Diana Mahoney

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

MAUI, HAWAII — Look for tumor mitotic rate to supplant Clark level in the forthcoming 7th edition of the American Joint Committee on Cancer melanoma staging system.

“Clark level will now only be considered for staging in the rare instances when mitotic rate is not known; otherwise it will no longer be part of the staging system,” Dr. Jeffrey E. Gershenwald said at the annual Hawaii Dermatology Seminar sponsored by Skin Disease Education Foundation.

This represents a break with the past. Within melanoma staging, Clark level enjoyed near-equal billing with tumor thickness before being downgraded in clinical relevance in the still-current 6th edition of the AJCC staging system, issued in 2002.

The 6th edition relegated Clark level to a limited role, with Clark level IV and V resulting in upstaging of thin melanomas from T1 to T1b, explained Dr. Gershenwald, vice chair of the AJCC task force charged with developing the new edition of the staging system.

The 7th edition of the AJCC melanoma staging system will be published this spring and will take effect early next year. The same changes will be made in the European staging system in coordinated fashion.

Mitotic rate will be introduced into the staging system on the basis of recent evidence suggesting that it is an independent prognostic factor. The presence of at least one mitosis per square centimeter will be sufficient to upgrade a thin melanoma from T1 to T1b.

As the AJCC staging system is rolled out, reports will be issued detailing how pathologists should determine mitotic rate, according to Dr. Gershenwald, professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston.

Clark level, he added, has caused a great deal of confusion among patients, who often confuse Clark level IV with stage IV melanoma.

“I can't tell you how many patients have come into the clinic thinking they have a stage IV melanoma and are reading their death sentence on the Internet when in fact they might very well have had a thin melanoma that happens to be Clark level IV,” he commented.

“In dialoging with your patients, please make sure they understand the difference,” Dr. Gershenwald urged.

The 7th edition of the staging system will make no major changes in the core TNM (tumor, node, metastasis) and stage grouping criteria for stages I-III melanoma. A thin melanoma will remain one that's up to 1.0 mm in thickness, and a thick one will still have to be greater than 4.0 mm. This was an evidence-based decision in response to analysis of an international database of more than 50,000 melanoma patients which validated the models utilized in the 6th edition.

There will be a few minor changes in the 6th edition having clinical relevance, however. For one, there will no longer be a lower limit as to what constitutes node-positive disease.

Also, immunohistochemical detection of nodal metastases—already in wide use in clinical practice—will for the first time become acceptable for staging purposes in the upcoming edition, Dr. Gershenwald said.

In the 7th edition, the essential elements of a pathology report for primary melanoma will be Breslow thickness, the presence or absence of ulceration, mitotic rate, and margin status.

SDEF and this newspaper are owned by Elsevier.

The 7th edition will make no major changes in the core TNM and stage grouping criteria for stages I-III melanoma. DR. GERSHENWALD

Staging, Lymph Node Assessment Are Key to Surgical Melanoma Management

The surgical management of primary melanoma varies by patient and depends in large part on key elements of the pathology report and the assessment of lymph node involvement, according to Dr. Gershenwald.

In terms of staging the disease, Breslow thickness, ulceration, mitotic rate, Clark level, and margin assessment should be considered prior to wide local excision of the tumor, he noted.

And because nodal involvement is the best predictor of recurrence and survival in melanoma, determining which patients have lymph node involvement and which patients do not is critical to the optimal management of the disease.

Lymphatic mapping together with sentinel lymph node biopsy is a relatively noninvasive way to accurately stage the regional nodal basin and enables a selective approach to regional node dissection, whereby lymphadectomy is reserved only for patients found to have pathologically documented disease, Dr. Gershenwald explained.

This combined diagnostic approach—in which a radioactive tracer is injected around the primary tumor site and a blue dye is used to identify sentinel lymph nodes to be removed for analysis—identifies regional lymph node disease that might not be seen with complete lymph node dissection and identifies patients in whom adjuvant therapy is warranted, he said.

Studies have suggested that early detection by sentinel node biopsy of sentinel lymph node metastasis is associated with a survival benefit when compared with a watch-and-wait approach in patients who develop clinical lymph node recurrence, Dr. Gershenwald noted.

With respect to the use of fluorodeoxyglucose positron-emission tomography (FDG-PET), which has been shown in several reports to be a more sensitive indicator of metastatic melanoma than conventional imaging, limitations in the study designs may overestimate the utility of this imaging modality for this indication, he said.

The literature supports the use of adjunctive PET imaging in properly selected patients with metastatic or recurrent melanoma, but it does not provide evidence suggesting that FDG-PET should be obtained in all melanoma patients, he reported.

Specifically, FDG-PET rarely identifies the presence of occult distant metastases in early stage melanoma patients who have been staged using sentinel node biopsy, whch means the likelihood is low that these patients will be upstaged based on the FDG-PET results.

BOSTON — Although asthma is a common cause of exercise-induced shortness of breath in children and adolescents, “it is not the only cause,” said pediatric pulmonologist Christina Scirica. “Failing to consider other possibilities can lead to mismanagement and the inappropriate use of medications.”

Cardiac disease, vocal cord dysfunction, restrictive physiology, anemia, anxiety, deconditioning from habitually low levels of activity, and normal breathlessness associated with extreme exercise are among the potential causes of exertional dyspnea in children, Dr. Scirica said at a meeting on primary care pediatrics sponsored by Harvard Medical School.

In fact, she noted, studies have shown that children with exercise-induced shortness of breath (SOB) who have no other asthma symptoms and normal pre-exercise lung function, and who don't respond to simplest asthma treatment measures, such as the use of a bronchodilator inhaler, often don't have asthma, despite being diagnosed with it, said Dr. Scirica of Boston's Massachusetts General Hospital.

Dr. Scirica offered a cognitive framework consisting of a series of questions to ask oneself while eliciting the patient history and conducting the examination. “In a nutshell,” she advised, “ask yourself, in this order: Does this sound like cardiac disease? Does this sound like vocal cord dysfunction? Does this sound like exercise-induced asthma? Does this sound like none of the above?”

Consider cardiac disease if the patient describes associated symptoms such as chest pain, dizziness, lightheadedness, or palpitations, or if there is a personal or family history of cardiac disease or an abnormal cardiac exam, Dr. Scirica said. A “yes” to any of these should prompt an electrocardiogram, a Holter study, and a referral to a cardiologist.

Described as paradoxical closure of vocal cords during inspiration, vocal cord dysfunction can cause SOB associated with throat tightness and inspiratory stridor, according to Dr. Scirica. One clue that exertional dyspnea might be linked to vocal cord dysfunction, she said, “is a lack of response to α-agonist therapy.” Patients with suspected vocal cord dysfunction should be referred to an ear, nose, and throat specialist for evaluation. “Visible adduction [via laryngoscopic examination] of the vocal cords during inspiration is the diagnostic gold standard,” said Dr. Scirica. Treatment for this condition includes vocal cord training by a speech therapist and, when necessary, psychiatric treatment for the underlying anxiety.

The tell-tale symptoms of asthma—expiratory, breathy wheezing, and cough—that occur during or after exercise and require 5–6 minutes of 80%–85% effort may signal exercise-induced asthma, said Dr. Scirica. “The symptoms may be exacerbated by such factors as cold air exposure, high pollen count, or upper respiratory infection,” she said, and are more likely in children with a past medical history of asthma or allergic rhinitis or a family history of asthma.

Exercise-induced asthma is responsive to corticosteroid and α-agonist therapy, said Dr. Scirica, noting, however, “that the α-agonist must be given 15–20 minutes prior to exercise and should be administered via a spacer.” Prevention strategies, such as pre-exercise warm up to induce refractory period and avoidance of environmental triggers—should also be encouraged. When a child or adolescent with presumed exercise-induced asthma does not respond to treatment or develops atypical symptoms, referral to a pulmonologist is warranted, she said.

When symptoms associated with the experience of exertional dyspnea are not suggestive of cardiac disease, vocal cord dysfunction, or asthma—or the symptoms are consistent with asthma but do not respond to appropriate therapy, “consider a referral to pulmonology for further evaluation,” which will likely include a clinical consultation, pulmonary function testing, treadmill test for exercise-induced asthma, and/or cardiopulmonary exercise testing, concluded Dr. Scirica, who reported no relevant conflicts of interest with respect to her presentation.

BOSTON — Although asthma is a common cause of exercise-induced shortness of breath in children and adolescents, “it is not the only cause,” said pediatric pulmonologist Christina Scirica. “Failing to consider other possibilities can lead to mismanagement and the inappropriate use of medications.”

Cardiac disease, vocal cord dysfunction, restrictive physiology, anemia, anxiety, deconditioning from habitually low levels of activity, and normal breathlessness associated with extreme exercise are among the potential causes of exertional dyspnea in children, Dr. Scirica said at a meeting on primary care pediatrics sponsored by Harvard Medical School.

In fact, she noted, studies have shown that children with exercise-induced shortness of breath (SOB) who have no other asthma symptoms and normal pre-exercise lung function, and who don't respond to simplest asthma treatment measures, such as the use of a bronchodilator inhaler, often don't have asthma, despite being diagnosed with it, said Dr. Scirica of Boston's Massachusetts General Hospital.

Dr. Scirica offered a cognitive framework consisting of a series of questions to ask oneself while eliciting the patient history and conducting the examination. “In a nutshell,” she advised, “ask yourself, in this order: Does this sound like cardiac disease? Does this sound like vocal cord dysfunction? Does this sound like exercise-induced asthma? Does this sound like none of the above?”

Consider cardiac disease if the patient describes associated symptoms such as chest pain, dizziness, lightheadedness, or palpitations, or if there is a personal or family history of cardiac disease or an abnormal cardiac exam, Dr. Scirica said. A “yes” to any of these should prompt an electrocardiogram, a Holter study, and a referral to a cardiologist.

Described as paradoxical closure of vocal cords during inspiration, vocal cord dysfunction can cause SOB associated with throat tightness and inspiratory stridor, according to Dr. Scirica. One clue that exertional dyspnea might be linked to vocal cord dysfunction, she said, “is a lack of response to α-agonist therapy.” Patients with suspected vocal cord dysfunction should be referred to an ear, nose, and throat specialist for evaluation. “Visible adduction [via laryngoscopic examination] of the vocal cords during inspiration is the diagnostic gold standard,” said Dr. Scirica. Treatment for this condition includes vocal cord training by a speech therapist and, when necessary, psychiatric treatment for the underlying anxiety.

The tell-tale symptoms of asthma—expiratory, breathy wheezing, and cough—that occur during or after exercise and require 5–6 minutes of 80%–85% effort may signal exercise-induced asthma, said Dr. Scirica. “The symptoms may be exacerbated by such factors as cold air exposure, high pollen count, or upper respiratory infection,” she said, and are more likely in children with a past medical history of asthma or allergic rhinitis or a family history of asthma.

Exercise-induced asthma is responsive to corticosteroid and α-agonist therapy, said Dr. Scirica, noting, however, “that the α-agonist must be given 15–20 minutes prior to exercise and should be administered via a spacer.” Prevention strategies, such as pre-exercise warm up to induce refractory period and avoidance of environmental triggers—should also be encouraged. When a child or adolescent with presumed exercise-induced asthma does not respond to treatment or develops atypical symptoms, referral to a pulmonologist is warranted, she said.

When symptoms associated with the experience of exertional dyspnea are not suggestive of cardiac disease, vocal cord dysfunction, or asthma—or the symptoms are consistent with asthma but do not respond to appropriate therapy, “consider a referral to pulmonology for further evaluation,” which will likely include a clinical consultation, pulmonary function testing, treadmill test for exercise-induced asthma, and/or cardiopulmonary exercise testing, concluded Dr. Scirica, who reported no relevant conflicts of interest with respect to her presentation.

BOSTON — Although asthma is a common cause of exercise-induced shortness of breath in children and adolescents, “it is not the only cause,” said pediatric pulmonologist Christina Scirica. “Failing to consider other possibilities can lead to mismanagement and the inappropriate use of medications.”

Cardiac disease, vocal cord dysfunction, restrictive physiology, anemia, anxiety, deconditioning from habitually low levels of activity, and normal breathlessness associated with extreme exercise are among the potential causes of exertional dyspnea in children, Dr. Scirica said at a meeting on primary care pediatrics sponsored by Harvard Medical School.

In fact, she noted, studies have shown that children with exercise-induced shortness of breath (SOB) who have no other asthma symptoms and normal pre-exercise lung function, and who don't respond to simplest asthma treatment measures, such as the use of a bronchodilator inhaler, often don't have asthma, despite being diagnosed with it, said Dr. Scirica of Boston's Massachusetts General Hospital.

