On April 19, 2010, Tina J. Garcia of Lyme Education Awareness Program submitted a letter to the Institute of Medicine’s Committee on Standards for Developing Trustworthy Clinical Practice Guidelines.  

 

Her submission outlined then Connecticut Attorney General Richard Blumenthal’s antitrust investigation and egregious findings of conflicts of interest regarding the Infectious Diseases Society of America’s (IDSA) Practice Guidelines for Lyme Disease.

 

The Attorney General revealed egregious financial conflicts of interest held by the most influential IDSA Lyme Disease Practice Guideline Committee members.  The authors of the IDSA Lyme Disease Practice Guidelines had financial ties to “drug companies, Lyme disease diagnostic tests, patents and consulting arrangements with insurance companies.”

Excerpt:

IDSA knows that chronic Lyme exists

The IDSA is aware that chronic Lyme exists. We know this because
members of the 2000 and 2006 Lyme disease guideline panels wrote, in
research articles and patents, that chronic Lyme exists.

Evidence about the existence of chronic Lyme borreliosis has increased
since the 2006 LD guidelines were published.

Scientists in California recently reported that not only can Bb persist
in mice despite treatment with ceftriaxone, but the Borrelia can also
infect other ticks and mice. (1) This study buttresses previous
studies that showed that Borrelia can persist in mice (2, 3), dogs (4,
5, 6), and ponies (7).

Studies have also shown that Bb can persist despite antibiotic
treatment in the following human cells, tissues, organs, and body
fluids:

* Fibroblasts (8; Mark Klempner, an IDSA LD guideline panel member in
2006, is an author of this study)

 http://www.idsociety.org/Content.aspx?id=15026

Excerpt: PHILADELPHIA — For pregnant women, an influenza vaccination leads to bigger babies and infants who are less likely to get the flu, according to three studies presented here.

Experts said the findings — presented at the annual meeting of the Infectious Diseases Society of America — might help persuade pregnant women reluctant to get a flu shot.

It might also bring the issue to the attention of obstetricians, who typically do not raise the notion of a flu shot with their patients, said William Schaffner, MD, of Vanderbilt University Medical Center in Nashville.

Introduction

Clinical practice guidelines are now ubiquitous throughout the
United States. The National Guidelines Clearing House, under the
category “diseases,” currently lists 2,126 separate guidelines on its
web site. Clinical guidelines are intended to assist physicians in
patient care by clearly communicating the results of the guideline
committees’ evaluation of available therapeutic options. However,
the processes by which individual guidelines are constructed may be
less clear, leading to disagreements between the issuing committee
and the physicians who treat patients-physicians who may well be
as experienced and knowledgeable as the guideline committee.

The 2006 Infectious Diseases Society of America (IDSA)
guidelines for Lyme disease were released in the fall of that year and
were soon the focus of an antitrust suit brought by Connecticut’s
attorney general. A settlement between the two sides was announced
on May 1, 2008; it called for the seating of a new panel and a
comprehensive review of the evidence, including a hearing to allow
for presentation of divergent medical points of view.

This article reviews the 2006 IDSA Lyme guidelines regarding the impact
various recommendations may have on the use of clinical judgment
in the diagnosis and treatment of patients with Lyme disease
Clinical Judgment in the Diagnosis of Lyme Disease

The IDSA in its 2006 Lyme disease guidelines states:
Clinical findings are sufficient for the diagnosis of
erythema migrans, but clinical findings alone are not
sufficient for diagnosis of extracutaneous manifestations of
Lyme disease or for diagnosis of [human granulocyctic
anaplasmosis] HGA or babesiosis.

Diagnostic testing performed in laboratories with excellent quality-control
procedures is required for confirmation of extra cutaneous
Lyme disease, HGA, and babesiosis.

Initially, the statement appears innocuous; laboratory
confirmation of any diagnosis is always reassuring. But here the
guidelines panel goes a step further. By requiring lab confirmation, it
sets up a diagnostic hierarchy in which testing supersedes clinical
judgment, negative results on indirect laboratory assessments of
infection overrule carefully constructed clinical assessments, and
tests are deemed infallible.

Yet, this diagnostic scheme is fallible. Consider the situation in
which 100 patients with undiagnosed Lyme disease seek medical
attention for evaluation of fever, headache, fatigue, and body aches
occurring at the end of June.

Recall that CDC data indicate that erythema migrans (EM) rashes are reported in 68% of patients
meeting the surveillance case definition, and that the guidelines
recommend two-tier serologic testing of patients lacking the
diagnostic rash. In the two-tier scheme, patients are first tested with
an enzyme-linked immunoabsorbant assay (ELISA) or indirect
fluorescent antibody (IFA) test, and those with positive or equivocal
results are then tested withWestern blotting; patients who are negative
on ELISA are not tested further.

Trevejo et al. found the sensitivity of
two-tier testing in early Lyme disease to be 29%-32%; Bacon et al.
found it to be 38%. As Table 1 demonstrates, the laboratory
confirmation requirement is problematic; as many as 22% of early
Lyme disease patients would go untreated.

Clearly, this is unacceptable; patients would be left untreated at the
stage when therapy is most efficacious. Owing to the potential for false
negative results in these circumstances, Steere et al. suggested that
physicians consider treating patients with “summertime flu”
symptoms.

The need for such a suggestion emphasizes the principal
reason for this challenge-laboratory confirmation requirements
undermine the value and primacy of clinical data and may impede care
as would be the case in this very common clinical scenario.

The same problem with laboratory confirmation holds true for late
neurologic Lyme disease. Starting again with 100 patients who have
undiagnosed Lyme disease and objective, non-EM findings, 43%-56%
would bemis diagnosed because of deficits in laboratory capabilities, as
shown in Table 2

In late Lyme, sensitivity of the testing procedure was
found to be 44% by Ledue et al. , and 57% by Dressler et al.
The low sensitivity of two-tier testing in late neurologic Lyme
disease can be traced back to the original paper by Dressler et al.,
from which the Centers for Disease Control and Prevention (CDC)
took its IgG Western blot criteria.

After identifying the 10 bands on Western blotting that yielded the highest specificity in a retrospective
study, Dressler et al. then tested the criteria in a prospective study. In
that study, the paper reports that 21 of 29 patients with
neuroborreliosis had positive IgG Western blot results, yielding a
sensitivity of 72%.
The ELISA used by Dressler et al. had a sensitivity of 79%. Performing the tests sequentially,
as is done in two tier testing, results in an overall sensitivity of 57% (79% x 72%).
With the two-tier sensitivity for late Lyme disease roughly 50%, a negative
result does not inform physicians, but may easily lead them astray.

Other studies on the two-tier strategy yield different and higher
values for sensitivity. Some studies speak of the “relative
sensitivity” of a test rather than the true sensitivity. The
disagreement between studies investigating the sensitivity of various
testing methodologies for Lyme disease indicates a problem with test reliability, which has been the subject of other papers. If the serologic tests for Lyme disease were equally reliable, sensitivity would be nearly identical across studies of similar, and appropriate, design. (A full
discussion on the limitations of serologic testing is beyond the scope of this paper.)

