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T h e n e w e ng l a n d j o u r na l o f m e dic i n e Current Concepts
Henry M. Feder, Jr., M.D., Barbara J.B. Johnson, Ph.D., Susan O'Connell, M.D., Eugene D. Shapiro, M.D., Allen C. Steere, M.D., Gary P. Wormser, M.D., and the Ad Hoc International Lyme Disease Group* From the Departments of Family Medi-cine and Pediatrics, Connecticut Chil- LB. bur yme disease, the most common tick-borne infection in the north- ern hemisphere, is a serious public health problem. In North America, it is dren's Medical Center, Hartford, and University of Connecticut Health Center, caused exclusively by Borrelia burgdorferi sensu stricto (hereafter referred to as gdorferi), whereas in Europe it is cau sed by B. afzelii, B. garinii, B. burgdorferi, and occasionally by other species of borrelia.1 tious Diseases, Centers for Diseases Control and Prevention, Fort Collins, CO This complex infection has a number of objective manifestations, including a char- (B.J.B.J.); Lyme Borreliosis Unit, Health acteristic skin lesion called erythema migrans (the most common presentation of early Lyme disease), certain neurologic and cardiac manifestations, and pauciarticu- tory, Southampton General Hospital, Southampton, United Kingdom (S.O.); lar arthritis (the most common presentation of late Lyme disease), all of which usu-Departments of Pediatrics and Epidemi- ally respond well to conventional antibiotic therapy.2 Despite resolution of the objec- ology and Public Health, Yale University tive manifestations of infection after antibiotic treatment, a minority of patients School of Medicine, New Haven, CT (E.D.S.); Division of Rheumatology, Al- have fatigue, musculoskeletal pain, difficulties with concentration or short-term lergy and Immunology, Massachusetts memory, or all of these symptoms. In this article, we refer to these usually mild and General Hospital, Harvard Medical self-limiting subjective symptoms as "post-Lyme disease symptoms," and if they last School, Boston (A.C.S.); and the Division of Infectious Diseases, Department of longer than 6 months, we call them "post-Lyme disease syndrome."Medicine, New York Medical College, The word "chronic" has been applied to Lyme disease in a wide variety of contexts and is sometimes used interchangeably with the preferred term "late Lyme disease." quests to Dr. Feder at the Departments of Family Medicine and Pediatrics, Uni- For example, in Europe, certain late neurologic manifestations of previously untreated versity of Connecticut Health Center, or inadequately treated infection, such as borrelial encephalomyelitis or long-standing meningitis, have been referred to as "chronic neuroborreliosis" (Table 1).1-3 In the United States, reports have described untreated patients with recurrent or persistent *Other investigators who participated in arthritis that lasts for up to several years, presumably because of active infection.4 the Ad Hoc International Lyme Disease The focus of this review, however, is not the objective manifestations of late Lyme disease but rather the imprecisely defined condition referred to as "chronic Lyme disease." This term is used by a small number of practitioners (often self-designated Copyright 2007 Massachusetts Medical Society. as "Lyme-literate physicians") to describe patients whom they believe have persistent B. burgdorferi infection, a condition they suggest requires long-term antibiotic treat- ment and may even be incurable.5 Although chronic Lyme disease clearly encom- passes post-Lyme disease syndrome, it also includes a broad array of illnesses or symptom complexes for which there is no reproducible or convincing scientific evi- dence of any relationship to B. burgdorferi infection. Chronic Lyme disease is used in North America and increasingly in Europe as a diagnosis for patients with persistent pain, neurocognitive symptoms, fatigue, or all of these symptoms, with or without clinical or serologic evidence of previous early or late Lyme disease.
n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. Table 1. Selected Late or Long-Term Manifestations of Borrelia burgdorferi Infection.*
Condition
Prevalence
Evidence of Active Infection
Comments
antibodies against B. burgdorferi; in Mild but objective cognitive abnormali- Pathogenesis thought to be for antibodies against B. burgdorferi; nostic; PCR to detect B. burgdorferi ies against B. burgdorferi; CSF may Extremely rare, with more cases in Objective abnormalities on neurologic Presents clinically with a pro- Objective and characteristic abnormali- May be associated with a pe- * PCR denotes polymerase chain reaction, CSF cerebrospinal fluid, CNS central nervous system, and MRI magnetic resonance imaging.