Dr. Scirica offered a cognitive framework consisting of a series of questions to ask oneself while eliciting the patient history and conducting the examination. “In a nutshell,” she advised, “ask yourself, in this order: Does this sound like cardiac disease? Does this sound like vocal cord dysfunction? Does this sound like exercise-induced asthma? Does this sound like none of the above?”

Consider cardiac disease if the patient describes associated symptoms such as chest pain, dizziness, lightheadedness, or palpitations, or if there is a personal or family history of cardiac disease or an abnormal cardiac exam, Dr. Scirica said. A “yes” to any of these should prompt an electrocardiogram, a Holter study, and a referral to a cardiologist.

Described as paradoxical closure of vocal cords during inspiration, vocal cord dysfunction can cause SOB associated with throat tightness and inspiratory stridor, according to Dr. Scirica. One clue that exertional dyspnea might be linked to vocal cord dysfunction, she said, “is a lack of response to α-agonist therapy.” Patients with suspected vocal cord dysfunction should be referred to an ear, nose, and throat specialist for evaluation. “Visible adduction [via laryngoscopic examination] of the vocal cords during inspiration is the diagnostic gold standard,” said Dr. Scirica. Treatment for this condition includes vocal cord training by a speech therapist and, when necessary, psychiatric treatment for the underlying anxiety.

The tell-tale symptoms of asthma—expiratory, breathy wheezing, and cough—that occur during or after exercise and require 5–6 minutes of 80%–85% effort may signal exercise-induced asthma, said Dr. Scirica. “The symptoms may be exacerbated by such factors as cold air exposure, high pollen count, or upper respiratory infection,” she said, and are more likely in children with a past medical history of asthma or allergic rhinitis or a family history of asthma.

Exercise-induced asthma is responsive to corticosteroid and α-agonist therapy, said Dr. Scirica, noting, however, “that the α-agonist must be given 15–20 minutes prior to exercise and should be administered via a spacer.” Prevention strategies, such as pre-exercise warm up to induce refractory period and avoidance of environmental triggers—should also be encouraged. When a child or adolescent with presumed exercise-induced asthma does not respond to treatment or develops atypical symptoms, referral to a pulmonologist is warranted, she said.

When symptoms associated with the experience of exertional dyspnea are not suggestive of cardiac disease, vocal cord dysfunction, or asthma—or the symptoms are consistent with asthma but do not respond to appropriate therapy, “consider a referral to pulmonology for further evaluation,” which will likely include a clinical consultation, pulmonary function testing, treadmill test for exercise-induced asthma, and/or cardiopulmonary exercise testing, concluded Dr. Scirica, who reported no relevant conflicts of interest with respect to her presentation.

New data indicating that a first simple febrile seizure in infants and young children rarely signals bacterial meningitis suggest the American Academy of Pediatrics' recommendation of lumbar puncture in this population should be reconsidered, researchers from Children's Hospital Boston have reported.

The American Academy of Pediatrics (AAP) recommended in its 1996 practice parameter for the neurodiagnostic evaluation of children with a first simple febrile seizure (FSFS) that lumbar puncture be strongly considered for infants younger than 12 months and that it be considered for those aged between 12 and 18 months who present within 12 hours of the event. The rationale was that bacterial meningitis commonly presents with seizure, and the identification of subtle signs of the infection via clinical assessment can be difficult and is dependent on the skill level and experience of the clinician (Pediatrics 1996;97:769–72).

In the current study, Dr. Amir A. Kimia and colleagues in the division of emergency medicine at Children's Hospital Boston, performed a retrospective cohort review for patients aged 6–18 months who were evaluated for FSFS in the hospital's emergency department (ED) between October 1995 and October 2006. Of the 71,234 ED visits for children aged 6–18 months during that period, 704 were for otherwise healthy children presenting with FSFS, including 188 for children younger than 12 months and 516 for children aged 12–18 months.

Of the 704 children, lumbar puncture was attempted in 271(38%) and cerebrospinal fluid (CSF) was successfully obtained in 260, including 131 children aged at least 6 months but younger than 12 months and 129 aged 12–18 months. Cerebrospinal fluid pleocytosis was found in 10 of the 260 samples and no pathogen was identified in CSF cultures.

“None of the 10 patients with CSF pleocytosis had isolation of bacteria from blood cultures,” the authors wrote, and “none of the 704 with FSFS returned to the hospital with a diagnosis of bacterial meningitis” (Pediatrics 2009;123:6–12). Of the remaining 70,530 patients aged 6–18 months without FSFS who were seen in the ED during the same period, 8 were diagnosed with bacterial meningitis.

When compliance with the AAP recommendations was considered, performance of lumbar punctures during the study period decreased significantly, from 70% for infants younger than 12 months old to 25% for infants aged 12–18 months, wrote the authors, who also observed that “rates of [lumbar puncture] performance decreased over time in both age groups.”

The 38% rate of lumber punctures performed at Children's Hospital Boston, a pediatric tertiary care facility, was significantly higher than that which has been reported for children aged younger than 18 months who received care in community EDs, the authors noted.

This fact, combined with the finding that it is very rare for bacterial meningitis to present as FSFS, suggests the AAP practice parameters “have limited utility,” they wrote. Given the lack of evidence to support a recommendation of lumbar puncture for first simple febrile seizures in young children, “the [AAP] recommendations should be changed to state simply that meningitis should be considered in the differential diagnosis for any febrile child and [lumbar puncture] should be performed if there are clinical signs or symptoms of concern,” they concluded.

The chair of the American Academy of Pediatrics Committee on Pediatric Emergency Medicine, Dr. Kathy N. Shaw, disagreed with their conclusion. “A lumbar puncture should be considered in all children who present with a simple febrile seizure,” she said in an interview. In fact, “the possibility of meningitis should always be considered in the emergency department evaluation of young, febrile infants. The younger the age, the more difficult it is to use clinical judgment alone, and the lower the threshold for performing a lumbar puncture. This statement is true regardless of whether the infant had as seizure or not.”

The authors reported having no relevant financial conflicts of interest with respect to this study.

New data indicating that a first simple febrile seizure in infants and young children rarely signals bacterial meningitis suggest the American Academy of Pediatrics' recommendation of lumbar puncture in this population should be reconsidered, researchers from Children's Hospital Boston have reported.

The American Academy of Pediatrics (AAP) recommended in its 1996 practice parameter for the neurodiagnostic evaluation of children with a first simple febrile seizure (FSFS) that lumbar puncture be strongly considered for infants younger than 12 months and that it be considered for those aged between 12 and 18 months who present within 12 hours of the event. The rationale was that bacterial meningitis commonly presents with seizure, and the identification of subtle signs of the infection via clinical assessment can be difficult and is dependent on the skill level and experience of the clinician (Pediatrics 1996;97:769–72).

In the current study, Dr. Amir A. Kimia and colleagues in the division of emergency medicine at Children's Hospital Boston, performed a retrospective cohort review for patients aged 6–18 months who were evaluated for FSFS in the hospital's emergency department (ED) between October 1995 and October 2006. Of the 71,234 ED visits for children aged 6–18 months during that period, 704 were for otherwise healthy children presenting with FSFS, including 188 for children younger than 12 months and 516 for children aged 12–18 months.

Of the 704 children, lumbar puncture was attempted in 271(38%) and cerebrospinal fluid (CSF) was successfully obtained in 260, including 131 children aged at least 6 months but younger than 12 months and 129 aged 12–18 months. Cerebrospinal fluid pleocytosis was found in 10 of the 260 samples and no pathogen was identified in CSF cultures.

“None of the 10 patients with CSF pleocytosis had isolation of bacteria from blood cultures,” the authors wrote, and “none of the 704 with FSFS returned to the hospital with a diagnosis of bacterial meningitis” (Pediatrics 2009;123:6–12). Of the remaining 70,530 patients aged 6–18 months without FSFS who were seen in the ED during the same period, 8 were diagnosed with bacterial meningitis.

When compliance with the AAP recommendations was considered, performance of lumbar punctures during the study period decreased significantly, from 70% for infants younger than 12 months old to 25% for infants aged 12–18 months, wrote the authors, who also observed that “rates of [lumbar puncture] performance decreased over time in both age groups.”

The 38% rate of lumber punctures performed at Children's Hospital Boston, a pediatric tertiary care facility, was significantly higher than that which has been reported for children aged younger than 18 months who received care in community EDs, the authors noted.

This fact, combined with the finding that it is very rare for bacterial meningitis to present as FSFS, suggests the AAP practice parameters “have limited utility,” they wrote. Given the lack of evidence to support a recommendation of lumbar puncture for first simple febrile seizures in young children, “the [AAP] recommendations should be changed to state simply that meningitis should be considered in the differential diagnosis for any febrile child and [lumbar puncture] should be performed if there are clinical signs or symptoms of concern,” they concluded.

The chair of the American Academy of Pediatrics Committee on Pediatric Emergency Medicine, Dr. Kathy N. Shaw, disagreed with their conclusion. “A lumbar puncture should be considered in all children who present with a simple febrile seizure,” she said in an interview. In fact, “the possibility of meningitis should always be considered in the emergency department evaluation of young, febrile infants. The younger the age, the more difficult it is to use clinical judgment alone, and the lower the threshold for performing a lumbar puncture. This statement is true regardless of whether the infant had as seizure or not.”

The authors reported having no relevant financial conflicts of interest with respect to this study.

New data indicating that a first simple febrile seizure in infants and young children rarely signals bacterial meningitis suggest the American Academy of Pediatrics' recommendation of lumbar puncture in this population should be reconsidered, researchers from Children's Hospital Boston have reported.

The American Academy of Pediatrics (AAP) recommended in its 1996 practice parameter for the neurodiagnostic evaluation of children with a first simple febrile seizure (FSFS) that lumbar puncture be strongly considered for infants younger than 12 months and that it be considered for those aged between 12 and 18 months who present within 12 hours of the event. The rationale was that bacterial meningitis commonly presents with seizure, and the identification of subtle signs of the infection via clinical assessment can be difficult and is dependent on the skill level and experience of the clinician (Pediatrics 1996;97:769–72).

In the current study, Dr. Amir A. Kimia and colleagues in the division of emergency medicine at Children's Hospital Boston, performed a retrospective cohort review for patients aged 6–18 months who were evaluated for FSFS in the hospital's emergency department (ED) between October 1995 and October 2006. Of the 71,234 ED visits for children aged 6–18 months during that period, 704 were for otherwise healthy children presenting with FSFS, including 188 for children younger than 12 months and 516 for children aged 12–18 months.

Of the 704 children, lumbar puncture was attempted in 271(38%) and cerebrospinal fluid (CSF) was successfully obtained in 260, including 131 children aged at least 6 months but younger than 12 months and 129 aged 12–18 months. Cerebrospinal fluid pleocytosis was found in 10 of the 260 samples and no pathogen was identified in CSF cultures.

“None of the 10 patients with CSF pleocytosis had isolation of bacteria from blood cultures,” the authors wrote, and “none of the 704 with FSFS returned to the hospital with a diagnosis of bacterial meningitis” (Pediatrics 2009;123:6–12). Of the remaining 70,530 patients aged 6–18 months without FSFS who were seen in the ED during the same period, 8 were diagnosed with bacterial meningitis.

When compliance with the AAP recommendations was considered, performance of lumbar punctures during the study period decreased significantly, from 70% for infants younger than 12 months old to 25% for infants aged 12–18 months, wrote the authors, who also observed that “rates of [lumbar puncture] performance decreased over time in both age groups.”

The 38% rate of lumber punctures performed at Children's Hospital Boston, a pediatric tertiary care facility, was significantly higher than that which has been reported for children aged younger than 18 months who received care in community EDs, the authors noted.

This fact, combined with the finding that it is very rare for bacterial meningitis to present as FSFS, suggests the AAP practice parameters “have limited utility,” they wrote. Given the lack of evidence to support a recommendation of lumbar puncture for first simple febrile seizures in young children, “the [AAP] recommendations should be changed to state simply that meningitis should be considered in the differential diagnosis for any febrile child and [lumbar puncture] should be performed if there are clinical signs or symptoms of concern,” they concluded.

The chair of the American Academy of Pediatrics Committee on Pediatric Emergency Medicine, Dr. Kathy N. Shaw, disagreed with their conclusion. “A lumbar puncture should be considered in all children who present with a simple febrile seizure,” she said in an interview. In fact, “the possibility of meningitis should always be considered in the emergency department evaluation of young, febrile infants. The younger the age, the more difficult it is to use clinical judgment alone, and the lower the threshold for performing a lumbar puncture. This statement is true regardless of whether the infant had as seizure or not.”

The authors reported having no relevant financial conflicts of interest with respect to this study.