Other methods available to support or confirm a clinical diagnosis of Lyme disease
in the absence of an EM have low sensitivity (polymerase chain reaction [PCR] of cerebrospinal fluid and blood), may be invasive,or are not clinically available.

With serologic testing being insensitive,clinical data-the history and physical
examination-become even more important.Relying on clinical data to make a diagnosis is
not unique to Lyme disease.

One study on the relative values of history, physical examination,and diagnostic studies found that internists used history alone to establish the correct diagnosis in 76% of test cases.
Another found that in distributing a 100% total relative value between these three types
of data, clinical faculty valued history at 63.3%, physical examination at 19.2%, and
laboratory/imaging data at 17.5%.

Such evidence establishes that the diagnostic hierarchy proposed by the guidelines is inconsistent with the way medicine is practiced. A Lyme disease history begins with the potential for exposure. This history,while a key element, is not always enlightening.

Patients may be unaware of whether they live/work/recreate in a Lyme endemic
area; they may forget about vacations in endemic areas. Questions regarding tick bites may lead to inappropriately ruling out Lyme disease; in one study on erythema migrans, only 14% of the patients recalled being bitten by a tick.

Clinically, and in keeping with its multi systemic nature, Lyme disease has been described as being “symptom rich, exam poor.” Symptoms may be specific or nonspecific, mundane or unusual, acute or chronic; some are prognostic. Some physicians have been
criticized for “seeing Lyme everywhere” in that they recognize scores of symptoms beyond EM rashes, Bell’s palsy, and arthritis as being associated with Lyme disease. Yet, early researchers also noted these symptoms. In a treatment trial on early Lyme disease, Massarotti et al. found that subjects reported the following symptoms: 56% had headache; 42%, stiff neck, with 19% having pain with neck flexion; 14%, dysesthesias; 11%, photophobia; and 4%, facial palsy. Consider these symptoms from Logigian et al.

The wide array of Lyme disease symptoms is consistent with ability to infect multiple organ systems;nervous system involvement creates the potential for varied and atypical symptoms. Common symptoms include: EMrash, fever, fatigue, headache, neck pain, joint or muscle pain, paresthesias, memory impairment, weakness of facial muscles, mood disorders,
neuropathic pain. Acompendium of manifestations by system is given inTable 3.

It is the multisystemic nature of the illness that provides physicians with useful diagnostic information. In fact, with the exception of an isolated EMrash or swollen joint, patients with symptoms restricted to a single system are unlikely to have Lyme disease. Recognizing the
potential for disease is different from “seeing it everywhere.” Failure to recognize Lyme disease may lead to serious harm, as antibiotics are delayed and the infection is unchecked.

The nonspecific nature of many Lyme disease symptoms leads some to suggest that such symptoms hold no diagnostic value. Lyme disease is like many other illnesses that present with nonspecific and often subtle symptoms-symptoms that may go unrecognized by physicians. Examples include hypothyroidism, ovarian cancer, and acute subendocardial myocardial infarction. What gives the individual symptoms of Lyme disease value is their occurrence in clusters; a single symptom means little but four or five may, for all practical purposes, make the case. Just as abdominal bloating, urinary urgency, and pelvic pain raise “red flags” for gynecologists, the combination of fatigue, paresthesias, arthralgias, and memory
complaints presenting in a single patient commands the attention of physicians aware of these potential Lyme disease symptoms.

Steere et al. noted that patients with early Lyme disease who lacked an EM rash presented with an average of four or more symptoms. Fever, chills, malaise, and myalgia, all nonspecific, were present in 46%-71% of the patients with definite Lyme disease alone.

In this group, it was the clustering of nonspecific symptoms in the appropriate setting that led to the correct diagnosis of Lyme disease. Logigian et al. also noted the nonspecific nature of identi-fying symptoms: “The most common form of chronic central nervous system involvement in our patients was subacute encephalopathy affecting memory, mood, and sleep, sometimes with subtle disturbances in language.  Diagnosis of this condition may be difficult because the typical symptoms are nonspecific ” [emphasis added].

To provide a clinical level of diagnostic sensitivity higher than two tier testing, physicians need to recognize the symptom clusters and aintain a high index of suspicion for Lyme disease

Symptoms not only form the basis of disease identification, they ay also inform on prognosis. Dysesthesias, paresthesias, ultiple EM lesions, increased irritability, persistent fatigue,
headache, stiff neck, and increased severity of the initial illness ere associated by various investigators in the early Lyme disease reatment trials with an increased risk of treatment failure. Symptoms wre also used in the trials as indicators that a strategy was working
or needed to be altered.

indings on physical exam are usually subtle and limited; they ay be variably present. The more common findings include: olitary or multiple EM lesions, manifestations of cranial
neuritis (such as extraocular palsies, ptosis, decreased facial ensation, facial nerve palsy, decreased hearing), swollen and ender joints, diminished sensation, andmotor weakness.

Cognitive deficits are usually not readily apparent on mental status testing, but patients may be disorganized or slow to respond to questions. A lack of physical findings does not necessarily indicate that the symptoms in those cases cannot be corroborated with objective evidence. Halperin et al. studied 14 patients with complaints of distal paresthesias; 10 had completely normal sensory, motor and reflex findings on examination, three had only mild sensory loss, and one had moderate sensory and motor losscoupled with decreased reflexes.

All underwent EMG testing; 13 ofthe 14 had “significant neurophysiologic findings.” Logigian et al. also found that detailed neuropsychometric testing could reveal cognitive deficits that were not apparent on routine mental status testing. Cost and time constraints do not allow for such complete testing in a community setting, but the studies suggests that with sufficiently detailed testing, objective evidence may be discovered and the subjective data supported. The absence of findings does not equal absence of disease.

Even the EMrash has a variable presentation that may cause less informed physicians to miss it. An EM lesion may have one or more of the following characteristics: homogeneously erythematous color,prominent central clearing, target-like appearance, central vesicles or
pustules, partially purpuric, and not scaly, unless topical corticosteroid creams have been applied or the rash is old and fading.

An EM rash must be distinguished from: tick bite hypersensitivity reactions, insect or spider bites, contact dermatitis,bacterial cellulitis, and tinea. An interesting study in compared responses from physicians in endemic and nonendemic areas with regard to what percentage of EM rashes in their practices had central clearing. Physicians from endemic areas thought it only 19%, while those from nonendemic estimated 80%. The authors did not give a reason for the disparity; possibilities include strain variation or physician experience. The variable presentation of the EMrash, coupled with the fact that it does not manifest in 32% of patients, makes it unwise to rely on EM as the only manifestation of Lyme disease that has clinical diagnostic utility.

Physicians use pattern recognition as a common diagnostic heuristic. These cognitive “shortcuts,” when used properly, allow physicians to move quickly to the correct diagnosis. Pattern recognition transforms exposure, individual symptoms, and the course of illness into a unified diagnosis; it is why some physicians specifically see “Lyme disease” when colleagues see only a generalized “positive review of systems.” For physicians unfamiliar
with the pattern of Lyme disease, serologic testing, combined with clinical data, offers the potential for reaching the correct diagnosis. However, serology alone cannot confirm or deny presence of infection. In Lyme disease, there is no testing shortcut

Furthermore, diagnostic criteria are situational. Clinical criteria are constructed to diagnose and treat ill patients. Research criteria are constructed to test a hypothesis in a uniform group of subjects; researchers have no duty to those excluded from the trial.