B. burgdorferi, they do not require objective clinical or laboratory evidence of infection as a diagnostic The diagnosis of chronic Lyme disease and its criterion.5,8-10 treatment differ substantively from the diagnosis Several lines of reasoning are used to provide and treatment of recognized infectious diseases. support for this diagnostic rationale. One is the The diagnosis is often based solely on clinical judg- unproven and very improbable assumption that ment rather than on well-defined clinical criteria chronic B. burgdorferi infection can occur in the and validated laboratory studies, and it is often absence of antibodies against B. burgdorferi in se- made regardless of whether patients have been in rum (Table 2). Negative results of serologic tests areas where Lyme disease is endemic.6,7 Although are often attributed to previous antibiotic therapy proponents of the chronic Lyme disease diagnosis or to the theory that chronic infection with B. burg- believe that patients are persistently infected with dorferi suppresses humoral immune responses; n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Diagnosis
Disease†
Putative
B. sential; diagnosis are in or poor pret may seropositivity duration phocyte assays; none of these tests have been validated.
Limitations
immunoblot than results cal objective no noblots the dence-based other with performed hood otherwise, value nostically be disease antibodies persist antibiotic of patients the testing mens thus tive contamination performing distinguish organisms America.*
cent from be ing disease; grans, time convert treated remain infection; among demic tomatic occur dorferi IFA disease . burgdorferi, lym and Technique
result or positive results are the tion on thereafter because false posi- tive immunoblot by used all-deficient or cystic form Centers Diagnosis
Table 2. Laboratory
Other ed cell sorting for cell w Information n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. neither theory is well supported by scientific an alternative diagnosis from a physician willing data.12-14 When physicians who diagnose chronic to treat them for chronic Lyme disease. Lyme disease obtain laboratory tests to provide Data from studies of patients who underwent support for their diagnoses, they often rely heavily reevaluation at academic medical centers suggest on "Lyme specialty laboratories." Such laboratories that the majority of patients presumed to have may perform unvalidated in-house tests that are chronic Lyme disease have category 1 or 2 dis- not regulated by the Food and Drug Administra- ease.8-10 Since patients in these two categories do tion, or they may perform standard serologic tests not have evidence of active infection with B. burg- interpreted with the use of criteria that are not dorferi, the potential benefit of treating them with antibiotics, beyond a placebo effect, would be at- Once the diagnosis of chronic Lyme disease is tributable to the antiinflammatory or other non- made, patients are commonly treated for months antimicrobial effects of antibiotics.26 Antibiotic to years with multiple antimicrobial agents, some therapy in these patients is not warranted.
of which are inactive in vitro against B. burgdor- Patients with category 3 disease do not have a feri.2,5,18-20 Antibiotics may be prescribed either si- history of objective clinical findings that are con- multaneously or sequentially, and they are often sistent with Lyme disease, but their serum samples administered parenterally. Occasionally, these pa- contain antibodies against B. burgdorferi, as deter- tients are treated with unconventional and highly mined by means of standardized assays that were dangerous methods such as bismuth injections or ordered to investigate chronic, subjective symp- deliberate inoculation of plasmodia to cause ma- toms of unknown cause.27 Patients with disease in laria.2,21,22 No other spirochetal infection, includ- this category have at most only equivocal evidence ing the neurologic complications of tertiary syph- of B. burgdorferi infection, since the predictive ilis, is managed in an analogous fashion.2,23 The value of positive serologic results in this setting duration of treatment commonly prescribed for is low.27,28 Although some clinicians would offer chronic Lyme disease often far surpasses even the patients with category 3 disease an empirical trial conventional 6-month course of therapy success- of 2 to 4 weeks of an oral antibiotic, such patients fully used for most cases of tuberculosis.
should be told that the diagnosis is uncertain and that a benefit from treatment is unlikely.
