Susan J. Mandel

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Associations guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Societys Journals Online web site at http://jcem.endojournals.org). EVIDENCE This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society, Asia and Oceania Thyroid Association, and the Latin American Thyroid Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS Practice guidelines are presented for diagnosis and treatment of patients with thyroid-related medical issues just before and during pregnancy and in the postpartum interval. These include evidence-based approaches to assessing the cause of the condition, treating it, and managing hypothyroidism, hyperthyroidism, gestational hyperthyroidism, thyroid autoimmunity, thyroid tumors, iodine nutrition, postpartum thyroiditis, and screening for thyroid disease. Indications and side effects of therapeutic agents used in treatment are also presented.

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Phase II Trial of Sorafenib in Advanced Thyroid Cancer

PURPOSE Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma. PATIENTS AND METHODS Eligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors. RESULTS Thirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18+ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89+ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related. CONCLUSION Sorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response + stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.

Usefulness of Ultrasonography in the Management of Nodular Thyroid Disease

Thyroid nodules are a common diagnostic challenge encountered in clinical medicine. Approximately 4% to 7% of adults have palpable thyroid nodules, and up to 70% have thyroid nodules visible on ultrasonography, many of which are less than 1 cm in diameter (1-5). Fine-needle aspiration biopsy is the standard diagnostic test for evaluating a palpable thyroid nodule in euthyroid patients. Previous studies have shown that the diagnostic accuracy of fine-needle aspiration biopsy is improved with ultrasonography guidance compared with palpation alone (6-9). In addition, ultrasonography guidance is required for aspiration of nonpalpable thyroid nodules (10-12). The objective of our study was to determine whether the routine use of ultrasonography in all patients with suspected thyroid nodules changed clinical management compared with palpation alone. Methods Patients The study sample consisted of all patients referred to the Brigham and Womens Hospital dual-discipline (endocrinology and radiology) Thyroid Nodule Clinic (Boston, Massachusetts) for suspected nodular thyroid disease or suspected recurrent thyroid cancer between October 1995 and March 1997. Clinicians were instructed to refer patients with suspected or diagnosed nodular thyroid disease and a normal serum thyrotropin level to the Thyroid Nodule Clinic. If patients had a suppressed thyrotropin level and were not taking thyroid hormone, a radionuclide scan was suggested. The clinic visit included thyroid ultrasonography performed by a radiologist, an evaluation by an endocrinologist, and ultrasonography-guided fine-needle aspiration biopsy of all nodules measuring at least 1 cm in maximum diameter (up to a maximum of four nodules). A cutoff of 1 cm was selected on the basis of recommendations in the literature (13). For patients seen more than once, only the initial visit was analyzed. Measurements Medical records were reviewed for the specialty of the referring clinician, the referring clinicians examination of the thyroid before referral, and the indication for referral. Sonography was performed by using 5- to 10-MHz transducers. Nodules were measured in three dimensions. Fine-needle aspiration was performed with a 25-gauge needle. Ultrasonography guidance was used to confirm placement of the needle in the nodule or to direct sampling into solid portions of partially cystic nodules. Four to six passes were made per nodule. The needles were rinsed and pooled in a single vial containing CytoLyt solution (CytoLyt Corp., Boxborough, Massachusetts). Two ThinPrep slides (Cytyc Corp., Marlborough, Massachusetts) were stained by using a modified Papanicolaou method and were read by a cytopathologist at the Brigham and Womens Hospital as benign, atypical, suspicious for a follicular or Hrthle cell neoplasm, suspicious or positive for papillary cancer, or nondiagnostic. Aspirates were considered nondiagnostic if they contained fewer than six groups of benign follicular cells. The atypical category was applied to cases in which a mild degree of cellular or architectural atypia precluded a benign diagnosis but was insufficient for a suspicious or positive diagnosis. Cytology reports were reviewed for all patients who had fine-needle aspiration biopsy, and histologic reports were reviewed for all patients who had surgery. Two endocrinologists reviewed the charts to compare the referring physicians findings on thyroid physical examination with the ultrasonography findings. If a discrepancy existed between the referring physicians clinical thyroid examination and the number of nodules requiring fine-needle aspiration biopsy based on ultrasonography ( 1 cm), ultrasonography was considered to have altered the clinical management. Role of the Funding Sources The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the paper for publication. Results Characteristics of the Study Group A total of 223 patients (203 women and 20 men [mean age, 46.3 15.3 years]) were evaluated at the Thyroid Nodule Clinic between October 1995 and March 1997. Sixty-one percent were referred by primary care physicians, 37% were referred by endocrinologists, and 2% were