Long-term low-dose aspirin does not prevent the development of type 2 diabetes in healthy women, according to new data from the Women's Health Study.

Among 19,326 initially healthy women randomly assigned to receive 100 mg of aspirin every other day as part of the large-scale, long-term clinical trial designed to assess the role of low-dose aspirin in the prevention of cardiovascular disease, there was no statistically significant difference in the incidence of type 2 diabetes, compared with 19,390 women in the study's placebo arm, Dr. Aruna D. Pradhan of Harvard Medical School, Boston, and colleagues reported in Diabetes Care.

Several small clinical studies have linked short-term high-dose aspirin with improved glucose handling and possible amelioration of insulin resistance, while other small trials have demonstrated an association between low-dose aspirin therapy and both the production of anti-inflammatory mediators and the reduction of systemic levels of inflammatory biomarkers. Dr. Pradhan and colleagues sought to determine whether chronic low-dose aspirin therapy might interfere in the development of clinical type 2 diabetes.

The Women's Health Study population included women who were at least 45 years old at the start of the trial with no previous history of cancer, cardiovascular disease, or other major chronic illness and who were not taking and had no history of adverse effects from aspirin or nonsteroidal anti-inflammatory drugs. For the current analysis, the investigators excluded those women with reported physician-diagnosed diabetes at baseline, according to the authors. Information on newly diagnosed diabetes was ascertained from follow-up questionnaires administered annually from baseline through the end of the 10-year trial.

After a median 10.2-year follow-up, “there were 849 cases [of clinical type 2 diabetes] in the aspirin group and 847 cases in the placebo group, with no significant risk reduction,” the authors wrote (Diabetes Care 2009;32:3–8).

In separate analyses assessing the affect of low-dose aspirin therapy on the incidence of diabetes over time, there was no difference in the risk of developing diabetes during the first 5 years of treatment, compared with more than 5 years of treatment, nor was there a difference after excluding patients with early cases of diabetes that were presumably undiagnosed at baseline or in analyses accounting for adherence to randomized assignment, they reported. Also, “the treatment effect did not vary significantly across subgroups of women at high risk for diabetes [because of] the presence of clinical risk factors, dyslipidemia, elevated [hemoglobin] A_1c, or [high-sensitivity C-reactive protein],” they noted.

Low-dose aspirin therapy in this study was associated with clinically significant bleeding episodes, the authors reported. The rates of any bleeding event were 4.5% in the treatment arm vs. 3.7% in the placebo group, and the comparative rates of transfusion-requiring bleeding, of peptic ulcer, and of epistaxis in the treatment vs. placebo arms were 0.6% vs. 0.4%, 2.7% vs. 2.1%, and 19% vs. 16.5%, respectively.

The study's strengths include its large size, long treatment duration, large number of events, assessment of several large and clinically important high-risk subgroups, and collection of systemic data on the occurrence of significant bleeding events, the authors wrote. “An important limitation is the lack of systemic screening for more sensitive measures of glucose intolerance and insulin resistance during follow-up. … We cannot with the current data determine the potential impact of low-dose aspirin on these subclinical markers of incipient disease.”

The observations from this study “do not pertain to other salicylate agents currently being evaluated for diabetes treatment or to intermediate or high doses of long-term aspirin in primary prevention,” the authors stressed.

Aspirin and placebo for this study were provided by Bayer HealthCare. The authors reported no other potential conflicts of interest.

Long-term low-dose aspirin does not prevent the development of type 2 diabetes in healthy women, according to new data from the Women's Health Study.

Among 19,326 initially healthy women randomly assigned to receive 100 mg of aspirin every other day as part of the large-scale, long-term clinical trial designed to assess the role of low-dose aspirin in the prevention of cardiovascular disease, there was no statistically significant difference in the incidence of type 2 diabetes, compared with 19,390 women in the study's placebo arm, Dr. Aruna D. Pradhan of Harvard Medical School, Boston, and colleagues reported in Diabetes Care.

Several small clinical studies have linked short-term high-dose aspirin with improved glucose handling and possible amelioration of insulin resistance, while other small trials have demonstrated an association between low-dose aspirin therapy and both the production of anti-inflammatory mediators and the reduction of systemic levels of inflammatory biomarkers. Dr. Pradhan and colleagues sought to determine whether chronic low-dose aspirin therapy might interfere in the development of clinical type 2 diabetes.

The Women's Health Study population included women who were at least 45 years old at the start of the trial with no previous history of cancer, cardiovascular disease, or other major chronic illness and who were not taking and had no history of adverse effects from aspirin or nonsteroidal anti-inflammatory drugs. For the current analysis, the investigators excluded those women with reported physician-diagnosed diabetes at baseline, according to the authors. Information on newly diagnosed diabetes was ascertained from follow-up questionnaires administered annually from baseline through the end of the 10-year trial.

After a median 10.2-year follow-up, “there were 849 cases [of clinical type 2 diabetes] in the aspirin group and 847 cases in the placebo group, with no significant risk reduction,” the authors wrote (Diabetes Care 2009;32:3–8).

In separate analyses assessing the affect of low-dose aspirin therapy on the incidence of diabetes over time, there was no difference in the risk of developing diabetes during the first 5 years of treatment, compared with more than 5 years of treatment, nor was there a difference after excluding patients with early cases of diabetes that were presumably undiagnosed at baseline or in analyses accounting for adherence to randomized assignment, they reported. Also, “the treatment effect did not vary significantly across subgroups of women at high risk for diabetes [because of] the presence of clinical risk factors, dyslipidemia, elevated [hemoglobin] A_1c, or [high-sensitivity C-reactive protein],” they noted.

Low-dose aspirin therapy in this study was associated with clinically significant bleeding episodes, the authors reported. The rates of any bleeding event were 4.5% in the treatment arm vs. 3.7% in the placebo group, and the comparative rates of transfusion-requiring bleeding, of peptic ulcer, and of epistaxis in the treatment vs. placebo arms were 0.6% vs. 0.4%, 2.7% vs. 2.1%, and 19% vs. 16.5%, respectively.

The study's strengths include its large size, long treatment duration, large number of events, assessment of several large and clinically important high-risk subgroups, and collection of systemic data on the occurrence of significant bleeding events, the authors wrote. “An important limitation is the lack of systemic screening for more sensitive measures of glucose intolerance and insulin resistance during follow-up. … We cannot with the current data determine the potential impact of low-dose aspirin on these subclinical markers of incipient disease.”

The observations from this study “do not pertain to other salicylate agents currently being evaluated for diabetes treatment or to intermediate or high doses of long-term aspirin in primary prevention,” the authors stressed.

Aspirin and placebo for this study were provided by Bayer HealthCare. The authors reported no other potential conflicts of interest.

Long-term low-dose aspirin does not prevent the development of type 2 diabetes in healthy women, according to new data from the Women's Health Study.

Among 19,326 initially healthy women randomly assigned to receive 100 mg of aspirin every other day as part of the large-scale, long-term clinical trial designed to assess the role of low-dose aspirin in the prevention of cardiovascular disease, there was no statistically significant difference in the incidence of type 2 diabetes, compared with 19,390 women in the study's placebo arm, Dr. Aruna D. Pradhan of Harvard Medical School, Boston, and colleagues reported in Diabetes Care.

Several small clinical studies have linked short-term high-dose aspirin with improved glucose handling and possible amelioration of insulin resistance, while other small trials have demonstrated an association between low-dose aspirin therapy and both the production of anti-inflammatory mediators and the reduction of systemic levels of inflammatory biomarkers. Dr. Pradhan and colleagues sought to determine whether chronic low-dose aspirin therapy might interfere in the development of clinical type 2 diabetes.

The Women's Health Study population included women who were at least 45 years old at the start of the trial with no previous history of cancer, cardiovascular disease, or other major chronic illness and who were not taking and had no history of adverse effects from aspirin or nonsteroidal anti-inflammatory drugs. For the current analysis, the investigators excluded those women with reported physician-diagnosed diabetes at baseline, according to the authors. Information on newly diagnosed diabetes was ascertained from follow-up questionnaires administered annually from baseline through the end of the 10-year trial.

After a median 10.2-year follow-up, “there were 849 cases [of clinical type 2 diabetes] in the aspirin group and 847 cases in the placebo group, with no significant risk reduction,” the authors wrote (Diabetes Care 2009;32:3–8).

In separate analyses assessing the affect of low-dose aspirin therapy on the incidence of diabetes over time, there was no difference in the risk of developing diabetes during the first 5 years of treatment, compared with more than 5 years of treatment, nor was there a difference after excluding patients with early cases of diabetes that were presumably undiagnosed at baseline or in analyses accounting for adherence to randomized assignment, they reported. Also, “the treatment effect did not vary significantly across subgroups of women at high risk for diabetes [because of] the presence of clinical risk factors, dyslipidemia, elevated [hemoglobin] A_1c, or [high-sensitivity C-reactive protein],” they noted.

Low-dose aspirin therapy in this study was associated with clinically significant bleeding episodes, the authors reported. The rates of any bleeding event were 4.5% in the treatment arm vs. 3.7% in the placebo group, and the comparative rates of transfusion-requiring bleeding, of peptic ulcer, and of epistaxis in the treatment vs. placebo arms were 0.6% vs. 0.4%, 2.7% vs. 2.1%, and 19% vs. 16.5%, respectively.

The study's strengths include its large size, long treatment duration, large number of events, assessment of several large and clinically important high-risk subgroups, and collection of systemic data on the occurrence of significant bleeding events, the authors wrote. “An important limitation is the lack of systemic screening for more sensitive measures of glucose intolerance and insulin resistance during follow-up. … We cannot with the current data determine the potential impact of low-dose aspirin on these subclinical markers of incipient disease.”

The observations from this study “do not pertain to other salicylate agents currently being evaluated for diabetes treatment or to intermediate or high doses of long-term aspirin in primary prevention,” the authors stressed.

Aspirin and placebo for this study were provided by Bayer HealthCare. The authors reported no other potential conflicts of interest.

New recommendations for the standardization of research on endothelial precursor cells are expected to optimize future investigations of these cells in systemic sclerosis and to simplify the comparison of different studies, according to the authors.

Endothelial precursor cells (EPCs) play an important role in the homeostasis of the vascular network and are considered potential candidates for novel therapeutic approaches as well as possible biomarkers for vascular repair, new vessel formation, and cardiovascular prognosis. However, methodical and other inconsistencies across research studies complicate data interpretation, wrote Dr. Jörg H.W. Distler of the University of Elrangen-Nuremberg (Germany) and colleagues in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group. Specifically, different protocols for EPC isolation, enrichment, culture, and quantification, as well as insufficient data on potentially confounding risk factors, have led to conflicting results in previous studies (Ann. Rheum. Dis. 2009;68:163–8).

Among the holes in the current pool of research is the absence of studies demonstrating EPCs in vascular lesions of animal models of systemic sclerosis, the authors wrote, noting that, to date, studies have shown EPCs in vascular lesions of ischemia. Additionally, “the mechanisms by which EPCs have contributed to vascular repair and neovascularization have not fully been elucidated,” they wrote. “It remains to be determined whether EPCs mediate their effects in humans independently from mature endothelial cells or whether EPCs function more as bystanders of angiogenesis.”

Finally, the numbers of EPCs characteristically in the blood of patients with systemic sclerosis is in need of clarification, as the results of existing studies are contradictory. “The initial study suggested a profound decrease of circulating EPCs, whereas subsequent studies found increased numbers of EPCs in patients with systemic sclerosis”—differences that might be a function of different disease durations in the study patients or different cell enrichment techniques prior to fluorescence-activated cell sorting (FACS) analysis, the authors wrote.

The following recommendations should be incorporated in future studies, the authors advised:

▸ Studies should include a detailed description of methods and materials used.

▸ Cardiovascular risk factors and drugs should be described in detail. Statins, in particular, impact circulating EPCs.

▸ Studies with small numbers of patients should be avoided because they are of limited help in light of the heterogeneity of systemic sclerosis and the large number of potential confounding factors that influence the number of EPCs.

▸ Basic methodological guidelines for the isolation, culture, enrichment, and detection of EPCs should be followed and described in detail.

▸ For in vitro EPC culture, the contents of endothelium growth medium 2 (EGM-2) are best defined and as such should be the medium of choice for future experiments.

▸ Culture dishes should be coated with laminin and type IV collagen because of the close resemblance to the vascular basal membrane.

▸ For all in vitro cultures, the endothelial phenotype should be confirmed at the end of the culture period.

▸ For the quantification of EPCs in the blood, the expression of CD133, vascular endothelial growth factor type 2 receptor (VEGFR2), and CD34 together with a viability marker should be evaluated in a multiparameter flow cytometer.

