Diana Mahoney

The salivary glands of children with oligoarticular-type juvenile idiopathic arthritis may be targets of inflammatory, oxidative stress-mediated injury, a study has shown.

In an investigation of the salivary gland involvement and saliva and serum antioxidant profiles in patients with juvenile idiopathic arthritis (JIA), Dr. Riva Brik of Meyer Children's Hospital in Haifa, Israel, and colleagues observed a major increase in antioxidant enzyme activity in the serum and saliva of children with systemic, polyarticular, and oligoarticular-type disease, as well as significant and specific damage to the salivary glands in those children with oligoarticular JIA.

Although there is a scarcity of data on salivary gland involvement or alterations in JIA, previous studies in adults with rheumatoid arthritis have shown direct relationships between disease severity and increased levels of antioxidant enzymes in secreted saliva and serum, suggesting that saliva—which is easier and less invasive to collect—might be suitable as a window into serum composition in children. Because adult studies also have identified oxidative stress as a major contributing factor to the chronic inflammatory process within the inflamed joint, the ability to measure such changes in saliva could have therapeutic implications in JIA (J. Rheumatol. 2006;33:2532–7).

Toward this end, the investigators studied the salivary composition and the saliva and serum antioxidant profiles of 22 children with JIA according to the American College of Rheumatology criteria and 15 healthy controls. Of the children with JIA, 10 had oligoarticular, 7 had polyarticular, and 5 had systemic-type disease. The mean age of the 15 girls and 7 boys with JIA was 12.2 years and the mean durations of follow-up and disease activity were 5.8 years and 5.1 years, respectively.

Saliva and serum samples were obtained concomitantly from each study participant. Saliva was analyzed for flow rate (volume of saliva secreted per minute), chemistry (pH, calcium, phosphate, magnesium, total protein, albumin, lactate dehydrogenase, and amylase), total antioxidant status, peroxidase activity, and uric acid. Serum was analyzed for total antioxidant status, peroxidase activity, uric acid, total protein, and albumin.

The analyses showed that the median salivary flow rates of the JIA patients as a whole were within normal range and were similar to those of the healthy controls. The median flow rate of children with oligoarticular arthritis was 33% lower than that of the control group. The difference did not reach statistical significance, however, due to the large standard error values, according to the authors.

Sialochemistry analysis findings indicated the saliva composition in children with oligoarticular JIA contained significantly lower levels of magnesium, total protein, amylase, and lactate dehydrogenase compared with the other JIA subtypes. Additionally, levels of salivary calcium and phosphate were low, bordering on a statistically significant difference. Compared with controls, there were no significant differences between the total JIA group and the healthy controls in measures of salivary calcium and albumin; however, patients with systemic disease showed increased levels of salivary total protein and polyarticular patients had significantly increased levels of amylase. Salivary pH was higher in all of the JIA patients compared with controls, and was highest in the oligoarticular group.

The salivary antioxidant analyses showed that salivary peroxidase activity was significantly higher (8.5%) in the JIA group as a whole compared with controls, and most notably among the polyarticular group, whose levels were 17% higher than controls. The antioxidant enzyme superoxide dismutase was significantly increased in the JIA patients, particularly in those with systemic-type disease in whom a 74% increase was noted, the authors wrote. Measures of salivary uric acid and total antioxidant status in the JIA patients were not statistically different from those of the controls. The results of the serum analyses showed significantly higher levels of serum peroxidase activity in the JIA group, with the maximal increase of 17% observed in the polyarticular subgroup. All of the JIA subgroups showed nonsignificant reductions in uric acid concentrations compared with controls and nonsignificant differences in total antioxidant status. A significant increase in serum albumin concentrations was seen in all three JIA subgroups, with a mean 9.3% increase in the total group compared with the control group.

“Our main finding was significant alterations in the saliva of patients with oligoarticular JIA compared to controls and also to other patients with JIA,” the authors wrote. “Whereas the total group of patients showed increased levels of antioxidant enzyme activity both in serum and in saliva, presumably as a result of the ongoing inflammatory process, only the patients with oligoarticular-type disease showed evidence of specific injury to the salivary glands, as reflected by a reduced salivary flow rate, low levels of amylase and LDH activity, and lower concentrations of total proteins.” The changes observed in the saliva of the children with oligoarticular-type disease “may designate the salivary glands [in similarity to joints] as target organs of inflammatory, oxidative stress-mediated injury,” they stated.

“We also showed that saliva is a reliable representative of serum composition and can be used for pertinent testing in children,” they noted.

The salivary glands of children with oligoarticular-type juvenile idiopathic arthritis may be targets of inflammatory, oxidative stress-mediated injury, a study has shown.

In an investigation of the salivary gland involvement and saliva and serum antioxidant profiles in patients with juvenile idiopathic arthritis (JIA), Dr. Riva Brik of Meyer Children's Hospital in Haifa, Israel, and colleagues observed a major increase in antioxidant enzyme activity in the serum and saliva of children with systemic, polyarticular, and oligoarticular-type disease, as well as significant and specific damage to the salivary glands in those children with oligoarticular JIA.

Although there is a scarcity of data on salivary gland involvement or alterations in JIA, previous studies in adults with rheumatoid arthritis have shown direct relationships between disease severity and increased levels of antioxidant enzymes in secreted saliva and serum, suggesting that saliva—which is easier and less invasive to collect—might be suitable as a window into serum composition in children. Because adult studies also have identified oxidative stress as a major contributing factor to the chronic inflammatory process within the inflamed joint, the ability to measure such changes in saliva could have therapeutic implications in JIA (J. Rheumatol. 2006;33:2532–7).