Patients with category 4 disease have symptoms associated with post-Lyme disease syndrome.29-31 In prospective studies of patients with erythema Diagnoses of chronic Lyme disease appear to fall migrans, subjective symptoms of unknown cause predominantly into one of four categories (Fig. were present 1 year or more after treatment in 1).8-10 Patients with category 1 disease do not have 0.5 to 13.1% of patients.31 Whether this prevalence objective clinical manifestations or laboratory evi- exceeds that of such symptoms in the general dence of B. burgdorferi infection, and they receive population is unknown, since none of these stud- a diagnosis on the basis of the presence of non- ies included a control group. A meta-analysis sug- specific symptoms such as fatigue, night sweats, gested that the prevalence of such symptoms ex- sore throat, swollen glands, stiff neck, arthral- ceeded that in control groups without Lyme gia, myalgia, palpitations, abdominal pain, nau- disease, but this analysis relied on several retro- sea, diarrhea, sleep disturbance, poor concentra- spective studies in which the diagnosis and treat- tion, irritability, depression, back pain, headache, ment of Lyme disease often did not meet current and dizziness.5 Nonspecific symptoms such as standards.30,31 these are common, and some occur in more than 10% of the general population, regardless of wheth- er Lyme disease is endemic in the area.24,25 Patients with category 2 disease have identifi- able illnesses or syndromes other than Lyme dis- Controlled treatment trials have been conducted ease. Such patients may or may not have a history only for patients with category 4 disease. Data of Lyme disease. They have received either a mis- from three double-blind, randomized, placebo- diagnosis or a diagnosis (e.g., multiple sclerosis) controlled trials have shown that there is substan- that they are reluctant to accept and have sought tial risk, with little or no benefit, associated with n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Category 1
Category 2
Category 3
Category 4
Figure 1. The Four Predominant Categories of Disease Associated with Chronic Lyme Disease.
Only patients with category 4 disease have post-Lyme disease symptoms.
SIZE y can cause considerable harm
propriate initial treatment for an episode of Lyme post-Lyme disease symptoms.2 Life-threatening AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset. biliary complications requiring
One of these trials enrolled 78 patients who cholecys Please check carefully. tectomy35 have occurred after ceftriaxone
feri at trial entry; a second trial enrolled 51 patients intravenous catheter has resulted in death.36 In an who were seronegative.32 All patients had anteced- unpublished study in which 37 patients underwent ent objective signs of Lyme disease, most often randomization to receive 10 weeks of treatment physician-diagnosed erythema migrans. Patients with either ceftriaxone or placebo, about one fifth were treated either with a 1-month course of cef- of the patients had serious adverse events, the ma- triaxone administered intravenously, followed by jority of which were related to intravenous cath- 2 months of doxycycline given orally, or with iden- eters.37 In light of the risk of serious adverse events tical-appearing intravenous and then oral place- in their study, Krupp et al. concluded that "re- bos. Patients were assessed at enrollment and peated courses of antibiotic treatment are not indi- 3 months after completion of treatment with the cated for persistent symptoms following Lyme use of the Medical Outcomes Study 36-item Short- disease, including those related to fatigue and Form General Health Survey (SF-36). There were cognitive dysfunction."33 no significant differences in the scores between Eligibility criteria for two controlled trials stip- the patients in the antibiotic and placebo groups.