▸ Standard operating procedures for FACS (see box) must be strictly followed.

The various authors reported receiving research grants and/or honoraria from several major pharmaceutical companies.

Flow Cytometry for EPC Detection

Strict adherence to the following standard operating procedures for fluorescence-activated cell sorting (FACS) analysis in endothelial cell precursor research is critical, according to the EUSTAR statement authors.

▸ Clean the flow cytometer rigorously to avoid sample contamination.

▸ Set and monitor the sensitivity of fluorescence detectors.

▸ Collect a minimum of 500,000 events to collect an adequate number of endothelial precursor cells.

▸ Use a real-time viability stain, such as 7AAD or propidium iodide, and identify and exclude dead cells to minimize nonspecific staining and improve assay resolution.

▸ Use a blocking serum to decrease nonspecific binding via Fc receptors.

▸ Establish a dump channel in order to exclude from analysis those cells that are not of interest.

New recommendations for the standardization of research on endothelial precursor cells are expected to optimize future investigations of these cells in systemic sclerosis and to simplify the comparison of different studies, according to the authors.

Endothelial precursor cells (EPCs) play an important role in the homeostasis of the vascular network and are considered potential candidates for novel therapeutic approaches as well as possible biomarkers for vascular repair, new vessel formation, and cardiovascular prognosis. However, methodical and other inconsistencies across research studies complicate data interpretation, wrote Dr. Jörg H.W. Distler of the University of Elrangen-Nuremberg (Germany) and colleagues in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group. Specifically, different protocols for EPC isolation, enrichment, culture, and quantification, as well as insufficient data on potentially confounding risk factors, have led to conflicting results in previous studies (Ann. Rheum. Dis. 2009;68:163–8).

Among the holes in the current pool of research is the absence of studies demonstrating EPCs in vascular lesions of animal models of systemic sclerosis, the authors wrote, noting that, to date, studies have shown EPCs in vascular lesions of ischemia. Additionally, “the mechanisms by which EPCs have contributed to vascular repair and neovascularization have not fully been elucidated,” they wrote. “It remains to be determined whether EPCs mediate their effects in humans independently from mature endothelial cells or whether EPCs function more as bystanders of angiogenesis.”

Finally, the numbers of EPCs characteristically in the blood of patients with systemic sclerosis is in need of clarification, as the results of existing studies are contradictory. “The initial study suggested a profound decrease of circulating EPCs, whereas subsequent studies found increased numbers of EPCs in patients with systemic sclerosis”—differences that might be a function of different disease durations in the study patients or different cell enrichment techniques prior to fluorescence-activated cell sorting (FACS) analysis, the authors wrote.

The following recommendations should be incorporated in future studies, the authors advised:

▸ Studies should include a detailed description of methods and materials used.

▸ Cardiovascular risk factors and drugs should be described in detail. Statins, in particular, impact circulating EPCs.

▸ Studies with small numbers of patients should be avoided because they are of limited help in light of the heterogeneity of systemic sclerosis and the large number of potential confounding factors that influence the number of EPCs.

▸ Basic methodological guidelines for the isolation, culture, enrichment, and detection of EPCs should be followed and described in detail.

▸ For in vitro EPC culture, the contents of endothelium growth medium 2 (EGM-2) are best defined and as such should be the medium of choice for future experiments.

▸ Culture dishes should be coated with laminin and type IV collagen because of the close resemblance to the vascular basal membrane.

▸ For all in vitro cultures, the endothelial phenotype should be confirmed at the end of the culture period.

▸ For the quantification of EPCs in the blood, the expression of CD133, vascular endothelial growth factor type 2 receptor (VEGFR2), and CD34 together with a viability marker should be evaluated in a multiparameter flow cytometer.

▸ Standard operating procedures for FACS (see box) must be strictly followed.

The various authors reported receiving research grants and/or honoraria from several major pharmaceutical companies.

Flow Cytometry for EPC Detection

Strict adherence to the following standard operating procedures for fluorescence-activated cell sorting (FACS) analysis in endothelial cell precursor research is critical, according to the EUSTAR statement authors.

▸ Clean the flow cytometer rigorously to avoid sample contamination.

▸ Set and monitor the sensitivity of fluorescence detectors.

▸ Collect a minimum of 500,000 events to collect an adequate number of endothelial precursor cells.

▸ Use a real-time viability stain, such as 7AAD or propidium iodide, and identify and exclude dead cells to minimize nonspecific staining and improve assay resolution.

▸ Use a blocking serum to decrease nonspecific binding via Fc receptors.

▸ Establish a dump channel in order to exclude from analysis those cells that are not of interest.

New recommendations for the standardization of research on endothelial precursor cells are expected to optimize future investigations of these cells in systemic sclerosis and to simplify the comparison of different studies, according to the authors.

Endothelial precursor cells (EPCs) play an important role in the homeostasis of the vascular network and are considered potential candidates for novel therapeutic approaches as well as possible biomarkers for vascular repair, new vessel formation, and cardiovascular prognosis. However, methodical and other inconsistencies across research studies complicate data interpretation, wrote Dr. Jörg H.W. Distler of the University of Elrangen-Nuremberg (Germany) and colleagues in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group. Specifically, different protocols for EPC isolation, enrichment, culture, and quantification, as well as insufficient data on potentially confounding risk factors, have led to conflicting results in previous studies (Ann. Rheum. Dis. 2009;68:163–8).

Among the holes in the current pool of research is the absence of studies demonstrating EPCs in vascular lesions of animal models of systemic sclerosis, the authors wrote, noting that, to date, studies have shown EPCs in vascular lesions of ischemia. Additionally, “the mechanisms by which EPCs have contributed to vascular repair and neovascularization have not fully been elucidated,” they wrote. “It remains to be determined whether EPCs mediate their effects in humans independently from mature endothelial cells or whether EPCs function more as bystanders of angiogenesis.”

Finally, the numbers of EPCs characteristically in the blood of patients with systemic sclerosis is in need of clarification, as the results of existing studies are contradictory. “The initial study suggested a profound decrease of circulating EPCs, whereas subsequent studies found increased numbers of EPCs in patients with systemic sclerosis”—differences that might be a function of different disease durations in the study patients or different cell enrichment techniques prior to fluorescence-activated cell sorting (FACS) analysis, the authors wrote.

The following recommendations should be incorporated in future studies, the authors advised:

▸ Studies should include a detailed description of methods and materials used.

▸ Cardiovascular risk factors and drugs should be described in detail. Statins, in particular, impact circulating EPCs.

▸ Studies with small numbers of patients should be avoided because they are of limited help in light of the heterogeneity of systemic sclerosis and the large number of potential confounding factors that influence the number of EPCs.

▸ Basic methodological guidelines for the isolation, culture, enrichment, and detection of EPCs should be followed and described in detail.

▸ For in vitro EPC culture, the contents of endothelium growth medium 2 (EGM-2) are best defined and as such should be the medium of choice for future experiments.

▸ Culture dishes should be coated with laminin and type IV collagen because of the close resemblance to the vascular basal membrane.

▸ For all in vitro cultures, the endothelial phenotype should be confirmed at the end of the culture period.

▸ For the quantification of EPCs in the blood, the expression of CD133, vascular endothelial growth factor type 2 receptor (VEGFR2), and CD34 together with a viability marker should be evaluated in a multiparameter flow cytometer.

▸ Standard operating procedures for FACS (see box) must be strictly followed.

The various authors reported receiving research grants and/or honoraria from several major pharmaceutical companies.

Flow Cytometry for EPC Detection

Strict adherence to the following standard operating procedures for fluorescence-activated cell sorting (FACS) analysis in endothelial cell precursor research is critical, according to the EUSTAR statement authors.

▸ Clean the flow cytometer rigorously to avoid sample contamination.

▸ Set and monitor the sensitivity of fluorescence detectors.

▸ Collect a minimum of 500,000 events to collect an adequate number of endothelial precursor cells.

▸ Use a real-time viability stain, such as 7AAD or propidium iodide, and identify and exclude dead cells to minimize nonspecific staining and improve assay resolution.

▸ Use a blocking serum to decrease nonspecific binding via Fc receptors.

▸ Establish a dump channel in order to exclude from analysis those cells that are not of interest.

Conjunctivitis: It's red, it's itchy, it's crusty, but it is not—repeat NOT—cause for automatic exclusion from day care or school, according to the latest edition of the American Academy of Pediatrics' “Managing Infectious Diseases in Child Care and Schools.”

The rationale behind this seemingly revolutionary recommendation is the fact that neither treatment nor exclusion of children with conjunctivitis from group settings reduces the spread of infection, Dr. Laura A. Jana discussed at the annual meeting of the American Academy of Pediatrics.

The same goes for many of the common childhood infections that incite knee-jerk reactions among schools, day care providers, and parents.

“Multiple studies have shown that most viruses are spread by children who seem well, which means that exposure happens before the school or day care facility can make the first phone call for the child to be picked up,” said Dr. Jana, a pediatrician and owner of a child care facility in Omaha, Neb.

So while conventional wisdom says that automatically excluding kids with conjunctivitis, fever, and stomachaches will prevent the spread of these infections, “the evidence doesn't back this up,” she said, noting that “hand and surface hygiene continue to be the best way to reduce infections in group care.”

The confusion regarding exclusion is understandable, said Dr. Jana. Unlike the best-practice guidelines issued in 2002 by the AAP, American Public Health Association, and others, state guidelines for exclusion from child care or school lack detail, are not based on medical evidence, and vary considerably by state.

“Most states do not require center and school policies to follow national guidelines, and individual exclusion policies must only comply with state licensing, which means children are often excluded for harmless conditions,” she said. The consequences of inappropriate exclusion policies and practices, she added, include excess health care visits, antibiotic-seeking behavior, and lost work and school time.

The one exclusion criterion from the national guidelines that is excluded most frequently, according to Dr. Jana, is the directive that a child should be excluded if the illness prevents him or her from participating comfortably in activities. “This child should really be at home,” she said. “Additionally, a child should be excluded from school or day care if the illness results in greater care than the staff can provide,” she noted, or if the illness poses a risk of spreading a harmful disease to others. (See box below.)

The common cold, for example, does not warrant exclusion, “unless the child is too uncomfortable to participate in routine daily activities,” Dr. Jana said. “The virus itself can be spread before, during, and well after the time of symptoms, so preventing a child's attendance won't significantly reduce the chance of spread.”

The updated “Managing Infectious Diseases in Child Care and Schools” (Elk Grove Village, Ill.: American Academy of Pediatrics, 2008), also recommends against exclusion for the following conditions that often incite red flags, according to Dr. Jana:

▸ Hand, foot, and mouth disease. “Children should not be excluded unless they have sores in their mouth with drooling or if the rash is associated with fever or behavior change,” Dr. Jana explained. “Good hygiene is the best way to minimize the opportunity for the spread of this common virus.”

▸ Fifth disease. Because there is little virus present when the telltale rash appears, exclusion has no preventive benefit.

▸ Draining skin infection, including methicillin-resistant Staphylococcus aureus (MRSA) infection. “Because of the media attention surrounding MRSA, there's a lot of anxiety about this, but the reality is, these children should be excluded only if the infection is accompanied by fever, pain, or behavior change,” said Dr. Jana. “There is no need for the caregiver to request a culture, because it won't affect how the infection will be handled. Some kids without symptoms have MRSA, and there is no good way to eradicate the germ yet from individuals, families, or classrooms.”

▸ Diarrhea. According to the revised guidelines, diapered children with diarrhea may remain in care if the diarrhea is contained in the diaper and the child has no more than two stools above normal baseline. “This is a departure from the previous recommendation that all diapered children be excluded until the diarrhea resolves or is deemed noninfectious,” said Dr. Jana. Children who are able to use the toilet may remain in care with good hand washing, as long as they don't have accidents. “Exclusion is appropriate for children with blood in their stool not explained by medication, hard stool, or diet,” she said.

▸ Vomiting. Exclusion is recommended for a child who has had two or more episodes of vomiting in the previous 24 hours and continuing exclusion until the vomiting resolves or a health care provider determines the cause is not contagious.

▸ Fever. “Children with fever should not be excluded automatically, unless the fever is accompanied by behavior change or other signs or symptoms of illness,” explained Dr. Jana. The exception to this is children younger than 4 months old with unexplained fever.

▸ Respiratory illness. Most respiratory illnesses do not require exclusion; however, a child with persistent coughing or trouble breathing should be evaluated for pneumonia, asthma, or serious respiratory infection, such as whooping cough.

▸ Earache, no fever. “This child should be excluded if he or she requires more care than the staff can reasonably provide,” said Dr. Jana. “Often, these kids are in a lot of pain and cannot participate in routine activities.”

