Although a diagnostic blood test for ovarian cancer may be years away, a new symptom index could help doctors detect the disease in its early, most treatable stages. Researchers from the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center say that women who experience abdominal or pelvic pain, increased abdominal size or bloating, difficulty eating, or feeling full for more than 12 days per month and for less than one year may be at high risk for ovarian cancer and warrant more extensive testing.

Health services researchers, health plan administrators, and health policymakers often need to identify people with specific chronic medical conditions, such as diabetes or heart failure. For example, researchers may be interested in assessing the outcomes of alternative treatments. Health plan administrators may wish to identify members for quality improvement or disease management programs. Policymakers may be interested in tracking access to or quality of care. These efforts typically rely on diagnoses listed on physician and hospital claims submitted by providers to health insurers, and pharmacy claims when available, to identify patients who have the conditions of interest.

Information about chronic conditions in administrative databases may be incomplete or inaccurate for a variety of reasons (Virnig and McBean 200l). For example, health care that is not covered or billed is not reflected in the data. Information that is unnecessary for processing payments may not be collected or recorded accurately. Even when care is sought for a chronic condition, the diagnosis might not appear on provider claims (Horner et al. 1991; Fowles et al. 1995; Fowles, Fowler, and Craft 1998). Conversely, diagnoses listed on claims may be related to testing for disease rather than confirmed disease. Despite these caveats, administrative data are used extensively by researchers and by the National Commission tot Quality Assurance, the Centers for Medicare and Medicaid Services, and managed care organizations to identify people that have specific chronic conditions (National Committee for Quality Assurance 1999; Centers for Medicare and Medicaid Services 2002a; Centers for Medicare and Medicaid Services 2002b).

Few studies have described efforts to maximize the performance of claims-based algorithms for identifying health plan enrollees with chronic medical conditions. We previously found that the positive predictive value of claims collected over a two-year period could be improved by requiring two or more claims rather than one claim listing a diagnosis of hypertension, or by combining the diagnostic criterion with the requirement for a pharmacy claim for a medication commonly used to treat hypertension (Quam et al. 1993). In a comparison of self-reports of chronic conditions and administrative data, Robinson et al. (1997) found that more cases of self-reported diabetes or hypertension were confirmed by administrative data as the number of years of claims data increased. Others studied factors that affect the sensitivity and specificity of case-finding algorithms using Medicare claims to identify people who reported they had diabetes on the Medicare Current Beneficiary Survey (Hebert et al. 1999). The sensitivity of their algorithms increased by approximately 10 percent with a small drop in specificity when two rather than one year of claims data were used. For different types of claims (hospital, physician, etc.) requiring the diabetes diagnosis to be the first one listed on the claim or listed on two claims rather than one or listed on claims associated with direct physician contact improved the already near-perfect specificity slightly and lowered the sensitivity.

Further investigation of the sensitivity and specificity of case-finding algorithms for chronic conditions using different administrative data is warranted given the extensive use of claims data for this purpose. This study extends previous research by systematically evaluating the performance of a wide range of alternative claims-based algorithms for identifying members of Medicare+Choice plans with six chronic medical conditions that are prevalent in the elderly population and are frequently the focus of research studies and managed care initiatives. We used survey data collected from members of two Medicare+Choice health plans to assess the sensitivity and specificity of algorithms that required different claims criteria for the diagnosis, more than one claim with the same diagnosis, one or two years of claims history, and incorporation of pharmacy claims to identify patients with hypertension, heart failure, diabetes, arthritis, glaucoma, or chronic lung disease.

METHODS

Setting

Both study plans had Medicare risk contracts under the Medicare+Choice program and contracted with health care providers in their communities to create provider networks. One plan was located in a Midwestern metropolitan area, the other in the Northeast. Members of both plans were required to select a primary care physician. Only members of the Northeastern plan were required to obtain a referral before they saw a specialist. During the period of the study (1999 and 2000), the copayment for an office visit was $10 in the Midwestern plan and $15 in the Northeastern plan. The annual limit on drug benefits in the Midwestern plan was $900 in 1999 and $500 in 2000; the limit in the Northeastern plan was $300 for both years.

