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Lyme Expert Defends North Carolina Infection Expert, Blasts AP for Many Errors and Takes On Drs. Shapiro and Mead

To the Associated Press,

The story entitled "Doctor Disciplined over Lyme Disease Treatment" (4/14/06) has numerous inaccuracies. First, the title makes it sound like Dr. Jemsek has already been convicted of some crime. Nothing could be further from the truth, as the story finally acknowledges in the fourth paragraph. By then the casual reader has been totally misled.

The story quotes Dr. Paul Mead of the Centers for Disease Control and Prevention (CDC), who makes comments about the treatment of chronic Lyme disease. Dr. Mead is a research epidemiologist at the CDC. He is not involved in direct patient care, and he has no expertise in the clinical management of patients with chronic Lyme disease. His comments are irrelevant to the thousands of patients suffering from chronic Lyme disease, and his uninformed clinical views are irrelevant to Dr. Jemsek's case.

The story also quotes Dr. Eugene Shapiro, a pediatric researcher from Yale University who helped formulate the now-obsolete Lyme guidelines of the Infectious Diseases Society of America. Dr, Shapiro makes another one of his nihilistic comments for which he is notorious:

"It's not that the people diagnosed with chronic Lyme disease don't have problems," he said. "It's that chronic Lyme disease is not the problem."

Over the past decade, it has become obvious that a major problem for people with chronic Lyme disease is Dr. Shapiro himself, who has used his stature as a university professor to spread misinformation about Lyme disease around the country. Sadly there are gullible reporters who blindly print his dismissive statements while ignoring the immense problems with chronic Lyme disease, which confers disability similar to congestive heart failure. Dr. Jemsek is trying to solve those problems. Dr. Shapiro is making them worse.

A story like this one should have included comments from more enlightened physician groups such as the International Lyme and Associated Diseases Society (ILADS, www.ilads.org) and from patient advocacy groups such as the national Lyme Disease Association (LDA, www.lymediseaseassociation.org). Let's hope that the Associated Press does a better job next time.

Sincerely,

Raphael Stricker, MD
President, ILADS
PO Box 341461
Bethesda, MD 20827


Are Various Babesia Species a Missed Cause for Hypereosinophilia? A Follow-up on the First Reported Case of Imatinib Mesylate for Idiopathic Hypereosinophilia

James L. Schaller, MD, MAR; Glenn A. Burkland, DMD; PJ Langhoff
Medscape General Medicine. 2007;9(1):38. 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.

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]