▸ Lice. “Lice are a nuisance, but they're not a health hazard,” said Dr. Jana. “Children with lice should be excluded, but they don't have to be sent home right away. It can wait until the end of the day, and they can return once treatment occurs,” she said.

“Of course, all of these are recommendations, and while they are based in evidence, they are not binding,” Dr. Jana concluded.

Revised 'When to Exclude' Criteria

With the exception of the noted updates, most of the exclusion criteria outlined in the revised “Managing Infectious Diseases in Child Care and Schools” are consistent with the national illness exclusion guidelines published jointly in 2002 by the AAP, APHA, the Maternal and Child Health Bureau, and the National Resource Center for Health and Safety in Child Care. These include:

▸ Tuberculosis, until an appropriate health care provider or health official certifies that the child is in appropriate therapy and can attend care.

▸ Impetigo, until 24 hours after treatment has been initiated.

▸ Chickenpox until all sores have dried and crusted (usually 6 days).

▸ Mumps, until 9 days after an onset of parotid gland swelling.

▸ Hepatitis A virus, until 1 week after an onset of illness or jaundice or as directed by the health department.

▸ Measles, until 4 days after an onset of rash.

▸ Rubella, until 6 days after an onset of rash.

▸ Fever, when accompanied by behavior changes or other symptoms such as a sore throat, rash, vomiting, diarrhea, earache, etc.

▸ Diarrhea (frequent, runny, watery stools).

▸ Blood in the stool not explained by dietary change, medication, or hard stool.

▸ Vomiting two or more times in a 24-hour period.

▸ Body rash with fever.

▸ Sore throat with fever and swollen glands or mouth sores with drooling.

▸ Severe coughing with the child getting red or blue in the face or making a high-pitched whooping sound after coughing.

▸ Persistent abdominal pain (more than 2 hours) or intermittent pain with other signs and symptoms.

▸ Signs of possible severe illness such as irritability, unusual tiredness, or neediness that compromises caregivers' ability to care for others.

▸ Uncontrolled coughing or wheezing, continuous crying, or difficulty breathing.

Conjunctivitis: It's red, it's itchy, it's crusty, but it is not—repeat NOT—cause for automatic exclusion from day care or school, according to the latest edition of the American Academy of Pediatrics' “Managing Infectious Diseases in Child Care and Schools.”

The rationale behind this seemingly revolutionary recommendation is the fact that neither treatment nor exclusion of children with conjunctivitis from group settings reduces the spread of infection, Dr. Laura A. Jana discussed at the annual meeting of the American Academy of Pediatrics.

The same goes for many of the common childhood infections that incite knee-jerk reactions among schools, day care providers, and parents.

“Multiple studies have shown that most viruses are spread by children who seem well, which means that exposure happens before the school or day care facility can make the first phone call for the child to be picked up,” said Dr. Jana, a pediatrician and owner of a child care facility in Omaha, Neb.

So while conventional wisdom says that automatically excluding kids with conjunctivitis, fever, and stomachaches will prevent the spread of these infections, “the evidence doesn't back this up,” she said, noting that “hand and surface hygiene continue to be the best way to reduce infections in group care.”

The confusion regarding exclusion is understandable, said Dr. Jana. Unlike the best-practice guidelines issued in 2002 by the AAP, American Public Health Association, and others, state guidelines for exclusion from child care or school lack detail, are not based on medical evidence, and vary considerably by state.

“Most states do not require center and school policies to follow national guidelines, and individual exclusion policies must only comply with state licensing, which means children are often excluded for harmless conditions,” she said. The consequences of inappropriate exclusion policies and practices, she added, include excess health care visits, antibiotic-seeking behavior, and lost work and school time.

The one exclusion criterion from the national guidelines that is excluded most frequently, according to Dr. Jana, is the directive that a child should be excluded if the illness prevents him or her from participating comfortably in activities. “This child should really be at home,” she said. “Additionally, a child should be excluded from school or day care if the illness results in greater care than the staff can provide,” she noted, or if the illness poses a risk of spreading a harmful disease to others. (See box below.)

The common cold, for example, does not warrant exclusion, “unless the child is too uncomfortable to participate in routine daily activities,” Dr. Jana said. “The virus itself can be spread before, during, and well after the time of symptoms, so preventing a child's attendance won't significantly reduce the chance of spread.”

The updated “Managing Infectious Diseases in Child Care and Schools” (Elk Grove Village, Ill.: American Academy of Pediatrics, 2008), also recommends against exclusion for the following conditions that often incite red flags, according to Dr. Jana:

▸ Hand, foot, and mouth disease. “Children should not be excluded unless they have sores in their mouth with drooling or if the rash is associated with fever or behavior change,” Dr. Jana explained. “Good hygiene is the best way to minimize the opportunity for the spread of this common virus.”

▸ Fifth disease. Because there is little virus present when the telltale rash appears, exclusion has no preventive benefit.

▸ Draining skin infection, including methicillin-resistant Staphylococcus aureus (MRSA) infection. “Because of the media attention surrounding MRSA, there's a lot of anxiety about this, but the reality is, these children should be excluded only if the infection is accompanied by fever, pain, or behavior change,” said Dr. Jana. “There is no need for the caregiver to request a culture, because it won't affect how the infection will be handled. Some kids without symptoms have MRSA, and there is no good way to eradicate the germ yet from individuals, families, or classrooms.”

▸ Diarrhea. According to the revised guidelines, diapered children with diarrhea may remain in care if the diarrhea is contained in the diaper and the child has no more than two stools above normal baseline. “This is a departure from the previous recommendation that all diapered children be excluded until the diarrhea resolves or is deemed noninfectious,” said Dr. Jana. Children who are able to use the toilet may remain in care with good hand washing, as long as they don't have accidents. “Exclusion is appropriate for children with blood in their stool not explained by medication, hard stool, or diet,” she said.

▸ Vomiting. Exclusion is recommended for a child who has had two or more episodes of vomiting in the previous 24 hours and continuing exclusion until the vomiting resolves or a health care provider determines the cause is not contagious.

▸ Fever. “Children with fever should not be excluded automatically, unless the fever is accompanied by behavior change or other signs or symptoms of illness,” explained Dr. Jana. The exception to this is children younger than 4 months old with unexplained fever.

▸ Respiratory illness. Most respiratory illnesses do not require exclusion; however, a child with persistent coughing or trouble breathing should be evaluated for pneumonia, asthma, or serious respiratory infection, such as whooping cough.

▸ Earache, no fever. “This child should be excluded if he or she requires more care than the staff can reasonably provide,” said Dr. Jana. “Often, these kids are in a lot of pain and cannot participate in routine activities.”

▸ Lice. “Lice are a nuisance, but they're not a health hazard,” said Dr. Jana. “Children with lice should be excluded, but they don't have to be sent home right away. It can wait until the end of the day, and they can return once treatment occurs,” she said.

“Of course, all of these are recommendations, and while they are based in evidence, they are not binding,” Dr. Jana concluded.

Revised 'When to Exclude' Criteria

With the exception of the noted updates, most of the exclusion criteria outlined in the revised “Managing Infectious Diseases in Child Care and Schools” are consistent with the national illness exclusion guidelines published jointly in 2002 by the AAP, APHA, the Maternal and Child Health Bureau, and the National Resource Center for Health and Safety in Child Care. These include:

▸ Tuberculosis, until an appropriate health care provider or health official certifies that the child is in appropriate therapy and can attend care.

▸ Impetigo, until 24 hours after treatment has been initiated.

▸ Chickenpox until all sores have dried and crusted (usually 6 days).

▸ Mumps, until 9 days after an onset of parotid gland swelling.

▸ Hepatitis A virus, until 1 week after an onset of illness or jaundice or as directed by the health department.

▸ Measles, until 4 days after an onset of rash.

▸ Rubella, until 6 days after an onset of rash.

▸ Fever, when accompanied by behavior changes or other symptoms such as a sore throat, rash, vomiting, diarrhea, earache, etc.

▸ Diarrhea (frequent, runny, watery stools).

▸ Blood in the stool not explained by dietary change, medication, or hard stool.

▸ Vomiting two or more times in a 24-hour period.

▸ Body rash with fever.

▸ Sore throat with fever and swollen glands or mouth sores with drooling.

▸ Severe coughing with the child getting red or blue in the face or making a high-pitched whooping sound after coughing.

▸ Persistent abdominal pain (more than 2 hours) or intermittent pain with other signs and symptoms.

▸ Signs of possible severe illness such as irritability, unusual tiredness, or neediness that compromises caregivers' ability to care for others.

▸ Uncontrolled coughing or wheezing, continuous crying, or difficulty breathing.

Conjunctivitis: It's red, it's itchy, it's crusty, but it is not—repeat NOT—cause for automatic exclusion from day care or school, according to the latest edition of the American Academy of Pediatrics' “Managing Infectious Diseases in Child Care and Schools.”

The rationale behind this seemingly revolutionary recommendation is the fact that neither treatment nor exclusion of children with conjunctivitis from group settings reduces the spread of infection, Dr. Laura A. Jana discussed at the annual meeting of the American Academy of Pediatrics.

The same goes for many of the common childhood infections that incite knee-jerk reactions among schools, day care providers, and parents.

“Multiple studies have shown that most viruses are spread by children who seem well, which means that exposure happens before the school or day care facility can make the first phone call for the child to be picked up,” said Dr. Jana, a pediatrician and owner of a child care facility in Omaha, Neb.

So while conventional wisdom says that automatically excluding kids with conjunctivitis, fever, and stomachaches will prevent the spread of these infections, “the evidence doesn't back this up,” she said, noting that “hand and surface hygiene continue to be the best way to reduce infections in group care.”

The confusion regarding exclusion is understandable, said Dr. Jana. Unlike the best-practice guidelines issued in 2002 by the AAP, American Public Health Association, and others, state guidelines for exclusion from child care or school lack detail, are not based on medical evidence, and vary considerably by state.

“Most states do not require center and school policies to follow national guidelines, and individual exclusion policies must only comply with state licensing, which means children are often excluded for harmless conditions,” she said. The consequences of inappropriate exclusion policies and practices, she added, include excess health care visits, antibiotic-seeking behavior, and lost work and school time.

The one exclusion criterion from the national guidelines that is excluded most frequently, according to Dr. Jana, is the directive that a child should be excluded if the illness prevents him or her from participating comfortably in activities. “This child should really be at home,” she said. “Additionally, a child should be excluded from school or day care if the illness results in greater care than the staff can provide,” she noted, or if the illness poses a risk of spreading a harmful disease to others. (See box below.)

The common cold, for example, does not warrant exclusion, “unless the child is too uncomfortable to participate in routine daily activities,” Dr. Jana said. “The virus itself can be spread before, during, and well after the time of symptoms, so preventing a child's attendance won't significantly reduce the chance of spread.”

The updated “Managing Infectious Diseases in Child Care and Schools” (Elk Grove Village, Ill.: American Academy of Pediatrics, 2008), also recommends against exclusion for the following conditions that often incite red flags, according to Dr. Jana:

▸ Hand, foot, and mouth disease. “Children should not be excluded unless they have sores in their mouth with drooling or if the rash is associated with fever or behavior change,” Dr. Jana explained. “Good hygiene is the best way to minimize the opportunity for the spread of this common virus.”

▸ Fifth disease. Because there is little virus present when the telltale rash appears, exclusion has no preventive benefit.

▸ Draining skin infection, including methicillin-resistant Staphylococcus aureus (MRSA) infection. “Because of the media attention surrounding MRSA, there's a lot of anxiety about this, but the reality is, these children should be excluded only if the infection is accompanied by fever, pain, or behavior change,” said Dr. Jana. “There is no need for the caregiver to request a culture, because it won't affect how the infection will be handled. Some kids without symptoms have MRSA, and there is no good way to eradicate the germ yet from individuals, families, or classrooms.”

▸ Diarrhea. According to the revised guidelines, diapered children with diarrhea may remain in care if the diarrhea is contained in the diaper and the child has no more than two stools above normal baseline. “This is a departure from the previous recommendation that all diapered children be excluded until the diarrhea resolves or is deemed noninfectious,” said Dr. Jana. Children who are able to use the toilet may remain in care with good hand washing, as long as they don't have accidents. “Exclusion is appropriate for children with blood in their stool not explained by medication, hard stool, or diet,” she said.

▸ Vomiting. Exclusion is recommended for a child who has had two or more episodes of vomiting in the previous 24 hours and continuing exclusion until the vomiting resolves or a health care provider determines the cause is not contagious.

▸ Fever. “Children with fever should not be excluded automatically, unless the fever is accompanied by behavior change or other signs or symptoms of illness,” explained Dr. Jana. The exception to this is children younger than 4 months old with unexplained fever.