Toward this end, the investigators studied the salivary composition and the saliva and serum antioxidant profiles of 22 children with JIA according to the American College of Rheumatology criteria and 15 healthy controls. Of the children with JIA, 10 had oligoarticular, 7 had polyarticular, and 5 had systemic-type disease. The mean age of the 15 girls and 7 boys with JIA was 12.2 years and the mean durations of follow-up and disease activity were 5.8 years and 5.1 years, respectively.

Saliva and serum samples were obtained concomitantly from each study participant. Saliva was analyzed for flow rate (volume of saliva secreted per minute), chemistry (pH, calcium, phosphate, magnesium, total protein, albumin, lactate dehydrogenase, and amylase), total antioxidant status, peroxidase activity, and uric acid. Serum was analyzed for total antioxidant status, peroxidase activity, uric acid, total protein, and albumin.

The analyses showed that the median salivary flow rates of the JIA patients as a whole were within normal range and were similar to those of the healthy controls. The median flow rate of children with oligoarticular arthritis was 33% lower than that of the control group. The difference did not reach statistical significance, however, due to the large standard error values, according to the authors.

Sialochemistry analysis findings indicated the saliva composition in children with oligoarticular JIA contained significantly lower levels of magnesium, total protein, amylase, and lactate dehydrogenase compared with the other JIA subtypes. Additionally, levels of salivary calcium and phosphate were low, bordering on a statistically significant difference. Compared with controls, there were no significant differences between the total JIA group and the healthy controls in measures of salivary calcium and albumin; however, patients with systemic disease showed increased levels of salivary total protein and polyarticular patients had significantly increased levels of amylase. Salivary pH was higher in all of the JIA patients compared with controls, and was highest in the oligoarticular group.

The salivary antioxidant analyses showed that salivary peroxidase activity was significantly higher (8.5%) in the JIA group as a whole compared with controls, and most notably among the polyarticular group, whose levels were 17% higher than controls. The antioxidant enzyme superoxide dismutase was significantly increased in the JIA patients, particularly in those with systemic-type disease in whom a 74% increase was noted, the authors wrote. Measures of salivary uric acid and total antioxidant status in the JIA patients were not statistically different from those of the controls. The results of the serum analyses showed significantly higher levels of serum peroxidase activity in the JIA group, with the maximal increase of 17% observed in the polyarticular subgroup. All of the JIA subgroups showed nonsignificant reductions in uric acid concentrations compared with controls and nonsignificant differences in total antioxidant status. A significant increase in serum albumin concentrations was seen in all three JIA subgroups, with a mean 9.3% increase in the total group compared with the control group.

“Our main finding was significant alterations in the saliva of patients with oligoarticular JIA compared to controls and also to other patients with JIA,” the authors wrote. “Whereas the total group of patients showed increased levels of antioxidant enzyme activity both in serum and in saliva, presumably as a result of the ongoing inflammatory process, only the patients with oligoarticular-type disease showed evidence of specific injury to the salivary glands, as reflected by a reduced salivary flow rate, low levels of amylase and LDH activity, and lower concentrations of total proteins.” The changes observed in the saliva of the children with oligoarticular-type disease “may designate the salivary glands [in similarity to joints] as target organs of inflammatory, oxidative stress-mediated injury,” they stated.

“We also showed that saliva is a reliable representative of serum composition and can be used for pertinent testing in children,” they noted.

The salivary glands of children with oligoarticular-type juvenile idiopathic arthritis may be targets of inflammatory, oxidative stress-mediated injury, a study has shown.

In an investigation of the salivary gland involvement and saliva and serum antioxidant profiles in patients with juvenile idiopathic arthritis (JIA), Dr. Riva Brik of Meyer Children's Hospital in Haifa, Israel, and colleagues observed a major increase in antioxidant enzyme activity in the serum and saliva of children with systemic, polyarticular, and oligoarticular-type disease, as well as significant and specific damage to the salivary glands in those children with oligoarticular JIA.

Although there is a scarcity of data on salivary gland involvement or alterations in JIA, previous studies in adults with rheumatoid arthritis have shown direct relationships between disease severity and increased levels of antioxidant enzymes in secreted saliva and serum, suggesting that saliva—which is easier and less invasive to collect—might be suitable as a window into serum composition in children. Because adult studies also have identified oxidative stress as a major contributing factor to the chronic inflammatory process within the inflamed joint, the ability to measure such changes in saliva could have therapeutic implications in JIA (J. Rheumatol. 2006;33:2532–7).

Toward this end, the investigators studied the salivary composition and the saliva and serum antioxidant profiles of 22 children with JIA according to the American College of Rheumatology criteria and 15 healthy controls. Of the children with JIA, 10 had oligoarticular, 7 had polyarticular, and 5 had systemic-type disease. The mean age of the 15 girls and 7 boys with JIA was 12.2 years and the mean durations of follow-up and disease activity were 5.8 years and 5.1 years, respectively.

Saliva and serum samples were obtained concomitantly from each study participant. Saliva was analyzed for flow rate (volume of saliva secreted per minute), chemistry (pH, calcium, phosphate, magnesium, total protein, albumin, lactate dehydrogenase, and amylase), total antioxidant status, peroxidase activity, and uric acid. Serum was analyzed for total antioxidant status, peroxidase activity, uric acid, total protein, and albumin.