ulated that symptoms must be severe enough to In a single-center trial conducted by Krupp et interfere with the patient's ability to function.32 al., 55 patients with severe fatigue (as measured Thus, the physical health status of the patients by an 11-item questionnaire) after treatment of enrolled in these two studies was equivalent to well-documented Lyme disease underwent ran- that of patients with congestive heart failure or domization to receive ceftriaxone or an identical- osteoarthritis.32 This finding was preordained by appearing placebo for 28 days.33 The investigators the study design, but it has been incorrectly inter- reported a reduction in scores for fatigue severity preted by some to indicate that patients with in the ceftriaxone group that exceeded the reduc- post-Lyme disease symptoms typically are severely tion in the placebo group by 13 percentage points disabled. (i.e., a reduction of 22% vs. 9%; P = 0.01) but no The investigators who conducted the controlled significant improvement in cognitive function. treatment trials had great difficulty finding pa- There was no significant difference between the tients who met the criteria for entry, despite inten- groups with regard to the degree of improvement sive efforts that included both the notification and in reported health status on the basis of the SF-36 involvement of Lyme disease support groups and score. Patients in the ceftriaxone group were sig- associations.32,33 For two of the three studies, ad- nificantly more likely than those in the placebo ditional sites had to be engaged,32 and the enroll- group to identify their treatment assignment cor- ment period had to be extended for all three stud- rectly at the end of therapy, raising a concern that ies.32,33 To enroll 55 patients in one of the studies, masking was compromised and that a placebo ef- investigators had to screen more than 500 people, fect may explain the greater improvement in scores most of whom were excluded because of the ab- for fatigue severity in the treated group.33 sence of a substantiated history of Lyme disease.33 n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. This difficulty with enrollment appears to reflect nearly three quarters of 97 patients who had re- the scarcity of persons with well-documented ceived the diagnosis of chronic Lyme disease.43 Lyme disease in whom clinically significant prob- However, the authors did not sequence the ampli- lems develop after conventional treatment.
cons to confirm that the DNA was from B. burg- Although anecdotal evidence and findings from dorferi. Such a high rate of positive results among uncontrolled studies have been used to provide patients who had been treated extensively with support for long-term treatment of chronic Lyme antibiotics is unlikely when one considers that only disease,18-20 a response to treatment alone is nei- 1 of 12 urine samples (8%) from untreated pa- ther a reliable indicator that the diagnosis is ac- tients with erythema migrans was found to be curate nor proof of an antimicrobial effect of positive in a careful evaluation of this technique's treatment. Many patients with intermittent or self- value as a diagnostic test.44 Moreover, detection limited symptoms may feel better over time as a of bacterial DNA is not necessarily an indicator result of the natural course of their condition, and of either active infection or clinical disease.45 controlled trials indicate that nearly 40% of pa- The central question is not whether a few spiro- tients with post-Lyme disease symptoms have a chetes might persist after antibiotic treatment, but positive response to placebo.32 In addition, the as- whether clinical disease can be attributed to their sessment of a change in symptoms may be con- presence.
founded by antiinflammatory and other nonanti- It is highly unlikely that post-Lyme disease microbial effects of antibiotics.26 Furthermore, the syndrome is a consequence of occult infection of published reports of uncontrolled trials of antibi- the central nervous system. This conclusion is otic treatment for chronic Lyme disease used based on evidence such as the absence of inflam- poorly standardized case definitions and either mation in the cerebrospinal fluid,32,33 negative re- undefined criteria for interpreting immunoblots sults of both cultures and PCR assays for B. burg- or criteria that have subsequently been found to dorferi in the cerebrospinal fluid,32,40 the absence have very low specificity (approximately 60%).38 of structural abnormalities of the brain parenchy- ma,46 and normal neurologic function, with no effect of antibiotic therapy (as compared with pla- Additional evidence against the hypothesis that chronic symptoms are due to persistent infection A report by Phillips and colleagues39 is often cited is the fact that antibodies against B. burgdorferi in to provide support for the hypothesis of persistent many of these patients