Surveillance criteria are much the same, the goal being selection of a homogeneous patient subset that can be observed over time and treatment. The difference between these situations is an important consideration. This distinction is highlighted by these comments from CDC epidemiologist Dr. PaulMead

Aclinical diagnosis is made for the purpose of treating an individual patient and should consider the many details associated with that patient’s illness. Surveillance case definitions are created for the purpose of standardization, not patient care; they exist so that health officials can reasonably compare the number and distribution of “cases” over space and time. Whereas physicians appropriately err on the side of over-diagnosis, thereby assuring they don’t miss a case, surveillance case definitions appropriately err on the side of specificity, thereby assuring that they do not inadvertently capture illnesses due to other conditions.

Recognition of the differing goals allows knowledgeable physicians the discretion to diagnose Lyme disease in patients lacking the five of 10 bands required for admittance into the surveillance group. Failure to acknowledge the distinction results in many patients with Lyme disease remaining undiagnosed and untreated.

Mandatory laboratory confirmation of clinical diagnoses, as advanced in the 2006 IDSA guidelines, reverses the roles of clinical and laboratory data in the diagnostic process and hierarchy. Substituting laboratory tests for physician judgment is not clinically
sound, particularly when laboratory tests lack sensitivity. This recommendation is a change from the 2000 IDSA guidelines on Lyme disease, but the 2006 panel did not discuss the reasons for this change nor cite any references from the literature to support it. Guideline developers have identified the need for reconciliation between new and former versions of the same disease guidelines; the IDSA, itself, endorsed the reconciliation process, yet it did not
occur in this instance.

Clinical Judgment in Management of Patients with Lyme Disease

Clinical judgment is required to appropriately manage patient care. Patient management is an evolutionary process, not a static state; ongoing assessment allows for refinement of the original diagnosis or the search for new one. Lyme disease is no exception to this rule; yet the 2006 IDSA guidelines reduce clinical management to a one-size-fits-all approach quickly chosen from a table. Clinical judgment is especially important when the clinical picture is unclear and laboratory data unhelpful. After careful investigation of other potential diagnoses, physicians may need to perform an empiric treatment trial as a diagnostic modality.The use of such trials extends well beyond Lyme disease. For example, patients with nonspecific
epigastric pain may be offered “GI cocktails” as a means to both diagnose and treat the condition

Clinical decision-making in Lyme disease requires ongoing information; the longitudinal treatment trials on Lyme disease demonstrated the value of this data. Historical and physical
examination data were gathered at defined points; on some occasions the information was used to alter the treatment protocol (investigators withdrew or re-treated some subjects). Followup visits in many of the studies on Lyme disease demonstrated apositive correlation between reported symptomatic changes and subsequent physical findings or test results. Long-term follow-up extending beyond the active treatment phase provides researchers, as
well as physicians in clinical practice, the ability to discern the difference between placebo and treatment effects

Clinical judgment in Lyme disease requires physicians to weigh risk-benefit concerns with individual patients. Treatment risks for the patient include potential adverse effects from antibiotic therapy (including risks associated with medication administration), costs,associated with therapy, and lifestyle changes to accommodate treatment

Patient benefits include improved health with attendant improvement in quality of life and lower medical costs following recovery. Antibiotic therapy, including long-term oral antibiotics, is
generally safe and well tolerated. A meta-analysis on the risks associated with intravenous (IV) access of various types found that peripheral intravenous catheters cause 0.5 bloodstream infections per 1,000 intravascular device (IVD) days while surgically implanted long-term central venous devices-cuffed and tunneled catheters-cause 1.6 infections per 1,000 IVD-days

Data from Lyme disease treatment trials can inform on the risk of IV antibiotic therapy in this patient population. Table 4 reports the complication rates in the treatment groups of Lyme disease studies which used IV ceftriaxone for a minimum of 30 days. Significant adverse events included medication-related events (severe allergic reactions, gall bladder toxicity, Clostridium difficile enterocolitis, renal failure) and catheter-related events (skin infiltration, infection, and thrombosis).

Adverse events in the Fallon study are considerably higher than in the others; reasons are unknown, and the small sample size makes it difficult to draw conclusions. There were three cases of ceftriaxone allergy in the 23 patients; this 13% allergic rate is higher than expected. Thrombi developed in two patients, but the paper does not provide details of the site of the peripherally inserted central catheter (PICC) or its specific type. Additional studies are needed to delineate the risk of IV antibiotic therapy extending beyond 30 days in better detail, and to determine whether there would be opportunities to minimize those factors contributing to the total risk

There are also risks to the patient associated with failure to treat a continuing infection. These include declining health, decreased productivity, a potential for increased costs as more health-related services are required, and costs related to palliative medications (including their potential adverse effects).

The IDSA guidelines raise concerns about the impact longer treatment regimens may have on society. While these concerns should not sway treating physicians who are entrusted with the care of individual patients, the concerns merit some comments. The guidelines authors focus attention on treatment risks to society, citing additional costs and the potential for increased bacterial resistance in the community. However, the authors ignored potential benefits to society from such treatment regimens. These benefits include improved health in the community, increased production from previously ill patients, and potential for success in this patient population to inform treatment decisions in other groups. Additionally, there are societal risks from not treating; these include ever increasing expenses for a chronically ill subpopulation and lost productivity from ill workers

In the individual patient, the decision to treat or to prolong treatment may depend on the length of time between onset of illness and diagnosis; severity of the patient’s presenting symptoms;
presence of neurological symptoms;whether the course of the illness is progressive; whether the illness significantly affects the patient’s quality of life or functional abilities; presence of untreated co-infections; the patient’s immune system status; whether diagnostic tests, symptoms or treatment response suggest ongoing infection; the patient’s response to treatment; which medications the patient can tolerate; the specifics of prior treatment regarding antibiotic type, dose, and duration; whether the patient relapses when treatment is
withdrawn; the risks/benefits of the treatment approach under consideration; and availability of any alternative treatment approaches and their attendant risks balanced against the risks
associated with failing to treat. These highly individualized decisions are best made by the treating physician and the patient

The controversy over antibiotic treatment duration for patients with Lyme disease exists because there is no test of cure, and individual patient responses to specific therapeutic approaches have been highly variable. Lyme disease, in many patients, is marked by
periods when the illness is relatively quiescent. Lacking a test of cure, physicians who do not rely on arbitrary cut-off points are faced with a difficult decision when attempting to determine an appropriate stopping point. Mixed results from the treatment trials add to the uncertainty

The variable response to treatment has been well documented; the causes remain unclear, as scientific evidence in this area is still evolving. Early hypotheses of autoimmune processes have not been substantiated; persistent infection, however, has been demonstrated in case reports and animal studies. Patients with Lyme disease are a heterogeneous group. Genetic variation may play a role in pathogenesis and treatment response. Just as HLA status may be related to treatment response in Lyme arthritis, the response in patients with other types
of Lyme disease pathology may be based on some yet to be discovered genetic subtype