The analyses showed that the median salivary flow rates of the JIA patients as a whole were within normal range and were similar to those of the healthy controls. The median flow rate of children with oligoarticular arthritis was 33% lower than that of the control group. The difference did not reach statistical significance, however, due to the large standard error values, according to the authors.

Sialochemistry analysis findings indicated the saliva composition in children with oligoarticular JIA contained significantly lower levels of magnesium, total protein, amylase, and lactate dehydrogenase compared with the other JIA subtypes. Additionally, levels of salivary calcium and phosphate were low, bordering on a statistically significant difference. Compared with controls, there were no significant differences between the total JIA group and the healthy controls in measures of salivary calcium and albumin; however, patients with systemic disease showed increased levels of salivary total protein and polyarticular patients had significantly increased levels of amylase. Salivary pH was higher in all of the JIA patients compared with controls, and was highest in the oligoarticular group.

The salivary antioxidant analyses showed that salivary peroxidase activity was significantly higher (8.5%) in the JIA group as a whole compared with controls, and most notably among the polyarticular group, whose levels were 17% higher than controls. The antioxidant enzyme superoxide dismutase was significantly increased in the JIA patients, particularly in those with systemic-type disease in whom a 74% increase was noted, the authors wrote. Measures of salivary uric acid and total antioxidant status in the JIA patients were not statistically different from those of the controls. The results of the serum analyses showed significantly higher levels of serum peroxidase activity in the JIA group, with the maximal increase of 17% observed in the polyarticular subgroup. All of the JIA subgroups showed nonsignificant reductions in uric acid concentrations compared with controls and nonsignificant differences in total antioxidant status. A significant increase in serum albumin concentrations was seen in all three JIA subgroups, with a mean 9.3% increase in the total group compared with the control group.

“Our main finding was significant alterations in the saliva of patients with oligoarticular JIA compared to controls and also to other patients with JIA,” the authors wrote. “Whereas the total group of patients showed increased levels of antioxidant enzyme activity both in serum and in saliva, presumably as a result of the ongoing inflammatory process, only the patients with oligoarticular-type disease showed evidence of specific injury to the salivary glands, as reflected by a reduced salivary flow rate, low levels of amylase and LDH activity, and lower concentrations of total proteins.” The changes observed in the saliva of the children with oligoarticular-type disease “may designate the salivary glands [in similarity to joints] as target organs of inflammatory, oxidative stress-mediated injury,” they stated.

“We also showed that saliva is a reliable representative of serum composition and can be used for pertinent testing in children,” they noted.

TORONTO — Advances in the fight against human bocavirus, infant botulism, and severe rotavirus gastroenteritis were among the topics selected as the top new findings in pediatric infectious disease at the annual meeting of the Infectious Diseases Society of America.

“There has been a lot of activity in pediatric infectious diseases, with some important observations over the past year that will likely have an impact on clinical practice,” said Dr. Joseph W. St. Geme III of Duke University, Durham, N.C., who, along with Dr. Janet Englund of the University of Washington, Seattle, presented the past year's top findings in pediatric infectious disease.

Human Bocavirus

“One of the major problems in pediatrics continues to be respiratory tract infections,” said Dr. St. Geme. Along these lines, Dr. John C. Arnold and his colleagues assessed the prevalence and clinical spectrum of the recently identified human bocavirus (HBoV) among nearly 1,500 children aged 0–18 years who were treated for respiratory tract infection over a 20-month period at the Children's Hospital, San Diego (Clin. Infect. Dis. 2006;43:283–8).

The investigators screened by polymerase chain reaction 1,474 nasal scraping specimens that had been collected and frozen, and they found HBoV DNA in 5.6% of the specimens. The researchers noted that the peak infection rate was between March and May in both 2004 and 2005 and that 63% of the patients were younger than 12 months.

Evidence of underlying disease, including asthma, bronchopulmonary dysplasia, neuromuscular disease, and trisomy 21, was present in roughly one-third of the patients.

The most common symptoms were cough (present in 85% of cases), rhinorrhea, and fever. Clinical evidence of lower respiratory tract HBoV infection was present in 62% of the children, and nearly half of the patients had hypoxemia. Approximately 19% of HBoV-infected patients had paroxysmal cough, which led to further testing for pertussis.

Based on the findings, “it's clear that more widely available diagnostic testing for human bocavirus will be a priority in terms of establishing a better understanding of the epidemiology and clinical manifestations,” said Dr. St. Geme.

Influenza in Young Children

“In contrast to a new virus that we can't diagnose, influenza is an old virus that we can diagnose,” said Dr. Englund while presenting a paper on the burden of influenza in young children by Dr. Catherine Poehling of Vanderbilt University, Nashville, Tenn., and her colleagues at the Center for Disease Control and Prevention's New Vaccine Surveillance Network (N. Engl. J. Med. 2006;355:31–40).

The investigators used population-based surveillance to assess the disease burden of influenza among children younger than 5 years who were seeking medical care for acute respiratory tract infection or fever at clinics, emergency departments, and hospitals in three U.S. counties. They collected outpatient data during two influenza seasons—2002–2003 and 2003–2004 (when influenza vaccine was recommended for all children between 6 and 23 months)—and inpatient data from 2000 to 2004.

The average annual rate of hospitalization associated with influenza was 0.9 per 1,000 children in 2000–2004. The estimated burden of outpatient visits associated with influenza was 50 clinic visits and 6 emergency department visits per 1,000 children during the 2002–2003 season and 95 clinic visits and 27 emergency department visits per 1,000 children during the 2003–2004 season.