▸ Respiratory illness. Most respiratory illnesses do not require exclusion; however, a child with persistent coughing or trouble breathing should be evaluated for pneumonia, asthma, or serious respiratory infection, such as whooping cough.

▸ Earache, no fever. “This child should be excluded if he or she requires more care than the staff can reasonably provide,” said Dr. Jana. “Often, these kids are in a lot of pain and cannot participate in routine activities.”

▸ Lice. “Lice are a nuisance, but they're not a health hazard,” said Dr. Jana. “Children with lice should be excluded, but they don't have to be sent home right away. It can wait until the end of the day, and they can return once treatment occurs,” she said.

“Of course, all of these are recommendations, and while they are based in evidence, they are not binding,” Dr. Jana concluded.

Revised 'When to Exclude' Criteria

With the exception of the noted updates, most of the exclusion criteria outlined in the revised “Managing Infectious Diseases in Child Care and Schools” are consistent with the national illness exclusion guidelines published jointly in 2002 by the AAP, APHA, the Maternal and Child Health Bureau, and the National Resource Center for Health and Safety in Child Care. These include:

▸ Tuberculosis, until an appropriate health care provider or health official certifies that the child is in appropriate therapy and can attend care.

▸ Impetigo, until 24 hours after treatment has been initiated.

▸ Chickenpox until all sores have dried and crusted (usually 6 days).

▸ Mumps, until 9 days after an onset of parotid gland swelling.

▸ Hepatitis A virus, until 1 week after an onset of illness or jaundice or as directed by the health department.

▸ Measles, until 4 days after an onset of rash.

▸ Rubella, until 6 days after an onset of rash.

▸ Fever, when accompanied by behavior changes or other symptoms such as a sore throat, rash, vomiting, diarrhea, earache, etc.

▸ Diarrhea (frequent, runny, watery stools).

▸ Blood in the stool not explained by dietary change, medication, or hard stool.

▸ Vomiting two or more times in a 24-hour period.

▸ Body rash with fever.

▸ Sore throat with fever and swollen glands or mouth sores with drooling.

▸ Severe coughing with the child getting red or blue in the face or making a high-pitched whooping sound after coughing.

▸ Persistent abdominal pain (more than 2 hours) or intermittent pain with other signs and symptoms.

▸ Signs of possible severe illness such as irritability, unusual tiredness, or neediness that compromises caregivers' ability to care for others.

▸ Uncontrolled coughing or wheezing, continuous crying, or difficulty breathing.

BOSTON — The recent finding that adverse reactions to antimicrobial agents cause more than 142,000 emergency department visits per year in the United States, and that the highest rate occurs in children under 1 year of age should be a wake-up call to health care providers to exercise caution when pulling out the prescription pad.

Dr. Barbara W. Stechenberg gave this warning at the annual meeting of the American Academy of Pediatrics.

The study used nationally representative surveillance data to estimate the rates of adverse events associated with systemic antibiotics and compared the results by antibiotic class, specific drug, and type of adverse event (Clin. Infect. Dis. 2008;47:735-43). Approximately half of the emergency department visits attributable to antimicrobial adverse events were for reactions to penicillins and half were for reactions to multiple other agents, according to researchers Dr. Nadine Shehab and her associates at the Centers for Disease Control and Prevention.

Although infants younger than 1 year accounted for only 6% of the emergency department visits, after controlling for prescription frequency, "the rate of visits [for antimicrobial-related adverse events] was highest in this age group," said Dr. Stechenberg, director of pediatric infectious diseases at Baystate Medical Center in Springfield, Mass.

The majority of adverse reactions seen in the above study—approximately 80%—were allergic reactions, ranging from rash to anaphylaxis, and the rest were toxicity related.

An awareness of the types of adverse reactions that can occur with different antimicrobial agents is critical to management, Dr. Stechenberg stressed. The following are some of the important points to consider with respect to different drug classes and specific drug reactions.

▸ Penicillins. "Penicillins are generally very safe. There is very little dose-related toxicity because of the wide dose range," said Dr. Stechenberg.

When immediate reactions to β-lactams, especially penicillins, do occur, they are often IgE mediated and typically present as urticaria. The more severe reactions include bronchospasm or hypertension, she said. "Most [IgE-mediated reactions] occur within the first 15-20 minutes, the vast majority in the first hour, but about 5% occur after the first hour, which is important to remember as you think about rechallenging someone with penicillin."

Among the late reactions to penicillins—which usually occur after 72 hours, often 5-10 days into the course of therapy—are maculopapular rashes and morbilliform rashes, often on the extremities, she said. More severe reactions include hemolytic anemia, neutropenia, and thrombocytopenia.

In terms of management, the timing and character of previous reactions is important. "Reactions late in the course are less likely to be IgE mediated. If the child previously had an idiopathic, nonpruritic late rash, you can consider giving the drug in the future," said Dr. Stechenberg. In patients with a history of immediate reactions or more severe late reactions, you wouldn't rechallenge with the same drug.

▸ Vancomycin. Most families think vancomycin hypersensitivity is an allergy. It's really a rate-dependent infusion reaction, said Dr. Stechenberg. It often happens on the first dose, which is different from anaphylaxis, and the rash is more likely to be a diffuse erythema, often on the upper trunk, face, and neck. The package insert states that the drug infusion shouldn't exceed 1 g over an hour. "Sometimes we have to modify that, but if there's a mild reaction, the best thing is to just stop the infusion and wait a short period, then restart at a slower rate," she said. "If there's a moderate reaction, one might want to treat with diphenhydramine and allow the symptoms to subside, then use a much longer rate." In patients with severe reactions, "you might have to use an alternate drug."

▸ Clindamycin. "The biggest issue with this drug is diarrhea. It's often mild and self-limited, which you can treat through. When it persists and is more severe, we worry about Clostridium difficile, which can have a wide range of presentations," Dr. Stechenberg said.

The first line of treatment for C. difficile is to stop the drug. "In 20%-25% of patients, this is all you need to do," Dr. Stechenberg said. If symptoms persist, "try oral metronidazole. We try not to use oral vancomycin because of concerns about vancomycin-resistant enterococcus, but for patients who can't tolerate or fail metronidazole, oral vancomycin is an option," she said. Another option is linezolid, but it is expensive and has been associated with thrombocytopenia in adults.

▸ Trim/sulfa. This broad-spectrum antibiotic "has been around for a long time, but it has new life in the therapy of methicillin-resistant Staph aureus," said Dr. Stechenberg. It has a reputation as a drug that can cause a rash because a lot of HIV patients who took it developed rashes. In the general population, however, the incidence of rash is fairly low, she said.

▸ Azithromycin. The most common reaction with this drug is gastrointestinal upset. "These are side effects, not allergy. Some people just cannot tolerate macrolides," Dr. Stechenberg noted. Although rash is uncommon with azithromycin, "when it does occur, it lasts for a long time. One of the nice things about this drug is that treatment is only for 5 days because it stays in the body for a long time, but that means when there's rash, it will persist," she said.

▸ Doxycycline. Concerns about tooth staining "have led to a magic cutoff age of 8-9 years old for doxycycline, after the eruption of maxillary central incisors," said Dr. Stechenberg. "In reality, tooth staining results from multiple courses of the drug over long periods."

Photosensitivity dermatitis also is a concern with doxycycline, but this can be prevented with anticipatory guidance regarding the use of broad-spectrum sunscreen and sun avoidance, she said.

▸ Fluoroquinolones. Small studies have shown that fluoroquinolones are reasonably safe in children, "but they should be reserved for patients who have no other reasonable options," she said. "Advise patients to report any joint pain so the medication can be stopped before the possibility of tendon rupture."

▸ Acyclovir. "This is a fairly safe drug to use in children," said Dr. Stechenberg. However, because it is excreted in the kidney almost unchanged, it can cause renal tubular dysfunction, crystalline nephropathy, and interstitial nephritis. She reported having no disclosures related to her presentation.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The recent finding that adverse reactions to antimicrobial agents cause more than 142,000 emergency department visits per year in the United States, and that the highest rate occurs in children under 1 year of age should be a wake-up call to health care providers to exercise caution when pulling out the prescription pad.

Dr. Barbara W. Stechenberg gave this warning at the annual meeting of the American Academy of Pediatrics.

The study used nationally representative surveillance data to estimate the rates of adverse events associated with systemic antibiotics and compared the results by antibiotic class, specific drug, and type of adverse event (Clin. Infect. Dis. 2008;47:735-43). Approximately half of the emergency department visits attributable to antimicrobial adverse events were for reactions to penicillins and half were for reactions to multiple other agents, according to researchers Dr. Nadine Shehab and her associates at the Centers for Disease Control and Prevention.

Although infants younger than 1 year accounted for only 6% of the emergency department visits, after controlling for prescription frequency, "the rate of visits [for antimicrobial-related adverse events] was highest in this age group," said Dr. Stechenberg, director of pediatric infectious diseases at Baystate Medical Center in Springfield, Mass.

The majority of adverse reactions seen in the above study—approximately 80%—were allergic reactions, ranging from rash to anaphylaxis, and the rest were toxicity related.

An awareness of the types of adverse reactions that can occur with different antimicrobial agents is critical to management, Dr. Stechenberg stressed. The following are some of the important points to consider with respect to different drug classes and specific drug reactions.

▸ Penicillins. "Penicillins are generally very safe. There is very little dose-related toxicity because of the wide dose range," said Dr. Stechenberg.

When immediate reactions to β-lactams, especially penicillins, do occur, they are often IgE mediated and typically present as urticaria. The more severe reactions include bronchospasm or hypertension, she said. "Most [IgE-mediated reactions] occur within the first 15-20 minutes, the vast majority in the first hour, but about 5% occur after the first hour, which is important to remember as you think about rechallenging someone with penicillin."

Among the late reactions to penicillins—which usually occur after 72 hours, often 5-10 days into the course of therapy—are maculopapular rashes and morbilliform rashes, often on the extremities, she said. More severe reactions include hemolytic anemia, neutropenia, and thrombocytopenia.

In terms of management, the timing and character of previous reactions is important. "Reactions late in the course are less likely to be IgE mediated. If the child previously had an idiopathic, nonpruritic late rash, you can consider giving the drug in the future," said Dr. Stechenberg. In patients with a history of immediate reactions or more severe late reactions, you wouldn't rechallenge with the same drug.

▸ Vancomycin. Most families think vancomycin hypersensitivity is an allergy. It's really a rate-dependent infusion reaction, said Dr. Stechenberg. It often happens on the first dose, which is different from anaphylaxis, and the rash is more likely to be a diffuse erythema, often on the upper trunk, face, and neck. The package insert states that the drug infusion shouldn't exceed 1 g over an hour. "Sometimes we have to modify that, but if there's a mild reaction, the best thing is to just stop the infusion and wait a short period, then restart at a slower rate," she said. "If there's a moderate reaction, one might want to treat with diphenhydramine and allow the symptoms to subside, then use a much longer rate." In patients with severe reactions, "you might have to use an alternate drug."

▸ Clindamycin. "The biggest issue with this drug is diarrhea. It's often mild and self-limited, which you can treat through. When it persists and is more severe, we worry about Clostridium difficile, which can have a wide range of presentations," Dr. Stechenberg said.

The first line of treatment for C. difficile is to stop the drug. "In 20%-25% of patients, this is all you need to do," Dr. Stechenberg said. If symptoms persist, "try oral metronidazole. We try not to use oral vancomycin because of concerns about vancomycin-resistant enterococcus, but for patients who can't tolerate or fail metronidazole, oral vancomycin is an option," she said. Another option is linezolid, but it is expensive and has been associated with thrombocytopenia in adults.

▸ Trim/sulfa. This broad-spectrum antibiotic "has been around for a long time, but it has new life in the therapy of methicillin-resistant Staph aureus," said Dr. Stechenberg. It has a reputation as a drug that can cause a rash because a lot of HIV patients who took it developed rashes. In the general population, however, the incidence of rash is fairly low, she said.

▸ Azithromycin. The most common reaction with this drug is gastrointestinal upset. "These are side effects, not allergy. Some people just cannot tolerate macrolides," Dr. Stechenberg noted. Although rash is uncommon with azithromycin, "when it does occur, it lasts for a long time. One of the nice things about this drug is that treatment is only for 5 days because it stays in the body for a long time, but that means when there's rash, it will persist," she said.

▸ Doxycycline. Concerns about tooth staining "have led to a magic cutoff age of 8-9 years old for doxycycline, after the eruption of maxillary central incisors," said Dr. Stechenberg. "In reality, tooth staining results from multiple courses of the drug over long periods."