are undetectable, which is B. burgdorferi infection. They indicated that they de- inconsistent with the well-established immunoge- tected B. burgdorferi in blood specimens from 43 of nicity of the spirochete's lipoproteins.13,14,20,29,32,47 47 patients who had received or were receiving pro- Patients in whom treatment for most infectious longed antibiotic therapy for chronic Lyme dis- diseases, including syphilis, has failed typically ease (91%). Other investigators have been unable have persistent or rising titers of antibodies be- to reproduce these findings in patients with well- cause of ongoing B-cell stimulation by microbial documented post-Lyme disease syndrome.32,40-42 antigens.23 Moreover, Phillips and colleagues used a new cul- The lack of convincing evidence for the persis- ture medium that specifically included Detroit tap tence of B. burgdorferi in treated patients (Table 3) water; this medium was subsequently shown to be is not surprising.2,20,23,24,29-33,40,47-49 The failure of bactericidal for B. burgdorferi.41 In contrast to the treatment for bacterial infections typically occurs findings from their report,39 B. burgdorferi could as a result of pathogens that either have or acquire not be detected in any of 843 specimens of blood resistance to antibiotics, difficulties in achieving or cerebrospinal fluid, tested by means of either sufficient concentrations of antibiotic at sites of culture or polymerase chain reaction (PCR), from infection, or impaired host-defense mechanisms.2 the 129 patients enrolled in two of the controlled None of these factors are generally applicable to treatment trials.32,40 Moreover, there was no sero- infection with B. burgdorferi. Although B. burgdorferi logic evidence of tick-borne coinfections in the vast can develop into cystlike forms in vitro under cer- tain conditions that can be created in the labora- In another report, DNA of B. burgdorferi was de- tory,50 there is no evidence that this phenomenon tected by means of PCR in urine specimens from has any clinical relevance. B. burgdorferi may pen- n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e in clear and empathetic language leaves the patient Table 3. Evidence against Active Infection in Patients with Subjective
susceptible to those who would offer unproven and Symptoms Persisting for More Than 6 Months after Antibiotic Treatment
for Lyme Disease.
potentially dangerous therapies. Additional advice to clinicians is included in the Supplementary Ap- Signs and symptoms
pendix, available with the full text of this article Absence of concomitant objective clinical signs of either disease or inflam- mation and no progression to objective signs or development of inflam- Similar symptoms common in persons who have never had Lyme dis- Laboratory tests
Physicians and laypeople who believe in the exis- Persistence of symptoms independently of persistent seropositivity20,29,32,47 tence of chronic Lyme disease have formed soci- Absence of either positive cultures or positive polymerase-chain-reaction re- eties, created charitable foundations, started nu- merous support groups (even in locations in which Treatment
B. burgdorferi infection is not endemic), and devel- No substantive response to antibiotic therapy in controlled treatment oped their own management guidelines.5 Scien- tists who challenge the notion of chronic Lyme No documented resistance of Borrelia burgdorferi to recommended anti- disease have been criticized severely.
The attorney general of Connecticut has begun Absence of recognized risks for failure of antibiotic therapy; these include an unprecedented antitrust investigation of the host immunodeficiency or an infection in which there is local ischemia, Infectious Diseases Society of America, which is- a foreign body (biofilm), a sequestrum, or an abscess2 sued treatment guidelines for Lyme disease that Other evidence
do not support open-ended antibiotic treatment regimens.2 In some states, legislation has been Lack of precedent for the use of long-term antibiotic treatment in other proposed to require insurance companies to pay for prolonged intravenous therapy to treat chronic Lyme disease. The media frequently disregard complex scientific data in favor of testimonials etrate cells in vitro, but there is no evidence that about patients suffering from purported chronic the organism may be sheltered from antibiotics Lyme disease and may even question the compe- during an intracellular phase and then disseminate tence of clinicians who are reluctant to diagnose and cause clinical relapse.51,52 Indeed, the strate- chronic Lyme disease. All these factors have con- gies used by B. burgdorferi to adapt to the vertebrate tributed to a great deal of public confusion with host and evade host defenses indicate an extracel- little appreciation of the serious harm caused to many patients who have received a misdiagnosis and have been inappropriately treated.