referred by surgeons. The indication for referral was abnormal findings on thyroid physical examination in 173 of 223 patients (78%); 114 were referred for a suspected solitary nodule, 33 were referred for diffuse or asymmetric goiter, and 26 were referred for multinodular goiter (Table 1). Ultrasonography-guided fine-needle aspiration biopsy was performed on 209 nodules in 156 patients. Sixty-seven patients had no aspirations, 112 had one aspiration, and 44 had two or more aspirations. Table 1. Indication for Referral to the Thyroid Nodule Clinic in 223 Patients Sonographic Findings Ultrasonography revealed solitary nodules in 33% of patients, a multinodular goiter (>1 nodule on ultrasonography) in 50%, and no nodules in 17% (excluding those with a history of thyroid cancer). Ultrasonography findings in the 173 patients referred for abnormal findings on thyroid physical examination are given in Table 2. Table 2. Sonographic Findings in 173 Patients Referred to the Thyroid Nodule Clinic for Abnormal Results on Physical Examination Management of Nodular Thyroid Disease Ultrasonography changed management in 44% (50 of 114) of the patients referred for a solitary nodule on physical examination. In 27 patients, an additional nonpalpable nodule at least 1 cm in diameter was found on ultrasonography and more than one nodule required aspiration. Eighteen patients had no nodules, and 5 patients had only small nodules (<1 cm); therefore, despite the results of the physical examination, no aspiration was required. For the remaining 64 patients referred for a solitary nodule (46 with a solitary nodule 1 cm and 18 with multiple nodules but only one nodule 1 cm), clinical management was not affected because the palpated nodule was the only nodule that was at least 1 cm in diameter on ultrasonography. Among the 33 patients referred for a diffuse or asymmetric goiter, 55% (18 of 33) had one or more nodules at least 1 cm in diameter on ultrasonography, which suggests that the examining physician recognized an abnormality but could not detect a discrete nodule. Among the 26 patients referred for a multinodular goiter, 5 did not require an aspiration based on the ultrasonography findings and 21 required one or more aspirations for discrete nodules at least 1 cm in diameter. In summary, ultrasonography altered clinical management in 109 of the 173 patients (63%) referred for abnormal findings on physical examination. It was needed for guidance of nonpalpable nodules that were at least 1 cm in diameter in 66 patients (27 referred for a solitary nodule with additional nodules 1 cm on ultrasonography, 21 referred for a multinodular goiter, and 18 referred for a diffuse or asymmetric goiter with discrete nodules 1 cm on ultrasonography) and documented no nodules that were at least 1 cm in diameter in 43 patients. In the 48 patients referred for other indications, ultrasonography helped 1) evaluate growth in patients with previous benign cytologic findings, 2) direct sampling of lymph nodes in patients with thyroid cancer, 3) direct sampling of nonpalpable nodules found incidentally on other radiology studies, and 4) screen for nodules in patients with previous exposure to radiation. Cytologic Findings after Fine-Needle Aspiration In the 153 patients with no history of thyroid cancer who had fine-needle aspiration, 130 of the 205 nodules aspirated (63%) were benign. Seven nodules (3%), all confirmed histologically, were positive for papillary cancer. Nine (4%) were suspicious for papillary cancer. Five of these (56%) were histologically confirmed as papillary cancer, and 2 were benign. One patient with 2 suspicious nodules sought a second opinion and was lost to follow-up. Seventeen nodules (8%) were suspicious for follicular or Hrthle cell neoplasm, of which 9 were excised; 1 was a follicular carcinoma and the others were benign. Nine nodules (4%) were characterized as atypical. Of these, 2 were found to be benign after surgery. Thirty-three nodules (16%), of which 13 were more than 50% cystic, had nondiagnostic cytologic characteristics. In 1 patient, surgery for papillary carcinoma in 1 nodule revealed papillary carcinoma in a second nodule whose cytologic characteristics were nondiagnostic. The occurrence of malignancy was similar in patients with solitary nodules and those with multiple nodules. Cancer was found in 4 of 60 patients with solitary nodules (6.7%) and 8 of 90 patients with multiple nodules (8.9%). In 4 of the 12 patients who received a diagnosis of thyroid cancer, the malignant nodule was not palpated by the referring physician. One patient was referred for a solitary palpable nodule, which was benign, but a nonpalpable malignant nodule in the contralateral lobe was detected on ultrasonography. In another patient, who was referred for follow-up of a benign nodule, a second nonpalpable nodule was found to be malignant. The malignant nodule was also nonpalpable in the other 2 patients who had either a multinodular or diffuse goiter on the referring clinicians examination. Fine-needle aspiration biopsies of 4 nonpalpable lymph nodes in the 3 patients with a history of thyroid cancer were all positive for recurrent papillary cancer. Discussion We routinely use ultrasonography and ultrasonography-guided fine-needle aspiration in patients referred to our Thyroid Nodule Clinic for suspected thyroid nodules. Almost half of the patients referred for a solitary nodule on physical examination (a group previously not thought to benefit from ultrasonography) were found to have multiple nodules, and many (27 of 48) required additional aspiration of a nonpalpable nodule. More than 50% of patients (18 of 33) with suspected diffuse or asymmetric goiter had discrete nodules requiring fi