Variation in infecting strains of B. Burgdorferi certainly is a factor. More than 100 strains of Bb have been identified. Certain strains are more virulent and pathogenic than others; instances of antibiotic susceptibility varying between strains is well documented. Coinfections and comorbidities also contribute to the heterogeneity of treatment response seen in Lyme
disease.  Ixodes scapularis is able to carry multiple known bacterial, viral, and parasitic pathogens, and evidence for additional tick-borne pathogens continues to emerge. Different combinations of pathogens require different treatment regimens; failure to identify and treat the specific pathogens causing an illness may partially explain variations in treatment responses

As explained by Kravitz et al., “[h]eterogeneity of treatment effects reflects patient diversity to risk of disease, responsiveness to treatment, vulnerability to adverse effects, and utility for different outcomes.” Kravitz et al. discuss the application of generalized, or averaged, results from treatment trials to the care of an individual patient, and pitfalls inherent in applying them too strictly, noting that “misapplying averages can cause harm, by either giving patients
treatments which do not help or denying patients treatments that would help them.” The individual patient is not a numeric average but, rather, falls somewhere on the continuum of the bell curve and,hence, requires individualized care.

Clinical guidelines should not supplant the judgment of treating physicians. Quality patient care requires the physician to consider management decisions in light of the details unique to each patient. When guideline recommendations are substituted for carefully derived, individualized decisions, there is a potential for harm. The American Academy of Pediatrics policy statement on guideline development recognizes this principle. The document outlines how evidentiary strength and risk-benefit analyses are integrated to yield a specific recommendation level. For example, strongly positive recommendations require benefits to clearly exceed risks, and supporting evidence must be of excellent quality

In this scheme, strong recommendations are not made based on low-quality evidence or expert opinion. Options identify treatment alternatives. Options recognize patient preferences and respect the clinician’s decision-making process. The U.S. Preventive Services Task Force also recognizes scenarios in which the certainty of the evidence is low. In those situations, no recommendation is made, regardless of the perceived net magnitude of benefit or harm.
Additionally, the Task Force advocates shared decision-making between individual patients and their physicians, instead of population-based recommendations, when issues under consideration are highly sensitive to patient utilities.

Guideline committees are not in a position to perform riskbenefit analyses for specific patients. Patient-specific riskbenefit analyses are the essence of clinical judgment. Such
judgments are the domain of individual treating physicians; guideline committees may inform judgments through their evaluation of therapeutic options, but they may not substitute their
judgments for those of the treating physicians. A recent editorial by Shaneyfelt and Centor said as much: “Guidelines are not patient-specific enough to be useful and rarely allow for
individualization of care. Most guidelines have a one-size-fits-all mentality and do not build flexibility or contextualization into the recommendations.” While the 2006 IDSA guidelines contain the typical legal disclaimer that “they are not intended to supplant physician judgment with respect to particular patients or special clinical situations,” formulaic disclaimers cannot overcome the failure of the guidelines to provide treatment options and to recognize the role of clinical judgment in individualized care. These shortcomings cannot be addressed in boilerplate disclaimers; they can only be addressed in the substance of the guidelines.

Available laboratory tests for Lyme disease have poor sensitivity. Treatment trials cited in the guidelines for early Lyme disease were dissimilar, making it hard to compare outcomes;
those for late neurologic Lyme disease involved only 96 patients whose treatment responses can be analyzed. Both the early and late treatment trials yielded poor outcome rates for complete recovery. The prophylaxis recommendation is based on a single study performed under conditions unlikely to be reproduced in community practices, and the list of “not recommended” therapeutic modalities is apparently based on panel opinion. Given the limits
of guidelines in general, and the specific shortcomings of the 2006 IDSA guidelines on Lyme disease, patients and their physicians should be free to act without interference; many may justifiably decide to decide for themselves which strategy to embrace

http://www.jpands.org/vol14no3/maloney.pdf

Elizabeth L. Maloney, M.D. Journal of American Physicians and Surgeons Volume 14 Number 3 Fall 2009

Regards,

Linda

January 15, 2009 News » Cover Story

http://www.csindy.com/colorado/the-tick-and-the-time-bomb/Content?oid=1146343

The tick and the time bomb

While patients wait in pain, a small group of doctors fights for chronic Lyme disease
by J. Adrian Stanley

click to enlarge
Casey Bradley Gent
Bill Rathbun sits in his back room, a storage space for memories from happier times. Even leaning slightly on his elbow causes him to wince.

The back room of Bill Rathbun’s house is dim and small. On this weekday evening, Rathbun is wedged between one side of the room that houses dozens of empty pill bottles, and the other side of the room inhabited by dusty remnants of a past life posters of the Cramps, the Adicts and Frank Zappa withered like bathroom wallpaper.

Rathbun looks strapping. But he can barely lift himself from a chair. At age 40, he sits in the back room, bookmarked between the two chapters of his life.

“It’s very hard to believe this is happening,” he says, cigarette trembling.

Three years ago, Rathbun got sick. His body’s strength and ease of movement was replaced by an incessant, horrific pain. He realized he was in a battle for his health, but didn’t then realize that he had also entered a war in the worldwide medical community. Even after Rathbun tested positive for Lyme disease, he says doctor after doctor looked him straight in the eye and told him he didn’t have it.

Lyme doesn’t exist in Colorado, they insisted. Maybe he had something else. Or maybe he was just crazy.

A cry for help

The scraggly doe appeared frequently on Rathbun’s Manitou Springs lawn. Like many of the town’s deer, she wasn’t skittish. So when Rathbun, moved by sympathy for her pathetic appearance, set out to tame her, he didn’t have too much trouble. Soon she was eating from his hand.

It was 1998, and Rathbun was healthy. He had always worked as a laborer, often putting in long days. But then came one blip in his otherwise stellar health: Around the time he befriended the doe, he broke out in a rash on his chest and came down with flu-like symptoms. After a few weeks, the rash disappeared. It returned a few months later, only to disappear again.

Eight years passed before Rathbun gave the rash any further thought. Hey, the Rathbun men were sturdy. Rathbun’s father and brother were loggers. Early this decade, Rathbun did some logging himself, for about a month in Montana. The rest of the time, he worked in Colorado, where he’d lived since he was 14. Save for a few days in Florida, he didn’t bother to leave the state for vacation.

Time passed peacefully until January 2006, when Rathbun blew a disc in his back lifting a 100-pound door at work. He was treated through workers’ compensation, but couldn’t shake the pain and other, bizarre symptoms that started cropping up. Worried, and finding little help from doctors, he began keeping a journal.

On Dec. 16, 2006, he wrote: “last night, L hand spasming below pinky, on side. Making pinky finger twitch sideways.”

A few months later, he wrote, “Yesterday, sharp pains L ear. On Tues. sharp pains R ear, alternating w/ sharp pain R side of head.”