Survey Data

A study of the influence of socioeconomic status on the utilization of medical care by elderly members of the study plans was the source of information on chronic conditions. Briefly, members who were enrolled in the plans in January 2000 were randomly sampled within socioeconomic strata defined by dual (Medicare and Medicaid) eligibility and household income at the zip code level. Members who were disabled and less than 65 years old, members in institutions or hospice programs, and members with end-stage renal disease were excluded from the study population. All 942 dually eligible members of the health plans were included in the sample, as were 700 members living in zip codes where approximately 50 percent of the households had incomes less than 200 percent of the poverty level, and 5,354 other members. The total sample consisted of 6,996 members equally distributed between the two plans.

To earn CEUs, see test on page 18.

LEARNING OBJECTIVES

Upon completion of this article the reader will be able to:

1. Recognize the history, hosts, vector, epidemiology, and probable origin of West Nile virus (WNV) in the United States.

2. Recognize the family of viruses and the nucleic acid for WNV.

3. Recognize the clinical presentations of WNV disease and who is at greatest risk of life-threatening disease.

4. Recognize nonvector pathways of contracting WNV and current methods of prevention.

5. Recognize the tests that are performed for early and late diagnosis and their advantages and disadvantages.

6. Recognize the most specific and most sensitive tests for WNV and how this relates to positive and negative predictive values.

A few years ago, most people living in the United States would not have known of the existence of a flavivirus known as West Nile virus (WNV). Indeed, most clinical microbiologists and medical laboratory scientists, would only have had a limited knowledge of the virus. All that has changed in the last three to four years.

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In 1999, WNV emerged in New York and from there has spread to most of the continental United States, with successive seasons seeing the migration of the infection north, south, and west from the New York epicenter.

WNV has a broad host range, including birds (the primary host), humans, and other animals. Indeed, WNV has had a significant health and economic impact on horses and industries dependent upon horses, such as horse racing. That birds are the primary host of WNV is important to the understanding of the importation and spread of the virus. As based on available evidence, the New York outbreak appears to have resulted from the importation of WNV via viremic migratory birds, with an isolate from a dead bird in New York being closely related to a 1998 isolate of WNV from a goose in Israel.

Basic science

West Nile virus is a member of the flaviviridae, which includes agents that cause such important diseases as yellow fever, Japanese encephalitis, dengue fever, St. Louis encephalitis (SLE), and Central European encephalitis. The flaviviruses are some of the medically most important of the arthropod-borne viruses (arboviruses), with the mosquito being the arthropod vector for a number of these viruses, including WNV. Flaviviruses are characterized as having a genome consisting of single-stranded RNA enclosed by a nucleocapsid, which, in turn, is enveloped in a lipid membrane.

The spread of the virus may be attributed to the primary reservoir for the virus: birds. Certainly, the introduction of WNV into North America has had an overwhelming impact on selected immunologically naive native species. Birds are the primary host, with humans and animals (such as horses) being secondary and usually “deadend” hosts.

Mosquitoes belonging to the Culex pipiens complex are the primary vector for WNV. A recent publication in Science has suggested differences in the behavior and physiology of members of the Culex pipiens complex in the United States may account for the rapid spread of the infection. Briefly, the report suggests that mosquitoes belonging to Culex pipiens complex in North America may bridge bird and human hosts, being both “bird-biters” and “human-biters,” whereas European counterparts appear to specialize as either “bird-biters” or “human-biters.”

Clinical presentation

In the United States, WNV infection is most commonly seen over the summer months. Cases begin to appear in June, peak in August and September, then disappear in the fall. This pattern of disease relates to climate and the activity of mosquitoes.

Human infection with WNV may be either silent or present as frank disease with a range of signs and symptoms. Symptoms may include a general malaise accompanied by fever and chills, headache, backache, and muscle and joint pain (myalgia and arthralgia). One of the signs that accompanies these symptoms is the occurrence of a maculopapular rash in up to half the patients presenting with symptoms. While such disease may be mild and self-limiting, in a subset of infected patients more severe disease is observed.