Of particular interest, Dr. Englund noted, was the fact that only 28% of the inpatient population and 17% of the outpatient population with laboratory- confirmed influenza received a discharge diagnosis of influenza by the treating physician, “despite the availability of on-site testing.” Of even more concern, she added, “is that fewer than half of the children in the ICU setting had a diagnosis of influenza made during their hospitalization.”

The take-home message is that “influenza is underrecognized and underappreciated, even by pediatricians,” noted Dr. Englund. Increasing awareness and adopting and promoting broader universal vaccination strategies “has the potential to decrease the outpatient burden.”

Infant Botulism

Infant botulism, caused by ingestion of Clostridium botulinum bacteria, which then germinate and produce toxins in a baby's large intestine, is the most common form of human botulism in the United States; 80–110 cases occur per year. A rare but serious and potentially fatal condition, infant botulism typically requires hospitalization for 4–6 weeks and often requires mechanical ventilation. Although adults with botulism poisoning can be treated effectively with an equine-derived botulism antitoxin, the treatment is not used in infants because of the risk of serious side effects, such as anaphylaxis and serum sickness.

For this reason, the development and successful testing in infants of a human-derived botulism antitoxin called BIG-IV (Human Botulism Immune Globulin-Intravenous) by Dr. Stephen S. Arnon of the California Department of Health Services and his colleagues in the Infant Botulism Treatment and Prevention Program was “tremendously important,” according to Dr. St. Geme. In the first of two studies included in the published paper, 122 infants (age range, 21–313 days) with laboratory-confirmed infant botulism were randomized to receive BIG-IV or placebo within 3 days of hospital admission. Infants who received BIG-IV had significantly shorter hospital stays, compared with the placebo group (mean 5.7 vs. 2.6 weeks), and shorter durations of intensive care (5.0 vs. 1.8 weeks), mechanical ventilation (4.4 vs. 1.8 weeks), and tube or intravenous feeding (10.6 vs. 3.6 weeks). Both type and frequency of adverse events were similar in the two groups.

In a subsequent open-label study that included 382 infants in 37 states, BIG-IV treatment within 3 days of admission significantly shortened mean length of hospital stay, compared with treatment within 4–7 days of admission: 2.0 vs. 2.9 weeks (N. Engl. J. Med. 2006; 354:462–71).

Rotavirus Vaccine

Two phase III trials of live, attenuated rotavirus vaccines for severe rotavirus gastroenteritis were among this year's most important pediatric infectious disease studies, said Dr. Englund. The vaccines—an oral pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq) and a two-dose oral monovalent human rotavirus vaccine (Rotarix)—were independently studied in large, multicenter trials that included more than 60,000 children each (N. Engl. J. Med. 2006; 354:11–22; N. Engl. J. Med. 2006;354:23–33). Compared with placebo, both vaccines demonstrated significant efficacy in reducing severe gastroenteritis and hospital admissions associated with rotavirus, and both reduced all diarrhea-associated hospital admissions by approximately half, which suggested that a high proportion of the diarrhea-associated admissions in the study areas were linked to rotavirus, noted Dr. Englund.

Both vaccines also had good safety profiles. In particular, there was no evidence of an increased intussusception risk following vaccine administration as had been reported with the first-generation rotavirus vaccine (RotaShield) that was on the market in the late 1990s.

Perhaps the most important outcome of both of these studies “is that they set the standard now for what all vaccine manufacturers are going to do or have the ability to do in the future,” said Dr. Englund.

As a result of the positive data coming out of these large trials, the Advisory Committee on Immunization Practices (ACIP) issued a recommendation in the summer of 2006 that all U.S. infants be immunized against rotavirus with three doses of the already Food and Drug Administration-approved RotaTeq vaccine, administered at 2, 4, and 6 months.

Because the rotavirus burden is highest in underdeveloped countries, “efforts should be made to conduct clinical trials in these regions and to determine ways to pay for the vaccine, which is relatively expensive,” Dr. Englund noted. “Such efforts are worthwhile considering the vaccine has the potential to prevent 5% of childhood deaths worldwide.”

Mumps Vaccination Update

Mumps also made its way into the infectious disease news this year. In response to outbreaks of the disease in early 2006 in the Midwestern United States, the ACIP updated its 1998 criteria for mumps immunity and mumps vaccination recommendations. Among the key changes, Dr. St. Geme noted, were the criteria for acceptable presumptive evidence of immunity for school-age children and adults at high risk, including those who work in health care facilities, international travelers, and college students. “Previously, documentation of adequate vaccination for these populations was one dose of a live mumps virus vaccine; now it's two doses,” he said.

Also, routine vaccination with two doses of a live mumps virus vaccine is recommended for health care workers born during or after 1957 without other evidence of immunity. One dose is recommended for health care workers born before 1957 without other evidence of immunity. In outbreak settings, a second dose of a live mumps virus vaccine should be considered for children ages 1–4 years and adults at low risk, within a 28-day interval. For health care workers born before 1957 without other evidence of immunity, two doses should be seriously considered (MMWR 2006;55:1–2).

Live Attenuated Influenza Virus Vaccine

The theoretical potential of secondary transmission of influenza has been a concern related to the use of the live attenuated influenza virus vaccine (FluMist). In previous studies, shedding of vaccine viruses has not been associated with viral transmission to close contacts.