Rathbun wondered if he had nerve damage. But there were other symptoms. He’d doze off at red lights. He’d get fluttering feelings in his heart, or chest pains so bad they doubled him over. He’d wake up and find that even lightly touching his head caused excruciating pain. He couldn’t sleep. His vision was blurry. His jaw ached and cracked. Sometimes he’d catch sight of something in his peripheral vision, only to turn and find nothing there.

“I thought I was dying,” he remembers. “I thought I was going crazy.”

In early 2007, at the suggestion of friends and his workers’ compensation doctors, Rathbun went to his own doctor to be tested for multiple sclerosis. His doctor sent him to a pain management specialist who ran a bunch of tests and then announced that Rathbun was slightly anemic, had carpel tunnel syndrome and was positive for Lyme disease.

Rathbun didn’t even know he’d been tested for Lyme. He didn’t know what it was. But he was overjoyed.

“I was so relieved,” he says. “I saw a light at the end of the tunnel.”

click to enlarge
Rathbun feeds a deer near his home in 1998.

Roaming the Internet, he stumbled upon a long list of symptoms for Lyme. It described his day-to-day life.

According to the Center for Disease Control (CDC), the Lyme bacteria can cause a red rash, sometimes with a central clearing, within 30 days of a tick bite. If left untreated, the bacteria will spread to other parts of the body, causing a variety of musculoskeletal, neurological and cardiac problems. Over years, it can lead to arthritis, nerve damage or brain damage.

Lyme disease was first noticed in the United States in 1975 when children in Lyme, Conn., began developing arthritis. Doctors later discovered the illness was caused by a tick-spread disease. In 1981, the disease was identified as a bacterial spirochete (a spiral-shaped bacteria similar to syphilis), which was then named Borrelia burgdorferi. The bacteria was found to be spread through the bite of a specific tick, often called a deer tick or a blacklegged tick.

Rathbun’s doctor told him that a routine course of antibiotics would cure him, and referred him to an infectious disease doctor. But the expert looked at Rathbun’s positive test and said it must have been inaccurate, saying there is no Lyme disease in Colorado.

This was the beginning of Rathbun’s nightmare. Suddenly, he was bouncing from doctor to doctor, trying to find one that would treat him for Lyme with long-term antibiotics since a short course of antibiotics given by one doctor was the only thing that made him feel any better. He met with a lot of rejection; even the doctor who originally diagnosed him deferred to the infectious disease doctor. When Rathbun tried to notify the El Paso County Department of Health and Environment of his disease, he was sent away. (Only doctors with patients meeting certain national requirements can report a Lyme case to the health department.)

Dr. David Martz, of Colorado Springs, says this type of scenario is common. Because guidelines for diagnosing Lyme are narrow, many doctors believe Lyme doesn’t exist in many areas, including Colorado.

“If Lyme disease is what the academicians say positive screening blood test, definite tick bite then Lyme disease, if it exists in Colorado, is very rare,” Martz says. “However, if that’s too narrow of a definition of Lyme and a more definitive blood test becomes available, then it may well be that there is lots of Lyme disease in Colorado.”

When local doctors wouldn’t treat him, Rathbun turned to the Internet. And he hit the jackpot.

Victims in the middle

You could spend days, even weeks, reading about Lyme online. There are studies, support groups, forums, medical societies, clinics, patient advocates. But you don’t have to do too much reading to realize Lyme attracts some of the most heated discussions in medicine today even with minimal attention from the media.

There is no disagreement that Lyme disease exists, or that it’s often painful. The debate is about how easily it’s cured, how long it can torment its host, and where and how it may be contracted. And boy, is it spirited, with doctors accusing each other of ignoring patients, or putting patients at risk, or setting up the world for an epidemic.

Most doctors say that treatment-wise, Lyme is barely more trouble than a sinus infection. You get it, you take some antibiotics, case closed. They say one kind of tick can transmit it, and that it’s a problem only in certain parts of the country, particularly the Northeast.

The most famous guidelines on treating Lyme, published by a panel of doctors for the Infectious Disease Society of America in 2006, say that in rare cases, patients can experience something called “Post-Lyme Disease Syndrome” symptoms that linger after the standard treatment. But IDSA doctors say the presence of symptoms in no way proves the bacteria is still alive in the patient’s body. It could be a psychological problem, or a misunderstanding of normal aches and pains, or something else entirely. But, they say, it’s definitely not Lyme.

Dr. Eugene Shapiro, one of the guidelines’ authors and a pediatric infectious disease doctor at the Yale University School of Medicine in Connecticut, says there’s “never been a shred of evidence” that Lyme can survive past the standard 10 to 28 days of antibiotics. If anything, he says, the guidelines probably prescribe more drugs than are needed.

“You don’t continue antibiotics just because someone is tired,” he says.

Shapiro believes doctors who treat Lyme patients with long-term antibiotics are selling their patients hope that they have something curable, or that their symptoms have a name. He also says they’re selling a lot of expensive intravenous antibiotics.

“One of the reasons [patients] get upset is when you say they don’t have chronic Lyme what they hear is ‘You’re full of it,'” he says. “Clearly these patients … are suffering … but there’s something called ‘medically unexplained symptoms.'”

In a 2007 article titled “A Critical Appraisal of ‘Chronic Lyme Disease,'” the New England Journal of Medicine said there is “substantial risk, with little or no benefit,” in prescribing additional antibiotic treatment for Lyme patients who have “long-standing subjective symptoms.”

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Courtesy underourskin.com
The bite of a tick can transfer Lyme bacteria (pictured below). Scientists are discovering that a single tick may transfer several types of bacteria, leading to a range of illnesses. Ticks can be as small as poppyseeds and often go unnoticed.

Then there’s the other camp.

A small, vocal group of doctors say Lyme can sicken patients for years, and even kill them. They say many doctors who are setting standards for Lyme are researchers working too far away from patients and too close to patents. In other words, the mainstream bigwigs are thinking with their pocketbooks, and leaving dissenters open to modern-day witch hunts by state medical boards.

Believers in chronic Lyme tend to be clinicians. They believe the disease is transmitted via several types of ticks, which are all over the country, and the world, for that matter. Left untreated, they say, Lyme bacteria will invade nearly every part of your body, from muscle tissue to the central nervous system to the insides of your cells. They believe the disease can hide in the body and can take months, even years, of antibiotic treatment to kill.

Or it can kill you.

From reading online, Rathbun quickly concluded he had chronic Lyme. He remembered the rash from 1998 and the close contact with the deer, an animal known to carry ticks. And though subsequent Lyme tests came up negative, Rathbun continued to believe the Lyme was there. Hiding in his body. Making him sick.

After searching the Web for support groups and networks of so-called “Lyme-literate” doctors, Rathbun found a doctor who agreed to put him on long-term antibiotic therapy. He’s been on the drugs for over a year. He’s still too symptomatic to return to work his sleep patterns are bizarre, and sometimes his pain is so intense he can barely move. When he’s feeling sick, his body shakes. His memory lapses. A strange red dot appears between his eyes.

Still, Rathbun says, it’s better than it was.

“Occasionally, I feel fairly normal,” he says.