Over the course of the spread of WNV across the United States, reported mortality rates have run at up to 10% of the diagnosed population. The mortality rate appeared to decrease in the 2003 season to approximately 3%, with over 9,000 cases reported to the Centers for Disease Control and Prevention (CDC). The apparent reduction in mortality may have been due to any one of three factors. First, the awareness of the infection and associated disease within the medical community may have resulted in earlier intervention in at-risk patients. Second, more asymptomatic individuals may have presented for testing, thus overstating the apparent disease burden. Third, the virus may be becoming less virulent. The first two are possible; the third awaits further data.

Pharyngitis is one of the most common conditions encountered by the family physician. The optimal approach for differentiating among various causes of pharyngitis requires a problem-focused history, a physical examination, and appropriate laboratory testing. Identifying the cause of pharyngitis, especially group A beta-hemolytic streptococcus (GABHS), is important to prevent potential life-threatening complications.

The 2000 National Ambulatory Medical Care Survey found that acute pharyngitis accounts for 1.1 percent of visits in the primary care setting and is ranked in the top 20 reported primary diagnoses resulting in office visits.  Peak seasons for sore throat include late winter and early spring.  Transmission of typical viral and GABHS pharyngitis occurs mostly by hand contact with nasal discharge, rather than by oral contact. Symptoms develop after a short incubation period of 24 to 72 hours.

Differential Diagnosis

Sore throat most often is caused by direct infection of the pharynx (pharyngitis), primarily by viruses or bacteria. GABHS pharyngitis accounts for 15 to 30 percent of cases in children and 5 to 15 percent of cases in adults. Sore throat also may be caused by other conditions, such as gastroesophageal reflux, postnasal drip secondary to rhinitis, persistent cough, thyroiditis, allergies, a foreign body, and smoking.

This article focuses on infectious causes of sore throat (pharyngitis). If patients do not have any other signs of infection or do not respond as expected to treatment of pharyngitis, physicians should investigate noninfectious causes.

VIRUSES

Viral pharyngitis, the most common cause of sore throat, has a wide differential. Furthermore, different viruses are more prevalent during certain seasons.  Coryza, conjunctivitis, malaise or fatigue, hoarseness, and low-grade fever suggest the presence of viral pharyngitis.  Children with viral pharyngitis also can present with atypical symptoms, such as mouth-breathing, vomiting, abdominal pain, and diarrhea.

INFECTIOUS MONONUCLEOSIS

Infectious mononucleosis is most common in patients 15 to 30 years of age.  Patients typically present with fever, sore throat, and malaise. On examination, there is pharyngeal injection with exudates. Posterior cervical lymphadenopathy is common in patients with infectious mononucleosis, and its absence makes the diagnosis much less likely. Hepatosplenomegaly also may be present.  If these patients are treated with amoxicillin or ampicillin, 90 percent will develop a classic maculopapular rash.

BACTERIA

Patients with bacterial pharyngitis generally do not have rhinorrhea, cough, or conjunctivitis. The incidence of bacterial pharyngitis is increased in temperate climates during winter and early spring.  There is often a history of streptococcal throat infection (strep throat) within the past year. GABHS is the most common bacterial cause of pharyngitis.  GABHS Infection. Symptoms of strep throat may include pharyngeal erythema and swelling, tonsillar exudate, edematous uvula, palatine petechiae, and anterior cervical lymphadenopathy. Untreated, GABHS infection lasts seven to 10 days. Patients with untreated streptococcal pharyngitis are infectious during the acute phase of the illness and for one additional week. Effective antibiotic therapy shortens the infectious period to 24 hours, reduces the duration of symptoms by about one day, and prevents most complications.

Complications of GABHS Infection. The incidence of complications with GABHS infection, such as rheumatic fever and peritonsillar abscess, is much lower than generally perceived.  Peritonsillar abscess occurs in fewer than 1 percent of patients treated with antibiotics.  Patients with peritonsillar abscess typically have a toxic appearance and may present with a “hot potato voice,” fluctuant peritonsillar mass, and asymmetric deviation of the uvula. However, clinical impression is only moderately accurate in diagnosing peritonsillar abscess (78 percent sensitivity and 50 percent specificity in one series of 14 patients).  Intraoral ultrasound examination is an accurate diagnostic test if abscess is suspected.