In an effort to estimate the probability of transmission in a “worst-case scenario,” Dr. Timo Vesikari of the University of Tampere (Finland) and colleagues conducted a trial in a day care setting, said Dr. Englund. “This study was designed by the authors to maximize opportunity for transmission by including young children without immunity and without prior exposure or minimum exposure to influenza in a close-contact setting,” she said.

The study included 197 children between 9–36 months of age from 52 different day care center rooms who were randomized 1:1 to receive the vaccine or placebo. Nasal swabs were taken at regular intervals to determine postvaccination viral shedding, genotype and phenotype of shed viruses, and the probability of secondary transmission of the vaccine influenza strains (Pediatr. Infect. Dis. J. 2006; 25:590–5).

Of the 98 children who received the vaccine, 80% shed at least one vaccine influenza strain. All of the vaccine virus isolates retained their cold adaptation and temperature sensitivity characteristics. There was one confirmed transmission of a vaccine strain to a placebo recipient, but the child did not exhibit any signs or symptoms of clinically significant influenza. The probability of secondary transmission of influenza from one vaccinated child was calculated to be approximately 0.58%.

“This study showed that, even in the worst conditions and despite the high rate of viral shedding following vaccination, there is a low potential for secondary transmission of influenza,” said Dr. Englund.

TORONTO — Advances in the fight against human bocavirus, infant botulism, and severe rotavirus gastroenteritis were among the topics selected as the top new findings in pediatric infectious disease at the annual meeting of the Infectious Diseases Society of America.

“There has been a lot of activity in pediatric infectious diseases, with some important observations over the past year that will likely have an impact on clinical practice,” said Dr. Joseph W. St. Geme III of Duke University, Durham, N.C., who, along with Dr. Janet Englund of the University of Washington, Seattle, presented the past year's top findings in pediatric infectious disease.

Human Bocavirus

“One of the major problems in pediatrics continues to be respiratory tract infections,” said Dr. St. Geme. Along these lines, Dr. John C. Arnold and his colleagues assessed the prevalence and clinical spectrum of the recently identified human bocavirus (HBoV) among nearly 1,500 children aged 0–18 years who were treated for respiratory tract infection over a 20-month period at the Children's Hospital, San Diego (Clin. Infect. Dis. 2006;43:283–8).

The investigators screened by polymerase chain reaction 1,474 nasal scraping specimens that had been collected and frozen, and they found HBoV DNA in 5.6% of the specimens. The researchers noted that the peak infection rate was between March and May in both 2004 and 2005 and that 63% of the patients were younger than 12 months.

Evidence of underlying disease, including asthma, bronchopulmonary dysplasia, neuromuscular disease, and trisomy 21, was present in roughly one-third of the patients.

The most common symptoms were cough (present in 85% of cases), rhinorrhea, and fever. Clinical evidence of lower respiratory tract HBoV infection was present in 62% of the children, and nearly half of the patients had hypoxemia. Approximately 19% of HBoV-infected patients had paroxysmal cough, which led to further testing for pertussis.

Based on the findings, “it's clear that more widely available diagnostic testing for human bocavirus will be a priority in terms of establishing a better understanding of the epidemiology and clinical manifestations,” said Dr. St. Geme.

Influenza in Young Children

“In contrast to a new virus that we can't diagnose, influenza is an old virus that we can diagnose,” said Dr. Englund while presenting a paper on the burden of influenza in young children by Dr. Catherine Poehling of Vanderbilt University, Nashville, Tenn., and her colleagues at the Center for Disease Control and Prevention's New Vaccine Surveillance Network (N. Engl. J. Med. 2006;355:31–40).

The investigators used population-based surveillance to assess the disease burden of influenza among children younger than 5 years who were seeking medical care for acute respiratory tract infection or fever at clinics, emergency departments, and hospitals in three U.S. counties. They collected outpatient data during two influenza seasons—2002–2003 and 2003–2004 (when influenza vaccine was recommended for all children between 6 and 23 months)—and inpatient data from 2000 to 2004.

The average annual rate of hospitalization associated with influenza was 0.9 per 1,000 children in 2000–2004. The estimated burden of outpatient visits associated with influenza was 50 clinic visits and 6 emergency department visits per 1,000 children during the 2002–2003 season and 95 clinic visits and 27 emergency department visits per 1,000 children during the 2003–2004 season.

Of particular interest, Dr. Englund noted, was the fact that only 28% of the inpatient population and 17% of the outpatient population with laboratory- confirmed influenza received a discharge diagnosis of influenza by the treating physician, “despite the availability of on-site testing.” Of even more concern, she added, “is that fewer than half of the children in the ICU setting had a diagnosis of influenza made during their hospitalization.”

The take-home message is that “influenza is underrecognized and underappreciated, even by pediatricians,” noted Dr. Englund. Increasing awareness and adopting and promoting broader universal vaccination strategies “has the potential to decrease the outpatient burden.”

Infant Botulism

Infant botulism, caused by ingestion of Clostridium botulinum bacteria, which then germinate and produce toxins in a baby's large intestine, is the most common form of human botulism in the United States; 80–110 cases occur per year. A rare but serious and potentially fatal condition, infant botulism typically requires hospitalization for 4–6 weeks and often requires mechanical ventilation. Although adults with botulism poisoning can be treated effectively with an equine-derived botulism antitoxin, the treatment is not used in infants because of the risk of serious side effects, such as anaphylaxis and serum sickness.