Rathbun now spends his days at home. He tries to force himself to leave the house once a day, however briefly. He says he misses working, and hates that his wife has to support him. Often alone, he spends time surfing the Web. He’s met many friends there, including Tracie Schissel, his “patient advocate.”

“When I found Tracie, it was the biggest relief,” Rathbun says. “It was the first time I’d talked to someone that understood.”

Patients helping patients

Minnesota would curse Tracie Schissel and her family.

But she didn’t know that when she moved there in 1987, toting her 4-year-old son. She was in her early 20s, a vibrant young woman. She entered school to become a cop, got engaged and convinced her parents, brother and sister to join her in Minnesota.

She and her family spent long afternoons gardening. She went camping and hiking in the lake-spotted wilderness. And she pulled tick after tick off her body and that of her son.

In 1989, she started having gastrointestinal problems, chronic fatigue and depression. Then in 1992, she was diagnosed with Crohn’s disease, which strikes the digestive system. It forced her to quit the police force in 1994, after only two years on the job. She suffered through six bowel obstructions.

“I’d be hospitalized for seven to 14 days, until my bowels would open up,” she remembers.

By 2005, Schissel had been working for a medical center for years, and was training to become a sleep lab technician. One day, she noticed what she thought was a spider bite. It was inches across and seeping, and antibiotics didn’t seem to help. Then she noticed a rash when she got out of the shower. Finally, her left knee began to swell.

Tests for Lyme came back positive, and Schissel was prescribed the normal short-term antibiotics. But she still felt sick when the pills were gone, and wanted more treatment. It took her months to get on long-term antibiotics.

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The actual Lyme bacteria is similar to that of syphilis.

She wanted to use her job to reach out to others, and help them recognize their symptoms, get tested and get treated. She started bringing literature to the doctors she worked with.

“Here I’ve got a PIC line in me [for Lyme antibiotics] that’s a catheter that goes all the way to your heart,” she says. “I’m somebody that works there. I would have doctors just look at me in the most arrogant and condescending way, and they would actually throw the information away while I was standing there. That’s when I knew we had a long road.”

A short time later, Schissel was on the phone with her sister, Leslie Wermers, describing the symptoms of her new diagnosis. Wermers had her own symptoms matching the Lyme profile she’d even had the characteristic rash in 1996. Back then, a doctor told her that he couldn’t diagnose her with Lyme because he couldn’t find a tick on her. (That, of course, was false.)

Remembering this, Wermers quickly had her records transferred to her sister’s doctor. Buried in her medical file was a positive test for Lyme disease. Wermers’ doctor had never told her about it.

“She never knew for 10 years that she had a positive,” Schissel says. “What if a patient came back positive for cancer, and they didn’t tell you?”

Wermers’ doctors had long suspected multiple sclerosis and had given Wermers an annual spinal tap for 10 years. By 2006, Wermers had lesions on her spine, brain, lungs and liver.

Schissel’s doctor tested Wermers for Lyme. She was positive. Now, both sisters were on long-term antibiotic therapy. And both sisters were mad as hell.

Together, they started the Minnesota Lymefighter’s Advocacy, with the intention of helping other Lyme patients in their state. But, through the Internet, they ended up helping patients from all over the world. They gave out information on chronic Lyme disease and connected patients with Lyme-literate doctors.

In the meantime, Schissel was slowly getting better. She began having normal bowel movements for the first time in about 17 years. Wermers came to stay with her sister for periods of time. Schissel would dutifully change Wermers’ positions at night to prevent her sister from getting bed sores.

“She would wake up and say, ‘I love you, Sis,'” Schissel remembers.

On Nov. 2, 2008, Wermers’ heart swelled while she slept. She never woke up. She was 41.

The doctor is in

In areas where Lyme is endemic, hunting chronic Lyme doctors seems to be an emerging sport for state medical boards.

Dr. Joseph Jemsek, a chronic Lyme physician who was taking an average of 80 new patients per month, was investigated by the North Carolina Medical Board and given a one-year “suspension with stay,” meaning he could continue to practice as long as he met stipulations.

Dr. Charles Ray Jones is in the midst of two legal battles with the Connecticut Medical Board. In chronic Lyme circles, he is considered the premier expert on treating children with the disease.

The situation has driven many doctors to hide their chronic Lyme practices from the public, according to patients, doctors and Web sites. Many clinics also don’t accept health insurance, fearing the companies will sue them to get their money back.

Martz, the Colorado Springs doctor, entered the fray several years ago when he stared at his own positive test for Lyme disease.

By most people’s judgment, Martz, now in his 60s, had lived a great life. He graduated from the University of Colorado at Denver’s medical school in 1965, followed by an internship and residency in St. Louis, and a year’s training at Stanford University. In 1970, he began practicing in the Springs, where he says he was consistently the early bird in discovering trends from HMOs to specialized cancer treatment. An internist, hematologist and oncologist, he once served as president of the El Paso County Medical Society, and he directed a local hospice program before retiring in 2003.

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Courtesy Ben Petrick
A few years ago, Ben Petrick played for the Colorado Rockies. Now he barely has the strength to care for his daughter.

In addition to a fulfilling career, Martz had a loving wife, Dee, two children and two stepchildren. But in April 2003, his luck changed.

“I suddenly got sick, and I’ve always been a healthy guy,” he says. “I was an 18-hour-a-day person, sometimes jokingly referred to as the Energizer Bunny of the senior citizens.”

Martz took every test his doctors could think of. But despite symptoms that sometimes left him crawling, they couldn’t diagnose him.

“Two months later, my neurologist said, ‘There’s no doubt that you have ALS. And, in fact, it’s moving pretty quickly. And chances are that within six months you’ll probably be in a wheelchair. And your life expectancy is probably just 2 1/2 years or so,'” Martz remembers.

Martz and his wife, practical people, weren’t interested in chasing a miracle cure. Martz worked on his relationships with family members. He went fishing in Canada. The couple traveled to Kenya for the trip of a lifetime.

But as he got sicker, Martz couldn’t shake a feeling of doubt. His arthritis, body pain and profound fatigue weren’t typical of ALS but they were of Lyme disease. So, even though he’d received a negative Lyme test, he sought “sensitive” testing for it at a controversial California lab called IGeneX.

The lab found him positive for Lyme. Martz started dosing himself with antibiotics.

“Within a month, my energy went from a half an hour of conversation to four or five hours being up around and able to go to Circuit City or something like that,” he says. “Within two months, for the first time, I could cross my legs without having to use my hands to pull them up. And within three months, for the first time in a year, I could get up out of a chair without having my wife pull me up.”

He’s never gotten back to 100 percent, and says there was likely some damage that will never heal. But by the end of the year of treatment, in early 2005, Martz says he was 60 percent of the man he had once been.

In February of that year, Martz opened Rocky Mountain Chronic Disease Specialists with a local friend and fellow retired doctor. The two foresaw a part-time gig, helping some Lyme and ALS patients and gathering information they could later transfer into research papers.

They were wrong. Martz found himself working full-time. His buddy went back into retirement, and Martz had to bring in other physicians, physician assistants and staff. He says he treated 850 to 900 patients from all over the nation, as well as Canada, England, Scotland, Norway and Spain. Much to his satisfaction, Martz noticed that 15 to 20 of his approximately 90 ALS patients were showing measurable improvement on antibiotics. Another 20 to 35 stopped declining.