Rheumatic fever is exceedingly rare in the United States and other developed countries (annual incidence less than one case per 100,000). This illness should be suspected in any patient with joint swelling and pain, subcutaneous nodules, erythema marginatum or heart murmur, and a confirmed streptococcal infection during the preceding month. Patients will have an elevated antistreptolysin-O titer and erthrocyte sedimentation rate.

Poststreptococcal glomerulonephritis is another rare complication of GABHS pharyngitis, although treatment with antibiotics does not prevent it. Patients present with hematuria and, frequently, edema in the setting of a recent streptococcal infection with an elevated antistreptolysin-O titer.

Hysterectomy is more common in the United States than in other developed countries, with considerable regional variation. Observational studies have reported improvement in sexual function and quality of life after hysterectomy, but this procedure also can result in early ovarian failure, incontinence in later life, and death. In this randomized trial, Kuppermann and colleagues compared a medical and a surgical approach to the treatment of uncontrolled abnormal uterine bleeding in women whose symptoms persisted despite medical treatment for a median of four years.

Premenopausal women 30 to 50 years of age with abnormal uterine bleeding who were treated previously with cyclic medroxyprogesterone were randomized to further medical treatment or hysterectomy and followed for two years. Outcome measures included health-related quality of life, symptom resolution, body image and sexual function, and psychologic distress and well-being.

Sixty-three women who failed to improve with medroxyprogesterone treatment were assigned randomly to receive expanded medical treatment or hysterectomy. The former group received a variety of treatment regimens; in the latter group, some women had abdominal hysterectomy, and some had vaginal hysterectomy. At four weeks, the patients who had hysterectomy experienced a decrease in physical health but had a somewhat higher mental health score than those in the medical groups.

At six months, the surgery group reported significantly greater improvement in quality of life, symptom resolution, satisfaction with degree of symptom resolution, sexual function and desire, and other parameters. These improvements were maintained after two years, at which time the medical group also experienced improvements. The only remaining difference between groups was an increase in sexual desire that favored the surgery group. However, by the end of two years, 53 percent of the women had crossed over to the hysterectomy group, with significant improvements in quality of life and in 11 of the 13 other measured outcomes, compared with no significant improvements in quality of life but improvements in seven of 13 other outcome measures in women who stayed with medical management.

The authors conclude that, with respect to outcomes such as quality of life and mental health, women who have hysterectomies for refractory abnormal uterine bleeding do better than women who are treated medically. This difference is substantial, particularly at six months, before the bulk of medical group crossover to hysterectomy occurred in this study. This improvement was attenuated at two years, and the difference between groups was nonsignificant in quality-of-life measures by the end of the study. However, many women in the medical group eventually opted for hysterectomy. Even so, many of the women who did not cross over to surgery experienced significant improvement in a variety of outcome measures.

Two companion papers in this issue of ARCHIVES, by Drs Kleinschmidt-DeMasters and Prayson, introduce a new feature directed toward pathology trainees. The authors present a series of algorithms and flow charts that are intended to help the pathology resident consider all possibilities before rendering a final diagnosis on a surgical neuropathology specimen. In Part I, the authors consider the initial step in the histologic evaluation of a neurosurgical specimen: deciding whether the tissue under examination is normal or abnormal, and if abnormal, the general etiologic category of the lesion. In Part II, the authors discuss the differential diagnoses of surgical specimens in which the salient histologic features include the presence of inflammation, macrophage infiltration, or abnormal vasculature.

As clearly stated by the authors, the algorithms are not intended to be comprehensive or definitive but rather are intended to serve as starting points for approaching the often-difficult differential diagnosis of central nervous system lesions. The algorithms are also intended to stimulate thought and discussion, and the authors encourage trainees to question, modify, and expand the algorithms as they test their utility in the real world crucible of the surgical pathology frozen section laboratory.