The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension

BACKGROUND Ultrasound and prophylactic dissections have facilitated identification of small-volume cervical lymph node (LN) metastases in patients with papillary thyroid carcinoma (PTC). Since most staging systems do not stratify risk based on size or number of LN metastases, even a single-microscopic LN metastasis can upstage a patient with low-risk papillary thyroid microcarcinoma (PMC) to an intermediate risk of recurrence in the American Thyroid Association (ATA) system and to an increased risk of death in the American Joint Committee on Cancer (AJCC) staging system (stage III if the metastatic node is in the central neck or stage IVA if the microscopic LN metastasis is identified in the lateral neck). Such microscopic upstaging may lead to potentially unnecessary or additional treatments and follow-up studies. The goal of this review is to determine if the literature supports the concept that specific characteristics (clinically apparent size, number, and extranodal extension) of LN metastases can be used to stratify the risk of recurrence in PTC. SUMMARY In patients with pathological proven cervical LN metastases (pathological N1 disease; pN1), the median risk of loco-regional LN recurrence varies markedly by clinical staging, with recurrence rates for patients who are initially clinically N0 (clinical N0 disease; cN0) of 2% (range 0%-9%) versus rates of recurrence for patients who are initially clinically N-positive (clinical N1 disease; cN1) of 22% (range 10%-42%). Furthermore, the median risk of recurrence in pN1 patients varies markedly by the number of positive nodes, <5 nodes (4%, range 3%-8%) vs. >5 nodes (19%, range 7%-21%). Additionally, the presence of extranodal extension was associated with a median risk of recurrence of 24% (range 15%-32%) and possibly a worse disease-specific survival. CONCLUSION Our previous paradigm assigned the same magnitude of risk for all patients with N1 disease. However, small-volume subclinical microscopic N1 disease clearly conveys a much smaller risk of recurrence than large-volume, macroscopic clinically apparent loco-regional metastases. Armed with this information, clinicians will be better able to tailor initial treatment and follow-up recommendations. Implications of N1 stratification for PTC into small-volume microscopic disease versus clinically apparent macroscopic disease importantly relate to issues of prophylactic neck dissection utility, need for pathologic nodal size description, and suggest potential modifications to the AJCC TNM (tumor, nodal disease, and distant metastasis) and ATA risk recurrence staging systems.

Radioactive Iodine and the Salivary Glands

Radioactive iodine ((131)I) targets the thyroid gland and has been proven to play an effective role in the treatment of differentiated papillary and follicular cancers. Simultaneously, this radioisotope hones in on the salivary glands where it is concentrated and secreted into the saliva. Dose related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, stomatitis, candidiasis, and neoplasia. Prevention of the (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Recently, amifostine has been advocated to prevent the effects of irradiation. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration.