But in August 2007, Martz closed the clinic.

“I could not stand the 50-hour workweek’s effect on my body,” he says. “In the course of four years, I had four heart attacks.”

Not to mention a bloodstream infection and clots in his lungs.

“It was a devastating decision for me,” he says. “Because there’s no other physician in the world that has been successfully treating ALS except our office.”

But now, Martz is planning four papers. Two concentrate on ALS patients. One describes in detail the symptoms and reactions to treatment of all of his patients, including chronic Lyme patients, and those with ALS, Parkinson’s disease and MS. One paper will focus solely on Lyme in rural Colorado Martz had about 45 patients with Lyme who lived in or around Yuma, on the eastern plains.

After treating so many patients, Martz has his theories about Lyme. Starting with this one: Lyme hides in the body, evading the immune system. As the body tries harder and harder to kill Lyme, that makes the carrier sick.

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Courtesy Tracie Schissel
Sisters Tracie Schissel (left) and Leslie Wermers were treated with long-term IV antibiotics. But for Wermers, the controversial care came too late.

He posits that since Lyme is closely related to syphilis, there’s reason to investigate how it could be spread. He says there’s plenty of clinical evidence that it can go from mother to child in the womb (the IDSA would disagree), but less investigation into whether it could spread sexually.

In short, Martz wants the medical community to take a second look.

“I am not a radical,” he says. “I’m not a zealot. I very strongly feel that this must be approached thoughtfully, and scientifically, and carefully, but I do think that there’s something there, and that we need to take more steps to sort out what it is. And those who don’t believe it and those who do believe it both need to set aside their prejudices and say, ‘Look, these are believable people with very disabling symptoms.'”

Dashed dreams

In 1999, when Ben Petrick was in his early 20s, it looked like he was going to make it. And he almost did. For four years, he was in and out of the major leagues, playing baseball for the Colorado Rockies.

But it didn’t last. His batting average began to drop, and then he fell off the baseball planet.

His dad, incidentally, fell with him. Both tested positive for Parkinson’s.

“We came down with it within seven months of each other,” Petrick says. “I was 22.”

Petrick played with his Parkinson’s pills in his back pocket. He didn’t tell his teammates. But when a fastball tipped off the edge of his catcher’s mitt, he realized he was losing his speed.

So Petrick now lives in Oregon with his wife and baby daughter. His wife teaches school, and he gives paid lessons for kids and lives off disability. He spends most of his day taking care of his little girl, and calls nearby relatives when his symptoms get so bad he can’t handle her.

Petrick should be waiting to die. But he’s holding on to hope, for one reason: Back in 2006, Martz diagnosed him with Lyme disease and put him on antibiotics.

“Within a week and a half, it was like, boom, I started feeling better,” Petrick says.

He cut back on his Parkinson’s meds until the antibiotics started to make him feel sick a common complaint from chronic Lyme patients, which some doctors blame on increased immune response or toxins from the die-off of the Lyme bacteria. So Petrick went off the antibiotics. But now, at 30, he says he’s ready to start them again.

Petrick’s wife, Kellie, believes the antibiotics will make him better.

“In my heart,” Ben says, “I do too.”

The green persuasion

In most cases, Lyme is easily treated with basic antibiotics like amoxicillin or doxycycline. No drugs have been formulated to treat it specifically.

The first vaccine was released in 1998. It flopped, and some patients sued the pharmaceutical company, saying it made them sick.

Tests developed for Lyme are inaccurate, say people on both sides of the argument. Shapiro, the Yale doctor, says they churn out many false positives. Chronic Lyme doctors say they often produce false negatives, because they don’t test for all Lyme antibodies.

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LAura Montgomery
Dr. David Martz stands in a historical medical exhibit at the Pioneers Museum. Medicine does evolve, he argues.

In 2006, as some companies tried to make a buck, the IDSA gathered experts to update its guidelines on treating Lyme guidelines that are still used by many insurance companies to set policy on what they’ll pay for.

It was 2006, and IDSA fielded a lineup of Ivy Leaguers. According to research by Kris Newby, senior producer for Under Our Skin (see “There’s a lot of money being made,” p. 22), nine of 14 of those doctors had received money from Lyme vaccine manufacturers. Four out of 14 had received money from manufacturers of test kits for Lyme or other tick-borne diseases. Three of the authors and three of their universities had patents on those test kits, including Yale University, Shapiro’s employer.

So chronic Lyme believers like to note that the 2006 guidelines recommend testing for patients if Lyme is suspected, even if the characteristic rash isn’t present despite the fact that the CDC says Lyme should be diagnosed based on a doctor’s judgment.

Asked if he felt he had a conflict of interest, Shapiro replies, “Definitely not. Why would I?”

When Yale’s patents are mentioned, he says, “I had nothing to do with it personally in any way, shape or form. I didn’t benefit from it at all.”

The IDSA is also quick to dismiss any allegations of wrongdoing.

“I really think that this is something that’s been brought up by this group of advocates with not a lot of evidence to back it up,” says spokesman Steve Baragona.

Baragona adds that the IDSA hired an individual in 2006 to oversee selection of panels and ensure there are no conflicts of interest. And the IDSA does have other professional societies backing its conclusions, like a panel with the American Academy of Neurology.

But the IDSA panel and the AAN panel shared several members, and were working on the guidelines at the same time.

It was enough to disturb Connecticut Attorney Gen. Richard Blumenthal, whose state is still ground zero for Lyme disease. An investigation he headed produced an out-of-court agreement in May, with the IDSA agreeing to form a new panel to review Lyme guidelines. An ombudsman whose main responsibility is to root out conflicts of interest will oversee the whole process. The IDSA says it’s close to announcing the new panel’s members.

Meanwhile, several states have passed or tried to pass laws protecting chronic Lyme doctors and/or ensuring that insurance companies pay for chronic Lyme treatment. The issue has even been raised in Congress.

Tracking ticks

Between 1992 and 2006, 248,074 cases of Lyme were reported to the CDC. Reported cases increased 101 percent from 1992 to 2006. But the CDC sets high standards for cases of Lyme disease that can be reported higher standards than those needed to diagnose Lyme, in fact.

Between 1992 and 2006, Lyme cases were reported from every state in the union, with a handful from Colorado a small number compared to states in the Northeast.

The chronic Lyme community believes Lyme is extremely underreported and has spread to every state and many other countries. Bacteria are being discovered that are closely related to the Lyme bacteria, cause the same symptoms as Lyme, and are spread by ticks different kinds of ticks that live in different parts of the country.

Martz says he had six patients who “clearly got sick after a Colorado-based tick bite.” In Boulder County, Mary Parker says she found a swollen bite on her body after hauling wood outside her home. She came down with the characteristic rash and was diagnosed over a year later. Several of her neighbors, and her dog, got Lyme, too, she adds.

In fact, many dogs in Colorado have been diagnosed with Lyme. Results from a single veterinary test facility, IDEXX labs, combined with telephone surveys and results from veterinary clinics, found 571 Colorado dogs with Lyme disease between 2001 and March 2007.