The authors’ emphasis on utilization of the algorithmic process during intraoperative frozen section consultation is appropriate. There are several principal indications for performing a frozen section,1 including confirmation of the identity of a specific tissue type that the surgeon seeks to resect (eg, parathyroid gland); evaluation of surgical margins for the presence of tumor; determination of the presence of an infectious etiology (tissue then to be sent sterilely from the operating room for culture); determination of benign tumor versus malignant tumor, primary tumor versus metastatic tumor, or specific type of neoplasm (eg, circumscribed vs diffuse glial neoplasm) when those determinations will influence the ongoing surgery (eg, proceed with gross total resection vs close and refer to radiation therapy); determination of whether adequate diagnostic tissue is present for triage to molecular studies or flow cytometry; and determination of whether adequate diagnostic tissue is present for evaluation on formalin-fixed, paraffin-embedded permanent sections. Consideration of the various aspects of the latter indication is particularly stressed in the present 2 papers.

As has been recently emphasized,2 the surgical pathologist’s formulation of a differential diagnosis list for a particular patient’s lesion most often begins well before entering the frozen section suite, with consideration of the patient’s age, the anatomic location of the lesion within the central nervous system, preoperative neuroimaging features, past medical and surgical history, and the nature and duration of the current presenting signs and symptoms. In modern surgical pathology practice, the process of ascertaining the clinical differential diagnosis can often be accomplished with relative ease the day before or on the morning of the surgery in the pathologist’s office through computer access to the hospital’s clinical, imaging, and pathology information systems. The present algorithms deal primarily with the second step in the process: modification of the differential diagnosis based on evaluation of the histologic features revealed by microscopic examination of cytologic preparations and frozen tissue sections. The process of refining the histopathologic differential diagnosis feeds back on the initial clinical differential diagnosis in an iterative fashion until the ‘’solution,” or final diagnosis, is reached; this, of course, is the essence of the mathematical problem-solving process first introduced by the ninth century mathematician and astronomer Muhammad ibn Musa al-Khwarizmi, from whose name our modern term algorithm is derived.

Based on an increased understanding of brain ischemia and the introduction of new treatment options, a working group has proposed redefining transient ischemic attack (TIA) as “a brief episode of neurological dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than one hour, and without evidence of acute infarction.” (1(p1715)) This definition underscores the urgency of recognizing TIA as an important warning of impending stroke and facilitating rapid evaluation and treatment of TIA to prevent permanent brain ischemia.

An estimated 200,000 to 500,000 TIAs occur annually in the United States. (2) One study (2) found that 25 percent of patients who presented to an emergency department with TIA had adverse events within 90 days; 10 percent of the events were strokes, and the vast majority of the strokes were fatal or disabling. (3) More than 50 percent of all adverse events occurred within the first four days after the TIA. Notably, of the patients with TIA who returned to the emergency department with stroke (10.5 percent), approximately one half had the stroke within the first 48 hours after the initial TIA. In 2.6 percent of patients with TIA, hospitalization was required for cardiac events, including congestive heart failure, unstable angina, cardiac arrest, and ventricular arrhythmia.

Clinical Presentation

The more common clinical presentations of TIA are described in Table 1. In general, a TIA presents as a syndrome rather than any one sign or symptom.

Pre-emergency Department Care

There is no reliable way to determine if the abrupt onset of neurologic deficits represents reversible ischemia without subsequent brain damage or if ischemia will result in permanent damage to the brain (e.g., stroke). Therefore, all patients with symptoms of TIA should receive an expedited evaluation.

Office staff should be trained to inform the family physician immediately if a patient calls or presents with symptoms that could represent a TIA. Neurologic symptoms that crescendo with increasing frequency, duration, or severity are particularly ominous signs of impending stroke.

Most patients with possible TIA should be sent immediately to the nearest emergency department. If they have had symptoms for fewer than 180 minutes, they should be sent to an emergency department that offers acute thrombolytic therapy. Patients should not drive themselves to the hospital. To speed evaluation, it is appropriate to activate the 9-1-1 Emergency Medical Service system for transport. (2,3)

On presentation to the emergency department, patients who have had symptoms for fewer than 180 minutes might be candidates for treatment with tissue-type plasminogen activator (tPA). (4,5) If a patient is not a candidate for tPA treatment, antiplatelet therapy should be initiated as soon as it can be determined that there are no contraindications. (4-6) [Reference 6: SOR A, rating of benefits]

Inpatient or Outpatient Evaluation

Guidelines issued by the National Stroke Association (7) recommend evaluation within hours of the onset of TIA symptoms, preferably in an emergency department. If appropriate imaging studies are not immediately available in the emergency department or outpatient setting, the patient should be hospitalized for observation. (7) [SOR C, expert opinion] Relative indications for more extended inpatient evaluation for TIA or stroke are listed in Table 2.

