
idiopathic HES case because parasitic infections can cause hypereosinophilia.
Yet many other causes of hypereosinophilia exist, eg, genetic
abnormalities, atopy, hypersensitivity reactions, collagen vascular
diseases, and tumors.
We have
shown that our HES patient has not relapsed over 5 years after
ending a successful trial of imatinib. Empirical treatment for
babesiosis produced significant improvements in long-standing
morbidity. Therefore, these specific emerging protozoa, Babesia,
should be considered in HES patients, especially those with
possibly common symptoms such as increased fatigue, fevers,
chills, or sweats.[36,37]
James L. Schaller, MD, MAR, Director, Professional
Medical Services of Naples, Naples and Tampa, Florida
Glenn A. Burkland, DMD, Associate Clinical
Professor, Temple University School of Dental Medicine, Philadelphia,
Pennsylvania
PJ Langhoff, medical author and science research
assistant, Hustisford, Wisconsin
Author's Email: jschaller@swfla.rr.com
Disclosure: James L. Schaller, MD, MAR, has disclosed that he
has received unrestricted research grants from Forest, Cephalon,
Wyeth, BioRay, Vitacost.com, QMEDRX, Zeneca, and AstraZeneca.
He is a medical advisory board consultant with stock ownership
in Nutraceutical Sciences Institute, and the inventor of a nutraceutical
transdermal bioidentical antidepressant with a patent pending.
Dr. Schaller has also disclosed that he is the author of books
on babesiosis, artemisinin, and Suboxone and that all 3 topics
are mentioned in this article.
Disclosure: Glenn A. Burkland, DMD, has disclosed no relevant
financial relationships.
Disclosure: PJ Langhoff has disclosed no relevant financial
relationships.
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