During the same time period, the CDC recorded one human case of Lyme in Colorado.

Back in his living room, Bill Rathbun paces the floor. He’s having a bad day. The inexplicable red dot has appeared between his eyes. His head tremors involuntarily. His mind wanders.

Rathbun feels like a victim, one of many in a worldwide epidemic. And he blames the mainstream doctors, who he believes are sacrificing his health, and the health of others, in the name of profit.

“I just can’t believe these doctors are getting away with it,” he says. “I can’t believe it.”

Suddenly, he is stuck on history. World War II. How the Holocaust went unnoticed by the world for so long, only being revealed when soldiers opened the gates to the death camps.

“When Hitler said people will more easily believe the great lie than the small lie,” he says, “he knew what he was talking about.”

stanley@csindy.com

Between 1994 and April 2009, IDSA issued 68 guidelines on 52 different topics (there have been 2 more since April). Most were published in Clinical Infectious Diseases. Of the 52 current guidelines, Dr. Lee’s team analyzed the 30 that followed IDSA’s standard grading system to evaluate the class of clinical recommendations and the strength of the supporting evidence underlying them.

“Our analysis revealed that more than half were based on expert opinion or not supported by properly controlled trials,” Dr. Lee announced. In an oral presentation, he reported that the 30 guidelines he analyzed contained a mean of 47 recommendations (range, 14 to 150). Recommendations ranged from class A (should always be offered) to class C (optional). The quality of evidence ranged from level I, consisting of 1 or more properly conducted RCTs, to level III, the opinion of respected authorities, based on clinical experience. Level II evidence is derived from 1 or more properly controlled trials without randomization.

The guidelines revealed a total of 589 class A recommendations. “Ideally, all should be [supported by] level I evidence,” Dr. Lee said. “However, a class A recommendation was supported by level I evidence only in 25% [of cases].” The rest were based on level II (40%) or level III (35%) evidence. Of all the guidelines evaluated, a median of 41% of recommendations were class A, but level I evidence supported them only 14% of the time.

Guidelines for common conditions were often based on fairly strong evidence. The recommendations that are most supported by level I evidence are in the guidelines for tropical medicine (41% of recommendations), intra-abdominal infection (39%), and asymptomatic bacteriuria (38%). “Influenza or Group A Streptococcus guidelines had less than 20% of level III evidence,” possibly because of the high prevalence of these diseases and the ease of designing studies, Dr. Lee reported.

He explained the lack of RCTs for some conditions, saying that certain infections occur rarely or present in heterogeneous forms, making it difficult to design a study. Furthermore, in some cases it might be unethical to conduct such a trial, and at times certain knowledge based on sound clinical judgment will never be tested in RCTs. Finally, funding to do trials might be lacking.

“Although a randomized controlled trial is referred to as level I evidence, not all RCTs are created equal,” he warned. “Some choose surrogate markers, others choose patient-centered outcomes. Well-designed nonrandomized trials may provide more information than certain randomized controlled trials, but I do think that a randomized controlled trial minimizes bias and does deserve the high levels of evidence.”

Dr. Lee summarized his presentation, saying that of the 1408 guideline recommendations he reviewed, “more than half were based on level III evidence, which is from expert opinion or not supported by properly controlled trials. Level I evidence was only 15%.” He said his study should help to point out where evidence is lacking and to suggest areas for further research.

Physicians and trainees should not just look at guidelines, but should also examine the strength of the evidence on which they are based, he advised. “When clinicians are using the guidelines, they should not assume that they are all based on well-designed studies. . . . Clinicians should remain cautious when using current guidelines as the sole source for guiding patient care.”

A second presentation supported the findings of Lee and coworkers. Abdur Khan, MD, assistant consultant at King Fahad Medical City in Riyadh, Saudi Arabia, presented his results in a poster session. Of the 65 IDSA guidelines, encompassing 6667 recommendations, issued between March 1994 and July 2009, he and his colleagues evaluated the 44, comprising 4206 recommendations, that were posted on the IDSA Web site at the end of July.

They, too, found that, overall, the strength of the recommendations did not correlate with the available evidence. Level I evidence was the basis for only 15% of the guidelines, which is in agreement with the findings that Lee and colleagues reported. Thirty percent of the evidence was level II.

“Around 55% of the guidelines had a level of evidence of III, which was based on expert opinion,” Dr. Khan toldMedscape Infectious Diseases, “but the class C recommendations [are] only 12%.” Guidelines for the treatment of fungal infections had the weakest supporting evidence; 46.5% to 89.5% of the recommendations were based on level III evidence.

Although the highest levels of evidence generally led to class A recommendations (25.9%), these strongest recommendations were most often based on lesser levels of evidence (36.3% on level II; 37.8% on level III).

Commenting on the studies’ findings, Richard Whitley, MD, professor of pediatrics, microbiology, medicine, and neurosurgery at the University of Alabama at Birmingham and president of IDSA, told Medscape Infectious Diseases that “one always has to be concerned when we don’t have randomized controlled trials that provide evidence-based medicine to write guidelines. Without a shadow of a doubt, the best evidence comes from controlled clinical trials that are adequately powered with a sample size to answer the targeted question.” But he noted that sometimes expert opinion or small uncontrolled studies have to suffice if there are not enough patients to conduct better trials.

In some situations, less than level I data can be powerful, Dr. Whitley observed. He cited the example that neuraminidase inhibitors can decrease mortality from influenza in elderly individuals. This finding was based on retrospective reviews of databases of Kaiser Permanente and other managed health care systems, he explained.

Looking forward, he said, “guidelines don’t necessarily just teach how to take care of patients. They identify areas for future investigation . . . because they tell us where the vagueness is and where we have to move forward.” This information can then be brought to the attention of the leadership of the National Institute of Allergy and Infectious Diseases so that they can fund studies and to the attention of the US Food and Drug Administration, which has funds to study targeted issues.

Dr. Whitley emphasized that “guidelines shouldn’t be just for patients in the United States. They should be for patients around the world.” As such, IDSA and the European Congress of Clinical Microbiology and Infectious Diseases will try to work on guidelines together, and IDSA will also work with Canadian colleagues “so that we can provide a level of care that’s standardized around the world,” he said. “Certainly, that’s optimistic.”

Neither of these studies received funding. Dr. Lee and Dr. Khan have disclosed no relevant financial relationships. Dr. Whitley reports being on the board of directors of Gilead Sciences and is a consultant for 3-V Biologics and Chimerix; his other consulting, review, advisory panel positions, investigator, or speaker honoraria relationships include Juvaris, Primus, Inhibitex, and JID.

Infectious Diseases Society of America (IDSA) 47th Annual Meeting: Abstract 1324. presented November 1, 2009; Abstract LB-31, presented October 31, 2009.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Clinical trials validate the severity of persistent Lyme disease symptoms.
Med Hypotheses.  2009; 72(2):153-6 (ISSN: 0306-9877)
Cameron DJ
First Medical Associates, Mt. Kisco, New York 10549, USA. Cameron@Lymeproject.com