Patients with symptoms of acute TIA for fewer than 24 to 48 hours should undergo diagnostic testing in the emergency department. 8 [SOR C, expert opinion] Patients whose symptoms have resolved for more than 48 hours should receive urgent inpatient or outpatient evaluation.

Initial Work-Up for Suspected TIA

The first step in evaluating a patient with symptoms of TIA is to confirm the diagnosis (Figure 1).

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DIFFERENTIAL DIAGNOSIS

The most common imitators of TIA are glucose derangement, migraine, seizure, postictal states, and tumors (especially with acute hemorrhage).

TIA typically has a rapid onset, and maximal intensity usually is reached within minutes. Fleeting episodes lasting one or two seconds or nonspecific symptoms such as fatigue, lightheadedness (in the absence of other cerebellar or brainstem symptoms), and bilateral rhythmic shaking of the limbs are less likely presentations of acute cerebral ischemia.

Distinguishing TIA from migraine aura can be difficult. Younger age, previous history of migraine (with or without aura), and associated headache, nausea, or photophobia are more suggestive of migraine than TIA. In general, migraine aura tends to have a marching quality; for example, symptoms such as tingling may progress from the fingers to the forearm to the face. Migraine aura also is more likely to have a more gradual onset and resolution, with a longer duration of symptoms than in a typical TIA.

If a patient has explosive onset of a severe headache, with or without photophobia, stiff neck, or syncope, acute subarachnoid hemorrhage is a possibility. Rarely, TIA is mistaken for the first presentation of multiple sclerosis in young patients or for amyotrophic lateral sclerosis in older patients.

Rationale: In a large proportion of patients with active pulmonary tuberculosis (pTB), acid-fast bacilli smear results for sputum and bronchial secretions are negative. Detectable growth of Mycobacterium tuberculosis (MTB) in cultures takes several weeks and MTB-specific DNA amplification results on sputum and bronchial secretions are variable in these patients.

Objective: We investigated whether a rapid diagnosis of pTB can be established by enumeration of MTB-specific mononuclear cells from bronchoalveolar lavage (BAL) fluid in routine clinical practice.

Methods: Patients presenting to a tertiary hospital with medical histories and pulmonary infiltrates compatible with tuberculosis, and negative acid-fast bacilli smear results (three) from sputum, were prospectively enrolled in this study. An MTB-specific enzyme-linked immunospot assay (ELISPOT [T-SPOT.TB; Oxford Immunotec, Abingdon, UK]) with early antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) peptides was performed on peripheral blood mononuclear cells (PBMCs) and mononuclear cells from the BAL fluid (BALMCs).

Measurements and Main Results: Of 37 patients, 12 were found to have smear-negative pTB and 25 were found to have an alternative diagnosis. Patients with tuberculosis had a median number of 17 ESAT-6-specific cells and 24.5 CFP-10-specific cells per 200,000 PBMCs and 37.5 ESAT-6-specific cells and 49.5 CFP-10-specific cells per 200,000 cells in the BAL fluid. Control patients had a median of 1 ESAT-6-specific cell and 1 CFP-10-specific cell per 200,000 PBMCs and no ESAT-6- and CFP-10-specific cells per 200,000 cells in the BAL fluid.

Conclusion: Smear-negative pulmonary tuberculosis can be diagnosed rapidly by identification of MTB-specific cells in the BAL fluid.