For this reason, the development and successful testing in infants of a human-derived botulism antitoxin called BIG-IV (Human Botulism Immune Globulin-Intravenous) by Dr. Stephen S. Arnon of the California Department of Health Services and his colleagues in the Infant Botulism Treatment and Prevention Program was “tremendously important,” according to Dr. St. Geme. In the first of two studies included in the published paper, 122 infants (age range, 21–313 days) with laboratory-confirmed infant botulism were randomized to receive BIG-IV or placebo within 3 days of hospital admission. Infants who received BIG-IV had significantly shorter hospital stays, compared with the placebo group (mean 5.7 vs. 2.6 weeks), and shorter durations of intensive care (5.0 vs. 1.8 weeks), mechanical ventilation (4.4 vs. 1.8 weeks), and tube or intravenous feeding (10.6 vs. 3.6 weeks). Both type and frequency of adverse events were similar in the two groups.

In a subsequent open-label study that included 382 infants in 37 states, BIG-IV treatment within 3 days of admission significantly shortened mean length of hospital stay, compared with treatment within 4–7 days of admission: 2.0 vs. 2.9 weeks (N. Engl. J. Med. 2006; 354:462–71).

Rotavirus Vaccine

Two phase III trials of live, attenuated rotavirus vaccines for severe rotavirus gastroenteritis were among this year's most important pediatric infectious disease studies, said Dr. Englund. The vaccines—an oral pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq) and a two-dose oral monovalent human rotavirus vaccine (Rotarix)—were independently studied in large, multicenter trials that included more than 60,000 children each (N. Engl. J. Med. 2006; 354:11–22; N. Engl. J. Med. 2006;354:23–33). Compared with placebo, both vaccines demonstrated significant efficacy in reducing severe gastroenteritis and hospital admissions associated with rotavirus, and both reduced all diarrhea-associated hospital admissions by approximately half, which suggested that a high proportion of the diarrhea-associated admissions in the study areas were linked to rotavirus, noted Dr. Englund.

Both vaccines also had good safety profiles. In particular, there was no evidence of an increased intussusception risk following vaccine administration as had been reported with the first-generation rotavirus vaccine (RotaShield) that was on the market in the late 1990s.

Perhaps the most important outcome of both of these studies “is that they set the standard now for what all vaccine manufacturers are going to do or have the ability to do in the future,” said Dr. Englund.

As a result of the positive data coming out of these large trials, the Advisory Committee on Immunization Practices (ACIP) issued a recommendation in the summer of 2006 that all U.S. infants be immunized against rotavirus with three doses of the already Food and Drug Administration-approved RotaTeq vaccine, administered at 2, 4, and 6 months.

Because the rotavirus burden is highest in underdeveloped countries, “efforts should be made to conduct clinical trials in these regions and to determine ways to pay for the vaccine, which is relatively expensive,” Dr. Englund noted. “Such efforts are worthwhile considering the vaccine has the potential to prevent 5% of childhood deaths worldwide.”

Mumps Vaccination Update

Mumps also made its way into the infectious disease news this year. In response to outbreaks of the disease in early 2006 in the Midwestern United States, the ACIP updated its 1998 criteria for mumps immunity and mumps vaccination recommendations. Among the key changes, Dr. St. Geme noted, were the criteria for acceptable presumptive evidence of immunity for school-age children and adults at high risk, including those who work in health care facilities, international travelers, and college students. “Previously, documentation of adequate vaccination for these populations was one dose of a live mumps virus vaccine; now it's two doses,” he said.

Also, routine vaccination with two doses of a live mumps virus vaccine is recommended for health care workers born during or after 1957 without other evidence of immunity. One dose is recommended for health care workers born before 1957 without other evidence of immunity. In outbreak settings, a second dose of a live mumps virus vaccine should be considered for children ages 1–4 years and adults at low risk, within a 28-day interval. For health care workers born before 1957 without other evidence of immunity, two doses should be seriously considered (MMWR 2006;55:1–2).

Live Attenuated Influenza Virus Vaccine

The theoretical potential of secondary transmission of influenza has been a concern related to the use of the live attenuated influenza virus vaccine (FluMist). In previous studies, shedding of vaccine viruses has not been associated with viral transmission to close contacts.

In an effort to estimate the probability of transmission in a “worst-case scenario,” Dr. Timo Vesikari of the University of Tampere (Finland) and colleagues conducted a trial in a day care setting, said Dr. Englund. “This study was designed by the authors to maximize opportunity for transmission by including young children without immunity and without prior exposure or minimum exposure to influenza in a close-contact setting,” she said.

The study included 197 children between 9–36 months of age from 52 different day care center rooms who were randomized 1:1 to receive the vaccine or placebo. Nasal swabs were taken at regular intervals to determine postvaccination viral shedding, genotype and phenotype of shed viruses, and the probability of secondary transmission of the vaccine influenza strains (Pediatr. Infect. Dis. J. 2006; 25:590–5).

Of the 98 children who received the vaccine, 80% shed at least one vaccine influenza strain. All of the vaccine virus isolates retained their cold adaptation and temperature sensitivity characteristics. There was one confirmed transmission of a vaccine strain to a placebo recipient, but the child did not exhibit any signs or symptoms of clinically significant influenza. The probability of secondary transmission of influenza from one vaccinated child was calculated to be approximately 0.58%.

“This study showed that, even in the worst conditions and despite the high rate of viral shedding following vaccination, there is a low potential for secondary transmission of influenza,” said Dr. Englund.