Diagnosis of Primary HIV-1 Infection

Primary HIV infection is characterized by diverse clinical symptoms (1, 2). Since patients with primary infection are just developing HIV antibodies, recognition of the syndrome in at-risk persons should prompt antibody testing as well as a virologic assay (3, 4). Diagnosing primary infection may decrease HIV transmission (5) and allow consideration of early treatment (2, 6). To date, the optimal patients to screen and the best algorithm for use of diagnostic tests have not been determined. The objectives of this study were to determine the sensitivity and specificity of virologic tests and specific clinical symptoms for diagnosing primary HIV infection. Methods Patients Patients with potential exposure to HIV and compatible symptoms were referred from clinics, testing centers, emergency departments, and community physicians for primary infection screening at Cedars-Sinai Medical Center in Los Angeles, California, and the University of California, San Diego. In Los Angeles, 127 patients were screened between March 1993 and August 1995 (cohort 1) for enrollment in a placebo-controlled trial of zidovudine (7). A similar group of 255 patients was screened in Los Angeles between June 1996 and July 1999 (cohort 2), and 54 patients were screened between June 1996 and March 1999 in San Diego (cohort 3). Patients in cohort 2 received a standardized questionnaire regarding results of past HIV tests, presence of specific symptoms, and potential exposure to HIV during the preceding 2 months. Virologic and Serologic Assays The study was approved by local institutional review boards. All patients provided informed consent and received pre- and post-test counseling. Patients in cohorts 1 and 2 had real-time testing for HIV antibodies and p24 antigen by a polyclonal enzyme immunoassay (Abbott Laboratories, Abbott Park, Illinois); plasma was stored at 70 C. In cohort 2, real-time plasma HIV RNA measurements were performed by branched-chain DNA (bDNA) assay, version 2.0 (lower limit of detection, 500 copies/mL), between June 1996 and July 1998 and by version 3.0 (lower limit of detection, 50 copies/mL) between August 1998 and July 1999 (Chiron Diagnostics, Emeryville, California). Stored samples from cohort 1 were retrospectively tested by bDNA assay, version 3.0. After April 1998, p24 antigen was measured by using the monoclonal HIV AG-1 enzyme immunoassay (Abbott Laboratories), which replaced the previous assay. All samples with detectable p24 antigen were confirmed by neutralization (Abbott Laboratories). Samples positive for HIV antibody were confirmed by Western blot (Cambridge Biotech Corp., Rockville, Maryland). Samples that yielded indeterminate Western blots (<2 envelope bands, core bands, or both) were tested again in approximately 1 month to document seroconversion. Patients in cohort 3 were screened in San Diego by using HIV antibody enzyme immunoassay (Abbott Laboratories). Plasma HIV RNA level was determined by using Amplicor HIV Monitor (Roche Diagnostic Systems, Indianapolis, Indiana), which had a lower limit of detection of 400 copies/mL. Samples that were positive for HIV RNA but negative for HIV antibody were tested for p24 antigen (Beckman Coulter, Fullerton, California). Statistical Analysis Primary infection was defined as a confirmed positive virologic test result with either a negative HIV antibody assay result or an indeterminate Western blot. Because there is no virologic gold standard, we assumed that levels of plasma HIV RNA had a sensitivity of 100% for diagnosing primary infection. False-positive HIV RNA measurements were defined as those that were negative on repeated testing and those obtained in patients who did not undergo seroconversion. In cohort 1, frozen plasma samples that were negative for HIV antibody and p24 antigen were retrospectively tested for HIV RNA. Follow-up was not available for these patients; therefore, before testing any samples, we determined that an HIV RNA level greater than 10 000 copies/mL would be considered a true-positive result. This HIV RNA level, in our experience, has not been seen in false-positive samples. Sensitivity and specificity, along with corresponding 95% confidence intervals, were determined by using tabulated exact binomial limits for sample sizes less than or equal to 100 (8) and by using the normal approximation to the binomial for sample sizes greater than 100. Patients in cohort 2 were analyzed for predictors of primary infection on the basis of uniformly collected demographic characteristics, exposure history, and symptoms. All variables were compared by using a two-sample t-test. To assess the impact of several predictor variables, a stepwise discriminant analysis was performed by using variables that differed significantly between patients with and those without primary infection (significance was indicated by a Pvalue<0.05). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Demographic characteristics were similar across cohorts. Overall, 89% of patients were male, 74% were white, 13% were Hispanic, and 9% were African American. Regarding risk factors, 77% of patients were homosexual men, 18% were heterosexual women, and 4% used intravenous drugs. Patients were categorized as having 1) primary infection with undetectable HIV antibodies or an indeterminate Western blot [12.4%], 2) chronic infection with a positive Western blot [18.1%], or 3) no infection (69.5%). Sensitivity and Specificity of Virologic Assays The results of screening tests are summarized in Table 1. Patients with primary infection had undetectable HIV antibodies or indeterminate Western blot but a confirmed positive virologic test result. Two patients in cohort 1 were negative for HIV antibody and p24 antigen but positive for HIV RNA, with levels greater than 100 000 copies/mL. For the purpose of this analysis, they were considered to be true positive for primary HIV infection. Overall, p24 antigen testing had a sensitivity of 88.7% (95% CI, 77.0% to 95.7%). The mean concentration of HIV RNA in the five patients who had primary infection but undetectable p24 antigen was 251 189 copies/mL (range, 100 000 to 630 957 copies/mL). The overall specificity of tests for HIV RNA and p24 antigen was 97.4% (CI, 94.9% to 98.9%) and 100% (CI, 99.3% to 100%), respectively. Eight of 303 uninfected patients (2.6%) had false-positive results on HIV RNA testing (mean concentration, 269 copies/mL [range, 52 to 1950 copies/mL]). Table 1. Serologic and Virologic Results in Patients Screened for Primary HIV Infection Predictors of Primary HIV Infection Cohort 2 was divided into patients with primary infection and those who were uninfected or had chronic HIV infection (Table 2). The primary infection group involved 25 patients who had a negative antibody test result or indeterminate Western blot and 15 patients who had had a negative antibody test result in the preceding 3 months. Of these 15, 4 had had a negative Western blot in the previous 3 weeks and 11 had had a documented negative antibody test result or evolving Western blot in the previous 3 months. Those with primary infection were more likely to be homosexual; to have been exposed to an HIV-infected person; and to report fever, myalgia, arthralgia, rash, or night sweats (P<0.05 for all comparisons) (Table 2). Combining fever, myalgia, and rash increased the predictive value of symptoms; however, no combination of symptoms identified more than 75% of patients with primary infection. Table 2. Clinical Predictors of Primary HIV Infection in Cohort 2 Discussion Our study shows that no clinical symptoms have sufficient sensitivity or specificity for primary infection to allow targeted screening of at-risk persons. In addition, we show that while both p24 antigen and plasma HIV RNA assays are useful virologic tests for diagnosing primary infection, each has limitations. Assays for HIV RNA are likely to be more sensitive but are associated with lower specificity and can therefore yield more false-positive results. Similar to our study, a study in India that screened patients in sexually transmitted disease clinics showed that certain symptoms occur with increased frequency in patients with primary HIV infection (9). Nevertheless, both this study and our study demonstrate that selective screening would miss a substantial number of patients with primary infection. Thus, to maximize the number of identified infected patients, many seronegative persons must be screened. Several groups have reported that assays for HIV RNA are more sensitive than those for p24 antigen in diagnosing primary infection. However, these studies often screened asymptomatic patients, such as those found to experience seroconversion during cohort studies (10) and those with indeterminate Western blots (11). This makes the findings less relevant for the prospective screening of symptomatic patients. Similar to our study, other studies have shown that the assay for p24 antigen is sensitive in symptomatic antibody-negative patients, in whom virologic testing is necessary for diagnosis (4, 7, 12). Overall, these studies and our own emphasize the importance of analyzing the sensitivity and specificity of virologic assays in the context of the patients clinical and serologic status. When selecting a virologic test, it is important to consider its cost in clinical practice. In our study, it cost approximately

Thyroid Aspiration Cytology: Current Status

6000 (