Keywords: bronchoalveolar lavage; CFP-10; ELISPOT; ESAT-6; tuberculosis

Tuberculosis (TB) is one of the leading causes of morbidity and mortality worldwide, affecting more than 8 million persons annually (1), mostly with pulmonary tuberculosis (pTB). Confirmation of the presumptive diagnosis of tuberculosis is usually delayed, as detection of growth of Mycobacterium tuberculosis (MTB) in liquid or solid medium takes an average of 2 wk of culture (2). However, only 72% of cases of pulmonary tuberculosis in Germany were culture positive in 2003 (3). The rapid diagnosis of pulmonary tuberculosis relies therefore on clinical symptoms and radiologic findings, and on the detection of acid/ alcohol-fast bacilli (AFB) in sputum or bronchial secretions. Detection of MTB-specific gene sequences in respiratory specimens by DNA amplification may rapidly confirm the diagnosis of pTB, but DNA amplification for the diagnosis of tuberculosis is not standardized and is available only in specialized institutions.

The sensitivity of sputum or bronchoalveolar lavage (BAL) microscopy for the detection of AFB is variable in pTB and ranges from 50 to 80% for three consecutive specimens (4). In patients with smear-negative pTB the sensitivity of sputum or BAL MTB-specific DNA amplification ranges from 48 to 80% (5). Thus, a substantial proportion of patients with pTB remain undiagnosed by current laboratory techniques until results of MTB cultures become available.

Enzyme-linked immunospot (ELISPOT) and enzyme-linked immunoassay (ELISA) techniques have been developed to rapidly detect IFN-? production by MTB-specific peripheral blood mononuclear cells (PBMCs) for the diagnosis of MTB infection. These assays use peptides from early antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), which are encoded by the region of difference-1 (RD-1) in the MTB genome, a region that is absent from all strains of Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine and most nontuberculous mycobacteria (6-9). The sensitivity of these tests in active TB ranges from 76 to 100% (9-17) whereas the specificity exceeds 88% (9, 14-16, 18). In TB contact tracing, these tests are a better indicator of close exposure to an index case than the tuberculin skin test (TST) (19-23). Although these tests are unaffected by prior BCG vaccination, they cannot distinguish between active and latent TB when performed on PBMCs (reviewed by Dheda and coworkers [24] and Pai and coworkers [25]).

Approximately 95 to 98% of T lymphocytes are confined to lymphatic organs (26). In tuberculosis, MTB-specific T cells clonally expand and are recruited to the site of infection (27, 28). In persons with pulmonary tuberculosis MTB-specific T cells should therefore be detectable among mononuclear cells derived by BAL of the affected pulmonary segment. In patients with suspected tuberculosis and smear-negative microscopy, bronchoscopy with BAL is a safe procedure when guidelines are followed and may be indicated to exclude other diseases such as bronchogenic carcinoma or sarcoidosis (29, 30). We therefore recruited consecutively all patients with a suspected diagnosis of pTB and smear-negative sputum microscopy and studied prospectively whether patients with smear-negative pTB can be detected rapidly by enumeration of ESAT-6- and CFP-10-specific IFN-?-producing T cells from BAL fluid.

Q I’m a very active 41-year-old man who works out routinely and is in decent physical shape. I’ve had no real physical problems, but as I get older, I fear the possibility of developing heart disease because several of my close family members have been victimized. As I said before, I’m in pretty good shape, but what should I do to put my mind at ease? For instance, are there benefits to having a heart scan?

J.L., Atlanta

A The best and first thing that you can do to put your mind at ease about possible heart disease is to visit your doctor for a complete physical examination that can give you a realistic view about your overall health.

As a part of that examination, some doctors are likely to recommend a heart scan, which screens for heart disease in people who are otherwise asymptomatic. Medical experts say the heart scan measures coronary calcifications and is more accurate than a treadmill test to detect heart problems.

The procedure is relatively inexpensive, noninvasive and takes only a few minutes to perform. Doctors say the heart scan is rapidly approaching the popularity of angiograms, which are performed on more than 2 million Americans each year to detect blocked arteries. Angiograms are highly accurate, but, according to doctors, carry a small risk of heart attack, stroke and bleeding.

In a recent study, results indicated that for many heart patients, heart scans are 95 percent as accurate as angiograms. A heart scan allows doctors to look at the heart from various positions, thanks to a 3-D image that can be enlarged, color-enhanced or rotated to reveal blocked arteries or other defects.