How should clinicians handle the referral of symp- tomatic patients who are purported to have chron- Chronic Lyme disease is the latest in a series of ic Lyme disease? The scientific evidence against the syndromes that have been postulated in an attempt concept of chronic Lyme disease should be dis- to attribute medically unexplained symptoms to cussed and the patient should be advised about the particular infections. Other examples that have risks of unnecessary antibiotic therapy. The patient now lost credibility are "chronic candida syndrome" should be thoroughly evaluated for medical condi- and "chronic Epstein-Barr virus infection."57,58 The tions that could explain the symptoms. If a diag- assumption that chronic, subjective symptoms are nosis for which there is a specific treatment cannot caused by persistent infection with B. burgdorferi is be made, the goal should be to provide emotional not supported by carefully conducted laboratory support and management of pain, fatigue, or other studies or by controlled treatment trials. Chronic symptoms as required.54-56 Explaining that there Lyme disease, which is equated with chronic B. burg- is no medication, such as an antibiotic, to cure the dorferi infection, is a misnomer, and the use of pro- condition is one of the most difficult aspects of car- longed, dangerous, and expensive antibiotic treat- ing for such patients. Nevertheless, failure to do so ments for it is not warranted.2 n engl j med 357;14 www.nejm.org october 4, 2007 Downloaded from www.nejm.org at STIFTUNG ZUERCHER BLUTSPENDEDIENST SRK on October 29, 2007. Copyright 2007 Massachusetts Medical Society. All rights reserved. Dr. Feder reports receiving lecture fees from Merck and serving Zeneca to New York Medical College for visiting lecturers for in- as an expert witness in medical-malpractice cases related to Lyme fectious-disease grand rounds, being part owner of Diaspex (a disease. Dr. Johnson reports holding patents on diagnostic anti- company that is now inactive with no products or services), own- gens for Lyme disease. Dr. O'Connell reports serving as an expert ing equity in Abbott, serving as an expert witness in a medical- witness related to Lyme disease issues in civil and criminal cases malpractice case, and being retained in other medical-malpractice in England. Dr. Shapiro reports serving as an expert witness in cases involving Lyme disease. He may become a consultant to medical-malpractice cases related to Lyme disease, reviewing Biopeptides. No other potential conflict of interest relevant to this claims of disability related to Lyme disease for Metropolitan Life article was reported.
Insurance Company, and receiving speaker's fees from Merck and The findings and conclusions in this article are those of the Sanofi-Aventis. Dr. Steere reports receiving a research grant from authors and do not necessarily represent the views of the Centers Viramed and fees from Novartis. Dr. Wormser reports receiving for Disease Control and Prevention.
research grants related to Lyme disease from Immunetics, Bio- We thank Alex P. Butensky, Julie Chacko, Rachel Hart, and Rad, and Biopeptides and education grants from Merck and Astra- Lisa Giarratano for assistance.
Appendix
The following were members of the Ad Hoc International Lyme Disease Group: Gundersen Lutheran Medical Foundation, La Crosse, WI - W.A. Agger; National Microbiology Laboratory, Health Canada, Winnipeg, MB, Canada - H. Artsob; Johns Hopkins Medical Institutions, Baltimore - P. Auwaerter, J.S. Dumler; St. Luke's Hospital, Duluth, MN - J.S. Bakken; Yale University School of Medicine, New Haven, CT - L.K. Bockenstedt, J. Green; New York Medical Col ege, Valhal a - R.J. Dattwyler, J. Munoz, R.B. Nadelman, I. Schwartz; Danbury Hospital, Danbury, CT - T. Draper; Johns Hopkins Medical Institutions, Crofton, MD - E. McSweegan; Atlantic Neuroscience Institute, Summit, NJ, and the New York University School of Medicine, New York - J.J. Halperin; Boston University School of Medicine and Boston Medical Center, Boston - M.S. Klempner; University of Connecticut School of Medicine and Connecticut Children's Medical Center, Farmington - P.J. Krause; Centers for Disease Control and Prevention, Fort Col ins, CO - P. Mead; University of British Columbia, Vancouver, Canada - M. Morshed; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway - R. Porwancher; University of Connecticut Health Center, Farmington - J.D. Radolf; Maine Medical Center, Portland, ME - R.P. Smith, Jr.; Schneider Children's Hospital at North Shore, Manhasset, NY - S. Sood; Washington Hospital Center and Georgetown University Medical Center, Washington, DC - A. Weinstein; Wadsworth Center, New York State Department of Health, Albany - S.J. Wong; and Con- necticut Children's Medical Center, University of Connecticut, Hartford - L. Zemel.
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