Photosensitivity dermatitis also is a concern with doxycycline, but this can be prevented with anticipatory guidance regarding the use of broad-spectrum sunscreen and sun avoidance, she said.

▸ Fluoroquinolones. Small studies have shown that fluoroquinolones are reasonably safe in children, "but they should be reserved for patients who have no other reasonable options," she said. "Advise patients to report any joint pain so the medication can be stopped before the possibility of tendon rupture."

▸ Acyclovir. "This is a fairly safe drug to use in children," said Dr. Stechenberg. However, because it is excreted in the kidney almost unchanged, it can cause renal tubular dysfunction, crystalline nephropathy, and interstitial nephritis. She reported having no disclosures related to her presentation.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The recent finding that adverse reactions to antimicrobial agents cause more than 142,000 emergency department visits per year in the United States, and that the highest rate occurs in children under 1 year of age should be a wake-up call to health care providers to exercise caution when pulling out the prescription pad.

Dr. Barbara W. Stechenberg gave this warning at the annual meeting of the American Academy of Pediatrics.

The study used nationally representative surveillance data to estimate the rates of adverse events associated with systemic antibiotics and compared the results by antibiotic class, specific drug, and type of adverse event (Clin. Infect. Dis. 2008;47:735-43). Approximately half of the emergency department visits attributable to antimicrobial adverse events were for reactions to penicillins and half were for reactions to multiple other agents, according to researchers Dr. Nadine Shehab and her associates at the Centers for Disease Control and Prevention.

Although infants younger than 1 year accounted for only 6% of the emergency department visits, after controlling for prescription frequency, "the rate of visits [for antimicrobial-related adverse events] was highest in this age group," said Dr. Stechenberg, director of pediatric infectious diseases at Baystate Medical Center in Springfield, Mass.

The majority of adverse reactions seen in the above study—approximately 80%—were allergic reactions, ranging from rash to anaphylaxis, and the rest were toxicity related.

An awareness of the types of adverse reactions that can occur with different antimicrobial agents is critical to management, Dr. Stechenberg stressed. The following are some of the important points to consider with respect to different drug classes and specific drug reactions.

▸ Penicillins. "Penicillins are generally very safe. There is very little dose-related toxicity because of the wide dose range," said Dr. Stechenberg.

When immediate reactions to β-lactams, especially penicillins, do occur, they are often IgE mediated and typically present as urticaria. The more severe reactions include bronchospasm or hypertension, she said. "Most [IgE-mediated reactions] occur within the first 15-20 minutes, the vast majority in the first hour, but about 5% occur after the first hour, which is important to remember as you think about rechallenging someone with penicillin."

Among the late reactions to penicillins—which usually occur after 72 hours, often 5-10 days into the course of therapy—are maculopapular rashes and morbilliform rashes, often on the extremities, she said. More severe reactions include hemolytic anemia, neutropenia, and thrombocytopenia.

In terms of management, the timing and character of previous reactions is important. "Reactions late in the course are less likely to be IgE mediated. If the child previously had an idiopathic, nonpruritic late rash, you can consider giving the drug in the future," said Dr. Stechenberg. In patients with a history of immediate reactions or more severe late reactions, you wouldn't rechallenge with the same drug.

▸ Vancomycin. Most families think vancomycin hypersensitivity is an allergy. It's really a rate-dependent infusion reaction, said Dr. Stechenberg. It often happens on the first dose, which is different from anaphylaxis, and the rash is more likely to be a diffuse erythema, often on the upper trunk, face, and neck. The package insert states that the drug infusion shouldn't exceed 1 g over an hour. "Sometimes we have to modify that, but if there's a mild reaction, the best thing is to just stop the infusion and wait a short period, then restart at a slower rate," she said. "If there's a moderate reaction, one might want to treat with diphenhydramine and allow the symptoms to subside, then use a much longer rate." In patients with severe reactions, "you might have to use an alternate drug."

▸ Clindamycin. "The biggest issue with this drug is diarrhea. It's often mild and self-limited, which you can treat through. When it persists and is more severe, we worry about Clostridium difficile, which can have a wide range of presentations," Dr. Stechenberg said.

The first line of treatment for C. difficile is to stop the drug. "In 20%-25% of patients, this is all you need to do," Dr. Stechenberg said. If symptoms persist, "try oral metronidazole. We try not to use oral vancomycin because of concerns about vancomycin-resistant enterococcus, but for patients who can't tolerate or fail metronidazole, oral vancomycin is an option," she said. Another option is linezolid, but it is expensive and has been associated with thrombocytopenia in adults.

▸ Trim/sulfa. This broad-spectrum antibiotic "has been around for a long time, but it has new life in the therapy of methicillin-resistant Staph aureus," said Dr. Stechenberg. It has a reputation as a drug that can cause a rash because a lot of HIV patients who took it developed rashes. In the general population, however, the incidence of rash is fairly low, she said.

▸ Azithromycin. The most common reaction with this drug is gastrointestinal upset. "These are side effects, not allergy. Some people just cannot tolerate macrolides," Dr. Stechenberg noted. Although rash is uncommon with azithromycin, "when it does occur, it lasts for a long time. One of the nice things about this drug is that treatment is only for 5 days because it stays in the body for a long time, but that means when there's rash, it will persist," she said.

▸ Doxycycline. Concerns about tooth staining "have led to a magic cutoff age of 8-9 years old for doxycycline, after the eruption of maxillary central incisors," said Dr. Stechenberg. "In reality, tooth staining results from multiple courses of the drug over long periods."

Photosensitivity dermatitis also is a concern with doxycycline, but this can be prevented with anticipatory guidance regarding the use of broad-spectrum sunscreen and sun avoidance, she said.

▸ Fluoroquinolones. Small studies have shown that fluoroquinolones are reasonably safe in children, "but they should be reserved for patients who have no other reasonable options," she said. "Advise patients to report any joint pain so the medication can be stopped before the possibility of tendon rupture."

▸ Acyclovir. "This is a fairly safe drug to use in children," said Dr. Stechenberg. However, because it is excreted in the kidney almost unchanged, it can cause renal tubular dysfunction, crystalline nephropathy, and interstitial nephritis. She reported having no disclosures related to her presentation.

ELSEVIER GLOBAL MEDICAL NEWS

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, thus drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725-33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1-2 weeks of treatment initiation.

▸ Modify treatment if there is not an adequate response within 6-8 weeks.

▸ Continue treatment for 4-9 months after a satisfactory response in patients with a first episode of major depressive disorder; and consider longer treatment after a response in patients who have had two or more episodes of depression.

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, thus drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725-33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1-2 weeks of treatment initiation.

▸ Modify treatment if there is not an adequate response within 6-8 weeks.

▸ Continue treatment for 4-9 months after a satisfactory response in patients with a first episode of major depressive disorder; and consider longer treatment after a response in patients who have had two or more episodes of depression.

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, thus drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725-33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1-2 weeks of treatment initiation.

▸ Modify treatment if there is not an adequate response within 6-8 weeks.

▸ Continue treatment for 4-9 months after a satisfactory response in patients with a first episode of major depressive disorder; and consider longer treatment after a response in patients who have had two or more episodes of depression.

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, so drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

They also determined that the efficacy and effectiveness of the various agents did not differ among subgroups based on age, sex, race, or ethnicity.

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725–33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. “In addition, SSRIs are associated with an increased risk for suicide attempts compared with placebo.”

The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1–2 weeks of treatment initiation.

▸ Modify treatment if the patient does not have an adequate response within 6–8 weeks.

▸ Continue treatment for 4–9 months after a satisfactory response in patients with a first episode of major depressive disorder, and consider longer treatment after a satisfactory response in patients who have had two or more episodes of depression.

The authors stress the importance of monitoring patients for behavioral changes that could indicate a worsening of depression and note that the risk for suicide attempts is greater during the first 2 months of treatment than during other times. Additionally, they state that “one of the most important aspects of care is assessing the response to treatment and making necessary changes in therapy,” including adding other therapeutic modalities or alternate drugs.

Acknowledging that other treatment approaches, such as cognitive-behavioral therapy and psychotherapy, can be used in the management of depression, “the scope of this guideline is limited to pharmacotherapy with second-generation antidepressants,” the authors wrote.

The American College of Physicians' recommendations are in line with the current treatment guidelines of the American Psychiatric Association, according to Dr. James Jefferson of the University of Wisconsin, Madison. “In general, I agree with the [ACP] recommendations, although I am sure various pharmaceutical companies are going to be going over them with a fine-toothed comb,” he said in an interview. The focus on drug therapy alone is not inappropriate, he noted, stating that the authors “had a very specific goal.”

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, so drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

They also determined that the efficacy and effectiveness of the various agents did not differ among subgroups based on age, sex, race, or ethnicity.

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725–33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. “In addition, SSRIs are associated with an increased risk for suicide attempts compared with placebo.”

The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1–2 weeks of treatment initiation.

▸ Modify treatment if the patient does not have an adequate response within 6–8 weeks.

▸ Continue treatment for 4–9 months after a satisfactory response in patients with a first episode of major depressive disorder, and consider longer treatment after a satisfactory response in patients who have had two or more episodes of depression.

The authors stress the importance of monitoring patients for behavioral changes that could indicate a worsening of depression and note that the risk for suicide attempts is greater during the first 2 months of treatment than during other times. Additionally, they state that “one of the most important aspects of care is assessing the response to treatment and making necessary changes in therapy,” including adding other therapeutic modalities or alternate drugs.

Acknowledging that other treatment approaches, such as cognitive-behavioral therapy and psychotherapy, can be used in the management of depression, “the scope of this guideline is limited to pharmacotherapy with second-generation antidepressants,” the authors wrote.

The American College of Physicians' recommendations are in line with the current treatment guidelines of the American Psychiatric Association, according to Dr. James Jefferson of the University of Wisconsin, Madison. “In general, I agree with the [ACP] recommendations, although I am sure various pharmaceutical companies are going to be going over them with a fine-toothed comb,” he said in an interview. The focus on drug therapy alone is not inappropriate, he noted, stating that the authors “had a very specific goal.”

Second-generation antidepressants are similarly effective in the treatment of major depression in adults, so drug selection should be driven by adverse event profile, cost, and patient preference, according to a clinical practice guideline issued by the American College of Physicians.

Basing their conclusions on evidence derived from 203 clinical studies involving selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and selective serotonin norepinephrine reuptake inhibitors (SSNRIs), the guideline authors wrote that “existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness.”

They also determined that the efficacy and effectiveness of the various agents did not differ among subgroups based on age, sex, race, or ethnicity.

Because the various agents are associated with different adverse events, “physicians and patients should discuss adverse event profiles before selecting a medication,” the authors wrote (Ann. Intern. Med. 2008;149:725–33).

For example, although sexual dysfunction is a commonly reported adverse event associated with second-generation antidepressants, “bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline, whereas paroxetine has higher rates of sexual dysfunction than fluoxetine, fluvoxamine, nefazodone, or sertraline,” they stated. “In addition, SSRIs are associated with an increased risk for suicide attempts compared with placebo.”

The practice guideline also recommends that clinicians:

▸ Regularly assess patient status, therapeutic response, and adverse effects of antidepressant therapy beginning within 1–2 weeks of treatment initiation.

▸ Modify treatment if the patient does not have an adequate response within 6–8 weeks.

▸ Continue treatment for 4–9 months after a satisfactory response in patients with a first episode of major depressive disorder, and consider longer treatment after a satisfactory response in patients who have had two or more episodes of depression.

The authors stress the importance of monitoring patients for behavioral changes that could indicate a worsening of depression and note that the risk for suicide attempts is greater during the first 2 months of treatment than during other times. Additionally, they state that “one of the most important aspects of care is assessing the response to treatment and making necessary changes in therapy,” including adding other therapeutic modalities or alternate drugs.

Acknowledging that other treatment approaches, such as cognitive-behavioral therapy and psychotherapy, can be used in the management of depression, “the scope of this guideline is limited to pharmacotherapy with second-generation antidepressants,” the authors wrote.

The American College of Physicians' recommendations are in line with the current treatment guidelines of the American Psychiatric Association, according to Dr. James Jefferson of the University of Wisconsin, Madison. “In general, I agree with the [ACP] recommendations, although I am sure various pharmaceutical companies are going to be going over them with a fine-toothed comb,” he said in an interview. The focus on drug therapy alone is not inappropriate, he noted, stating that the authors “had a very specific goal.”

The unique lifetime care needs of adults with congenital heart disease—particularly young adults who are making the transition out of pediatric cardiology care—are the focus of new practice guidelines released jointly by the American College of Cardiology and the American Heart Association.