Abstract

Low to mid potency corticosteroids remain a cornerstone of therapy for atopic dermatitis (AD). Since AD is most prevalent in the younger pediatric population and is chronic in nature, safety is of particular concern especially for children under 2 years of age. A novel desonide (0.05%) formulation was developed in a nonirritating and moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. The safety and efficacy of this new class VI low potency topical steroid was substantiated in 2 phase III clinical trials in mild to moderate AD subjects aged 3 months to 18 years (mean age 6.7 years and 30% under 3 years). A total of 425 subjects were treated with desonide hydrogel and 157 subjects with the hydrogel vehicle. Desonide hydrogel 0.05% was extremely well-tolerated and provided statistically significant improvements in all primary (P<.001) and secondary (P[less than or equal to].006) efficacy endpoints in both studies. This novel desonide formulation represents an advancement in the treatment of AD.

Atopic dermatitis (AD) is a chronic inflammatory pruritic dermatosis with a multifactorial etiology. This condition affects 10% to 20% of infants in the US (1) and is a lead diagnosis for many pediatric healthcare visits as it is the eighth most common disease in patients under the age of 25. (2,3) The exact cause of AD is unknown, but genetic factors are considered to play an important role in the development of this disease. In the vast majority of patients with AD, the condition develops during the first 2 years of life, but the likelihood of new disease onset declines and disease severity tends to improve with age although adult populations are still affected as well.

Topical corticosteroids have been the gold standard for the treatment of AD for decades. Recently, newer nonsteroid topical agents such as tacrolimus and pimecrolimus (topical calcineurin inhibitors) have been introduced; however, these agents have had diminished use due to parental and physician concerns regarding long-term safety, despite a lack of substantiating studies. (4,5) Consequently, for the management of steroid responsive dermatoses such as AD, safe and effective lower potency topical steroids will likely remain the cornerstone of therapy, especially in younger patients. Nonetheless, poor patient compliance with topical corticosteroids can often be linked to patient, parent, and care-provider fears of steroid side effects (6,7) or tolerability issues. (8,9) Similarly, validation of the safety of these products has been a practitioner concern especially with respect to their use in very young patients where increased surface to body mass ratios increase the potential risk for systemic as well as local side effects. (10)

During the past 10 years there has been very little innovation in the low potency, class VI, steroid arena. Recently, a novel formulation of desonide has been developed to address the practitioner and patient concerns discussed above. Desonide is a well known synthetic, nonfluorinated corticosteroid with anti-inflammatory and antipruritic properties. The safety and efficacy of desonide as an active pharmaceutical ingredient has been well demonstrated over many years. (11,12) Until recently, only traditional creams, ointments, and lotions were available in this potency class. This new formulation is distinguished as an alcohol and surfactant-free carbopol-based polymer that contains 0.05% (w/w) of micronized desonide. This hydrogel formulation was designed to be mild, free from sensitizing ingredients, moisturizing, cosmetically elegant, and easily applied over a large surface for AD patients aged 3 months and older.

A wide variety of studies have been performed to validate the safety and efficacy of this new product. These studies are notable in that they include patients as young as 3 months of age with a mean BSA involvement of at least 20%. These studies support a very favorable safety, tolerability and efficacy profile for 0.05% desonide hydrogel. This paper focuses on the presentation of the 2 phase III multi-center, randomized, blinded, vehicle-controlled studies in pediatric patients with mild to moderate AD which substantiates the safety, efficacy, and tolerability of this novel hydrogel formulation.

Methods

Two phase III studies of slightly different design were conducted. Both trials were randomized, blinded, vehicle-controlled trials in which neither the subject nor the investigator knew the identity of the assigned test material. Assignment to treatment arms in these studies included a desonide hydrogel to vehicle ratio of 3 to 1 for the first study and a ratio of 2 to 1 for the second study.

Unless specifically noted, analogous methods were used for both phase III studies. Protocols were reviewed and approved by institutional review boards (IRBs). All subjects provided consent prior to participation and subjects less than 18 years of age considered by their IRB to be capable of giving assent, signed a written assent form in addition to having their guardian or parent’s consent to participate. The studies were conducted in accordance with the ethical principles originating from the World Medical Association Declaration of Helsinki and International Conference on Harmonization and good clinical practice guidelines.