TORONTO — Advances in the fight against human bocavirus, infant botulism, and severe rotavirus gastroenteritis were among the topics selected as the top new findings in pediatric infectious disease at the annual meeting of the Infectious Diseases Society of America.

“There has been a lot of activity in pediatric infectious diseases, with some important observations over the past year that will likely have an impact on clinical practice,” said Dr. Joseph W. St. Geme III of Duke University, Durham, N.C., who, along with Dr. Janet Englund of the University of Washington, Seattle, presented the past year's top findings in pediatric infectious disease.

Human Bocavirus

“One of the major problems in pediatrics continues to be respiratory tract infections,” said Dr. St. Geme. Along these lines, Dr. John C. Arnold and his colleagues assessed the prevalence and clinical spectrum of the recently identified human bocavirus (HBoV) among nearly 1,500 children aged 0–18 years who were treated for respiratory tract infection over a 20-month period at the Children's Hospital, San Diego (Clin. Infect. Dis. 2006;43:283–8).

The investigators screened by polymerase chain reaction 1,474 nasal scraping specimens that had been collected and frozen, and they found HBoV DNA in 5.6% of the specimens. The researchers noted that the peak infection rate was between March and May in both 2004 and 2005 and that 63% of the patients were younger than 12 months.

Evidence of underlying disease, including asthma, bronchopulmonary dysplasia, neuromuscular disease, and trisomy 21, was present in roughly one-third of the patients.

The most common symptoms were cough (present in 85% of cases), rhinorrhea, and fever. Clinical evidence of lower respiratory tract HBoV infection was present in 62% of the children, and nearly half of the patients had hypoxemia. Approximately 19% of HBoV-infected patients had paroxysmal cough, which led to further testing for pertussis.

Based on the findings, “it's clear that more widely available diagnostic testing for human bocavirus will be a priority in terms of establishing a better understanding of the epidemiology and clinical manifestations,” said Dr. St. Geme.

Influenza in Young Children

“In contrast to a new virus that we can't diagnose, influenza is an old virus that we can diagnose,” said Dr. Englund while presenting a paper on the burden of influenza in young children by Dr. Catherine Poehling of Vanderbilt University, Nashville, Tenn., and her colleagues at the Center for Disease Control and Prevention's New Vaccine Surveillance Network (N. Engl. J. Med. 2006;355:31–40).

The investigators used population-based surveillance to assess the disease burden of influenza among children younger than 5 years who were seeking medical care for acute respiratory tract infection or fever at clinics, emergency departments, and hospitals in three U.S. counties. They collected outpatient data during two influenza seasons—2002–2003 and 2003–2004 (when influenza vaccine was recommended for all children between 6 and 23 months)—and inpatient data from 2000 to 2004.

The average annual rate of hospitalization associated with influenza was 0.9 per 1,000 children in 2000–2004. The estimated burden of outpatient visits associated with influenza was 50 clinic visits and 6 emergency department visits per 1,000 children during the 2002–2003 season and 95 clinic visits and 27 emergency department visits per 1,000 children during the 2003–2004 season.

Of particular interest, Dr. Englund noted, was the fact that only 28% of the inpatient population and 17% of the outpatient population with laboratory- confirmed influenza received a discharge diagnosis of influenza by the treating physician, “despite the availability of on-site testing.” Of even more concern, she added, “is that fewer than half of the children in the ICU setting had a diagnosis of influenza made during their hospitalization.”

The take-home message is that “influenza is underrecognized and underappreciated, even by pediatricians,” noted Dr. Englund. Increasing awareness and adopting and promoting broader universal vaccination strategies “has the potential to decrease the outpatient burden.”

Infant Botulism

Infant botulism, caused by ingestion of Clostridium botulinum bacteria, which then germinate and produce toxins in a baby's large intestine, is the most common form of human botulism in the United States; 80–110 cases occur per year. A rare but serious and potentially fatal condition, infant botulism typically requires hospitalization for 4–6 weeks and often requires mechanical ventilation. Although adults with botulism poisoning can be treated effectively with an equine-derived botulism antitoxin, the treatment is not used in infants because of the risk of serious side effects, such as anaphylaxis and serum sickness.

For this reason, the development and successful testing in infants of a human-derived botulism antitoxin called BIG-IV (Human Botulism Immune Globulin-Intravenous) by Dr. Stephen S. Arnon of the California Department of Health Services and his colleagues in the Infant Botulism Treatment and Prevention Program was “tremendously important,” according to Dr. St. Geme. In the first of two studies included in the published paper, 122 infants (age range, 21–313 days) with laboratory-confirmed infant botulism were randomized to receive BIG-IV or placebo within 3 days of hospital admission. Infants who received BIG-IV had significantly shorter hospital stays, compared with the placebo group (mean 5.7 vs. 2.6 weeks), and shorter durations of intensive care (5.0 vs. 1.8 weeks), mechanical ventilation (4.4 vs. 1.8 weeks), and tube or intravenous feeding (10.6 vs. 3.6 weeks). Both type and frequency of adverse events were similar in the two groups.

In a subsequent open-label study that included 382 infants in 37 states, BIG-IV treatment within 3 days of admission significantly shortened mean length of hospital stay, compared with treatment within 4–7 days of admission: 2.0 vs. 2.9 weeks (N. Engl. J. Med. 2006; 354:462–71).