References

  1. Schaller JL, Burkland GA. Rapid and complete control of idiopathic hypereosinophilia with imatinib mesylate. Medscape General Medicine. 2001;3(3). Available at: www.medscape.com/viewarticle/408170 Accessed February 9, 2007.
  2. Schaller JL. The Health Care Professional's Guide to the Treatment and Diagnosis of Human Babesiosis, An Extensive Review of New Human Species and Advanced Treatments. Tampa, Fla: Hope Academic Press; 2006:43-49.
  3. Conrad PA, Kjemtrup AM, Carreno RA, et al. Description of Babesia duncani n.sp. (Apicomplexa: Babesiidae) from humans and its differentiation from other piroplasms. Int J Parasitol. 2006;36:779-789. Epub 2006 May 4.
  4. Gutierrez Y. Blood apicomplexa: plasmodium, Babesia and entopolypoides. In: Diagnostic Pathology of Parasitic Infections With Clinical Correlations. Philadelphia, Pa: Lea Febiger; 1990;9:146.
  5. Leeflang P, Oomen JMV, Zwart D, et al. The prevalence of Babesia antibodies in Nigerians. Int J Parasitol. 1976;6:156-161.
  6. Osorno BM, Vega C, Ristic M, et al. Isolation of Babesia spp. from asymptomatic human beings. Vet Parasitol. 1976;2:111-120.
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  8. Anghel G, De Rosa L, Ruscio C, et al. Efficacy of imatinib mesylate in a patient with idiopathic hypereosinophilic syndrome and severe heart involvement. Tumori. 2005;91:67-70.
  9. Ault P, Cortes J, Koller C, Kaled ES, Kantarjian H. Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate. Leuk Res. 2002;26:881-884.
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  11. Musto P, Falcone A, Sanpaolo G, et al. Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis. Leuk Lymphoma. 2004;45:1219-1222.
  12. Cortes J, Ault P, Koller C, et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood. 2003;101:4714-4716. Epub 2003 Feb 20.
  13. Tan D, Hwang W, Ng HJ, Goh YT, Tan P. Successful treatment of idiopathic hypereosinophilic syndrome with imatinib mesylate: a case report. Int J Hematol. 2004;80:75-77.
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  15. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201-1214.
  16. Imashuku S, Kakazu N, Ueda I, et al. Response to imatinib mesylate in a patient with idiopathic hypereosinophilic syndrome associated with cyclic eosinophil oscillations. Int J Hematol. 2005;81:310-314.
  17. Quick RE, Herwaldt BL, Thomford JW, et al. Babesiosis in Washington State: a new species of Babesia? Ann Intern Med. 1993;119:284-290.
  18. Lin AJ, Ager AL Jr, Klayman DL. Antimalarial activity of dihydroartemisinin derivatives by transdermal application. Am J Trop Med Hyg. 1994;50:777-783.
  19. Klayman D, Ager LA Jr, Fleckenstein L, Lin AJ. Transdermal artelinic acid: an effective treatment for Plasmodium berghei-infected mice. Am J Trop Med Hyg. 1991;45:602-607.
  20. Zhao KC, Xuan WY, Zhao Y, Song ZY. The pharmacokinetics of a transdermal preparation of artesunate in mice and rabbits. Yao Xue Xue Bao. 1989;34:813-816.
  21. Thriemer K, Wernsdorfer G, Rojanawatsirivet C, Kollaritsch H, Sirichainsinthop J, Wernsdorfer WH. In vitro activity of artemisinin alone and in combination with retinol against Plasmodium falciparum. Wien Klin Wochenschr. 2005;117(suppl 4):45-48.
  22. LaValle JA, Krinsky DL, Hawkin EB, Pelton R, Willis A. Natural Therapeutics Pocket Guide 2000-2001. Hudson, Ohio: Lexi-Comp; 518, 531.
  23. World Health Organization. The use of artemisinin and its derivatives as anti-malarial drugs. WHO/MAL/98.1086. Malaria Unit, Division of Control of Tropical Diseases. Geneva: WHO; 1998.
  24. WHO and UNICEF. Global Financing, Commodities and Service Delivery. World Malaria Report 2005. Available at: rbm.who.int/wmr2005/html/3-1.htm Accessed February 9, 2007.
  25. Schaller JL. Artemisin, Artesunate, Artemisinic Acid and Other Derivatives of Artemisia Used for Malaria, Babesia and Cancer: A Health Care Practitioner's Guide to Dosage, Side Effects, Effectiveness, Toxicity and Interations. A Review of the Research on the Most Common Clinical Artemisia Medications. Tampa, Fla: Hope Academic Press; 2006:134-138.
  26. Schaller JL. Suboxone. Tampa, Fla: Hope Academic Press; 2006:11-14, 33-35.
  27. Orinda GO, Waltisbuhl DJ, Young AS, Wright IG. Low doses of natural human interferon alpha inhibit the development of Babesia microti infection in BALB/c mice. Vet Parasitol. 1994;53:53-58.
  28. Igarashi I, Suzuki R, Waki S, et al. Roles of CD4(+) T cells and gamma interferon in protective immunity against Babesia microti infection in mice. Infect Immun. 1999;67:4143-4148.
  29. Schaller JL. The Health Care Professional's Guide to the Treatment and Diagnosis of Human Babesiosis: An Extensive Review of New Human Species and Advanced Treatments. Tampa, Fla: Hope Academic Press; 2006:105-106.
  30. Yoon TY, Ahn GB, Chang SH. Complete remission of hypereosinophilic syndrome after interferon-alpha therapy: report of a case and literature review. J Dermatol. 2000;27:110-115.
  31. Ahmed JS. The role of cytokines in immunity and immunopathogenesis of pirolasmoses. Parasitol Res. 2002;88(13 suppl 1):S48-S50.
  32. Munter S, Way M, Frischknecht F. Signaling during pathogen infection. Sci STKE. 2006;2006(335):re5.
  33. Ray A, Quade J, Carson CA, Ray BK. Calcium-dependent protein phosphorylation in Babesia bovis and its role in growth regulation. J Parasitol. 1990;76:153-161.
  34. Tefferi A. Modern diagnosis and treatment of primary eosinophilia. Acta Haematol. 2005;114:52-60.
  35. Rothschild BM. Hypereosinophilic syndrome. eMedicine from WebMD. 2005 Jan 31. Available at: www.emedicine.com/ped/topic1069.htm Accessed January 2, 2007.
  36. Butterfield JH. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis. Acta Haematol. 2005;114:26-40.
  37. Henderson SO, Magana RN. Babesiosis. eMedicine from WebMD. 2006 Mar 8. Available at: www.emedicine.com/emerg/topic49.htm Accessed January 2, 2007.
  38. 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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