The first of their kind in the United States, the adult congenital heart disease (CHD) guidelines are designed to help cardiologists make routine clinical decisions for the ever-increasing number of patients who, thanks to advances in the treatment of CHD, are now surviving into adulthood but are doing so with complex cardiac anatomy and physiology related to the repaired heart defects, according to Dr. Carole A. Warnes and her colleagues on the American College of Cardiology/American Heart Association guidelines writing committee. “In particular, there are a substantial number of young adults with single-ventricle physiology, systemic right ventricles, or complex intracardiac baffles who are now entering adult life,” the authors wrote in the executive summary of the guidelines (J. Am. Coll. Cardiol. 2008;52:1–121; Circulation 2008;118:2395–451).

The infrastructure of most pediatric cardiology centers supports the multiple unique needs of children with CHD through, for example, comprehensive case management by advanced practice nurses and social workers, but the adult health care system is not similarly structured, the authors noted. Additionally, “young adults have many psychological, social, and financial issues that present barriers to proactive health management,” they wrote. In an effort to minimize “the compound effects of a complex and unfamiliar disease with an unprepared patient and healthcare system,” the practice guidelines outline the most important diagnostic and management strategies and indicate when to refer patients to a highly specialized center.

Improving the delivery of care and ensuring access to care figure prominently in the recommendations. The guidelines include these recommendations:

▸ Care of adult CHD patients should be coordinated by regional centers of excellence.

▸ Adult CHD patients should carry a complete “medical passport” containing their medical histories and contact information for the regional centers of excellence.

▸ Designated health care guardians should be included in the medical decision-making process for patients whose care is complicated by additional special needs.

▸ Patients should have a primary care physician and a local cardiovascular specialist, each of whom has copies of current clinical records on file.

▸ Patients should establish a relationship with a regional adult CHD center to ensure the availability of care when needed.

The guidelines specify that, in the absence of specific training or experience in adult CHD, primary caregivers and cardiologists of patients with CHD should work in collaboration with trained specialists, and patients should have access to specialized follow-up care. For example, the guidelines state that patients with low-risk, simple CHD should have at least one follow-up at a regional adult CHD center, while more frequent follow-up (every 12–24 months) is advised for “adults with complex and moderate CHD.”

Additionally, certain clinical scenarios warrant consultation with, treatment at, or transfer to a regional adult CHD center. Such scenarios include hospital admission for urgent or acute care in most cases, the performance of diagnostic or interventional procedures, surgical procedures requiring general anesthesia or conscious sedation, urgent or acute care of cardiac problems, and urgent or acute care of noncardiac problems in high-risk patients.

The guidelines also address the psychosocial needs of adult CHD patients with the recommendation that the comprehensive care of these patients should incorporate individual and family psychosocial screening, counseling, and education regarding the possible social, emotional, and vocational impact of CHD.

Because CHD patients are at increased risk for infectious endocarditis, it is important that patients and their families be educated about the signs and symptoms of infectious complications, as well as how to prevent them, according to the authors. Specifically, the guidelines recommend antibiotic prophylaxis in high-risk CHD patients “before dental procedures that involved manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa.” However, antibiotic prophylaxis against infectious endocarditis “is not recommended for nondental procedures [such as esophagogastroduodenoscopy or colonoscopy] in the absence of active infection,” the guidelines state.

Pregnancy and contraception require special consideration in women with CHD. With respect to contraception, oral estrogen-containing drugs are not recommended for patients at risk of thromboembolism, including those with pulmonary arterial hypertension or cyanosis related to an intracardiac shunt, according to the guidelines. Patients are advised to consult with an adult CHD expert to determine a labor and delivery management plan prior to becoming pregnant.

In addition to the general recommendations for the care of adult CHD patients, the guidelines also include comprehensive information on the clinical features, diagnosis, treatment, and preventive strategies related to specific lesions.

Although the guideline recommendations are evidence based wherever possible, “unlike other ACC/AHA practice guidelines, there is not a large body of peer-reviewed published evidence to support most recommendations,” the authors wrote. For this reason, the evidence supporting many of the recommendations comes from the consensus of experts.

An increasing number of patients are now surviving into adulthood with complex cardiac anatomy and physiology. DR. WARNES

The unique lifetime care needs of adults with congenital heart disease—particularly young adults who are making the transition out of pediatric cardiology care—are the focus of new practice guidelines released jointly by the American College of Cardiology and the American Heart Association.

The first of their kind in the United States, the adult congenital heart disease (CHD) guidelines are designed to help cardiologists make routine clinical decisions for the ever-increasing number of patients who, thanks to advances in the treatment of CHD, are now surviving into adulthood but are doing so with complex cardiac anatomy and physiology related to the repaired heart defects, according to Dr. Carole A. Warnes and her colleagues on the American College of Cardiology/American Heart Association guidelines writing committee. “In particular, there are a substantial number of young adults with single-ventricle physiology, systemic right ventricles, or complex intracardiac baffles who are now entering adult life,” the authors wrote in the executive summary of the guidelines (J. Am. Coll. Cardiol. 2008;52:1–121; Circulation 2008;118:2395–451).

The infrastructure of most pediatric cardiology centers supports the multiple unique needs of children with CHD through, for example, comprehensive case management by advanced practice nurses and social workers, but the adult health care system is not similarly structured, the authors noted. Additionally, “young adults have many psychological, social, and financial issues that present barriers to proactive health management,” they wrote. In an effort to minimize “the compound effects of a complex and unfamiliar disease with an unprepared patient and healthcare system,” the practice guidelines outline the most important diagnostic and management strategies and indicate when to refer patients to a highly specialized center.

Improving the delivery of care and ensuring access to care figure prominently in the recommendations. The guidelines include these recommendations:

▸ Care of adult CHD patients should be coordinated by regional centers of excellence.

▸ Adult CHD patients should carry a complete “medical passport” containing their medical histories and contact information for the regional centers of excellence.

▸ Designated health care guardians should be included in the medical decision-making process for patients whose care is complicated by additional special needs.

▸ Patients should have a primary care physician and a local cardiovascular specialist, each of whom has copies of current clinical records on file.

▸ Patients should establish a relationship with a regional adult CHD center to ensure the availability of care when needed.

The guidelines specify that, in the absence of specific training or experience in adult CHD, primary caregivers and cardiologists of patients with CHD should work in collaboration with trained specialists, and patients should have access to specialized follow-up care. For example, the guidelines state that patients with low-risk, simple CHD should have at least one follow-up at a regional adult CHD center, while more frequent follow-up (every 12–24 months) is advised for “adults with complex and moderate CHD.”

Additionally, certain clinical scenarios warrant consultation with, treatment at, or transfer to a regional adult CHD center. Such scenarios include hospital admission for urgent or acute care in most cases, the performance of diagnostic or interventional procedures, surgical procedures requiring general anesthesia or conscious sedation, urgent or acute care of cardiac problems, and urgent or acute care of noncardiac problems in high-risk patients.

The guidelines also address the psychosocial needs of adult CHD patients with the recommendation that the comprehensive care of these patients should incorporate individual and family psychosocial screening, counseling, and education regarding the possible social, emotional, and vocational impact of CHD.

Because CHD patients are at increased risk for infectious endocarditis, it is important that patients and their families be educated about the signs and symptoms of infectious complications, as well as how to prevent them, according to the authors. Specifically, the guidelines recommend antibiotic prophylaxis in high-risk CHD patients “before dental procedures that involved manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa.” However, antibiotic prophylaxis against infectious endocarditis “is not recommended for nondental procedures [such as esophagogastroduodenoscopy or colonoscopy] in the absence of active infection,” the guidelines state.

Pregnancy and contraception require special consideration in women with CHD. With respect to contraception, oral estrogen-containing drugs are not recommended for patients at risk of thromboembolism, including those with pulmonary arterial hypertension or cyanosis related to an intracardiac shunt, according to the guidelines. Patients are advised to consult with an adult CHD expert to determine a labor and delivery management plan prior to becoming pregnant.

In addition to the general recommendations for the care of adult CHD patients, the guidelines also include comprehensive information on the clinical features, diagnosis, treatment, and preventive strategies related to specific lesions.

Although the guideline recommendations are evidence based wherever possible, “unlike other ACC/AHA practice guidelines, there is not a large body of peer-reviewed published evidence to support most recommendations,” the authors wrote. For this reason, the evidence supporting many of the recommendations comes from the consensus of experts.

An increasing number of patients are now surviving into adulthood with complex cardiac anatomy and physiology. DR. WARNES

The unique lifetime care needs of adults with congenital heart disease—particularly young adults who are making the transition out of pediatric cardiology care—are the focus of new practice guidelines released jointly by the American College of Cardiology and the American Heart Association.

The first of their kind in the United States, the adult congenital heart disease (CHD) guidelines are designed to help cardiologists make routine clinical decisions for the ever-increasing number of patients who, thanks to advances in the treatment of CHD, are now surviving into adulthood but are doing so with complex cardiac anatomy and physiology related to the repaired heart defects, according to Dr. Carole A. Warnes and her colleagues on the American College of Cardiology/American Heart Association guidelines writing committee. “In particular, there are a substantial number of young adults with single-ventricle physiology, systemic right ventricles, or complex intracardiac baffles who are now entering adult life,” the authors wrote in the executive summary of the guidelines (J. Am. Coll. Cardiol. 2008;52:1–121; Circulation 2008;118:2395–451).

The infrastructure of most pediatric cardiology centers supports the multiple unique needs of children with CHD through, for example, comprehensive case management by advanced practice nurses and social workers, but the adult health care system is not similarly structured, the authors noted. Additionally, “young adults have many psychological, social, and financial issues that present barriers to proactive health management,” they wrote. In an effort to minimize “the compound effects of a complex and unfamiliar disease with an unprepared patient and healthcare system,” the practice guidelines outline the most important diagnostic and management strategies and indicate when to refer patients to a highly specialized center.

Improving the delivery of care and ensuring access to care figure prominently in the recommendations. The guidelines include these recommendations:

▸ Care of adult CHD patients should be coordinated by regional centers of excellence.

▸ Adult CHD patients should carry a complete “medical passport” containing their medical histories and contact information for the regional centers of excellence.

▸ Designated health care guardians should be included in the medical decision-making process for patients whose care is complicated by additional special needs.

▸ Patients should have a primary care physician and a local cardiovascular specialist, each of whom has copies of current clinical records on file.

▸ Patients should establish a relationship with a regional adult CHD center to ensure the availability of care when needed.

The guidelines specify that, in the absence of specific training or experience in adult CHD, primary caregivers and cardiologists of patients with CHD should work in collaboration with trained specialists, and patients should have access to specialized follow-up care. For example, the guidelines state that patients with low-risk, simple CHD should have at least one follow-up at a regional adult CHD center, while more frequent follow-up (every 12–24 months) is advised for “adults with complex and moderate CHD.”

Additionally, certain clinical scenarios warrant consultation with, treatment at, or transfer to a regional adult CHD center. Such scenarios include hospital admission for urgent or acute care in most cases, the performance of diagnostic or interventional procedures, surgical procedures requiring general anesthesia or conscious sedation, urgent or acute care of cardiac problems, and urgent or acute care of noncardiac problems in high-risk patients.

The guidelines also address the psychosocial needs of adult CHD patients with the recommendation that the comprehensive care of these patients should incorporate individual and family psychosocial screening, counseling, and education regarding the possible social, emotional, and vocational impact of CHD.

Because CHD patients are at increased risk for infectious endocarditis, it is important that patients and their families be educated about the signs and symptoms of infectious complications, as well as how to prevent them, according to the authors. Specifically, the guidelines recommend antibiotic prophylaxis in high-risk CHD patients “before dental procedures that involved manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa.” However, antibiotic prophylaxis against infectious endocarditis “is not recommended for nondental procedures [such as esophagogastroduodenoscopy or colonoscopy] in the absence of active infection,” the guidelines state.

Pregnancy and contraception require special consideration in women with CHD. With respect to contraception, oral estrogen-containing drugs are not recommended for patients at risk of thromboembolism, including those with pulmonary arterial hypertension or cyanosis related to an intracardiac shunt, according to the guidelines. Patients are advised to consult with an adult CHD expert to determine a labor and delivery management plan prior to becoming pregnant.

In addition to the general recommendations for the care of adult CHD patients, the guidelines also include comprehensive information on the clinical features, diagnosis, treatment, and preventive strategies related to specific lesions.

Although the guideline recommendations are evidence based wherever possible, “unlike other ACC/AHA practice guidelines, there is not a large body of peer-reviewed published evidence to support most recommendations,” the authors wrote. For this reason, the evidence supporting many of the recommendations comes from the consensus of experts.

An increasing number of patients are now surviving into adulthood with complex cardiac anatomy and physiology. DR. WARNES