Rotavirus Vaccine

Two phase III trials of live, attenuated rotavirus vaccines for severe rotavirus gastroenteritis were among this year's most important pediatric infectious disease studies, said Dr. Englund. The vaccines—an oral pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq) and a two-dose oral monovalent human rotavirus vaccine (Rotarix)—were independently studied in large, multicenter trials that included more than 60,000 children each (N. Engl. J. Med. 2006; 354:11–22; N. Engl. J. Med. 2006;354:23–33). Compared with placebo, both vaccines demonstrated significant efficacy in reducing severe gastroenteritis and hospital admissions associated with rotavirus, and both reduced all diarrhea-associated hospital admissions by approximately half, which suggested that a high proportion of the diarrhea-associated admissions in the study areas were linked to rotavirus, noted Dr. Englund.

Both vaccines also had good safety profiles. In particular, there was no evidence of an increased intussusception risk following vaccine administration as had been reported with the first-generation rotavirus vaccine (RotaShield) that was on the market in the late 1990s.

Perhaps the most important outcome of both of these studies “is that they set the standard now for what all vaccine manufacturers are going to do or have the ability to do in the future,” said Dr. Englund.

As a result of the positive data coming out of these large trials, the Advisory Committee on Immunization Practices (ACIP) issued a recommendation in the summer of 2006 that all U.S. infants be immunized against rotavirus with three doses of the already Food and Drug Administration-approved RotaTeq vaccine, administered at 2, 4, and 6 months.

Because the rotavirus burden is highest in underdeveloped countries, “efforts should be made to conduct clinical trials in these regions and to determine ways to pay for the vaccine, which is relatively expensive,” Dr. Englund noted. “Such efforts are worthwhile considering the vaccine has the potential to prevent 5% of childhood deaths worldwide.”

Mumps Vaccination Update

Mumps also made its way into the infectious disease news this year. In response to outbreaks of the disease in early 2006 in the Midwestern United States, the ACIP updated its 1998 criteria for mumps immunity and mumps vaccination recommendations. Among the key changes, Dr. St. Geme noted, were the criteria for acceptable presumptive evidence of immunity for school-age children and adults at high risk, including those who work in health care facilities, international travelers, and college students. “Previously, documentation of adequate vaccination for these populations was one dose of a live mumps virus vaccine; now it's two doses,” he said.

Also, routine vaccination with two doses of a live mumps virus vaccine is recommended for health care workers born during or after 1957 without other evidence of immunity. One dose is recommended for health care workers born before 1957 without other evidence of immunity. In outbreak settings, a second dose of a live mumps virus vaccine should be considered for children ages 1–4 years and adults at low risk, within a 28-day interval. For health care workers born before 1957 without other evidence of immunity, two doses should be seriously considered (MMWR 2006;55:1–2).

Live Attenuated Influenza Virus Vaccine

The theoretical potential of secondary transmission of influenza has been a concern related to the use of the live attenuated influenza virus vaccine (FluMist). In previous studies, shedding of vaccine viruses has not been associated with viral transmission to close contacts.

In an effort to estimate the probability of transmission in a “worst-case scenario,” Dr. Timo Vesikari of the University of Tampere (Finland) and colleagues conducted a trial in a day care setting, said Dr. Englund. “This study was designed by the authors to maximize opportunity for transmission by including young children without immunity and without prior exposure or minimum exposure to influenza in a close-contact setting,” she said.

The study included 197 children between 9–36 months of age from 52 different day care center rooms who were randomized 1:1 to receive the vaccine or placebo. Nasal swabs were taken at regular intervals to determine postvaccination viral shedding, genotype and phenotype of shed viruses, and the probability of secondary transmission of the vaccine influenza strains (Pediatr. Infect. Dis. J. 2006; 25:590–5).

Of the 98 children who received the vaccine, 80% shed at least one vaccine influenza strain. All of the vaccine virus isolates retained their cold adaptation and temperature sensitivity characteristics. There was one confirmed transmission of a vaccine strain to a placebo recipient, but the child did not exhibit any signs or symptoms of clinically significant influenza. The probability of secondary transmission of influenza from one vaccinated child was calculated to be approximately 0.58%.

“This study showed that, even in the worst conditions and despite the high rate of viral shedding following vaccination, there is a low potential for secondary transmission of influenza,” said Dr. Englund.

TORONTO—Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

“It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient,” Dr. Kanwar suggested.

To determine the effect of this recommendation on CAP diagnosis and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, ICU transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group, compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported.

Increases in the misdiagnosis of CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes.

Dr. Kanwar reported having no related financial disclosures.

TORONTO—Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

“It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient,” Dr. Kanwar suggested.

To determine the effect of this recommendation on CAP diagnosis and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, ICU transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group, compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported.

Increases in the misdiagnosis of CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes.

Dr. Kanwar reported having no related financial disclosures.

TORONTO—Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

“It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient,” Dr. Kanwar suggested.

To determine the effect of this recommendation on CAP diagnosis and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, ICU transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group, compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported.

Increases in the misdiagnosis of CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes.

Dr. Kanwar reported having no related financial disclosures.

TORONTO—Early, empiric antimicrobial therapy for possible necrotizing fasciitis should include coverage for methicillin-resistant Staphylococcus aureus in regions of the United States where the bacteria are endemic, according to Dr. Lisa S. Young of the University of Colorado Health Sciences Center, Denver.

Although the severe soft tissue infection continues to be rare, “community-acquired MRSA is on the rise and clinicians need to be aware of the potential association [with necrotizing fasciitis], especially in areas with high or increasing rates of community-acquired MSRA,” Dr. Young said at the annual meeting of the Infectious Diseases Society of America.

In the wake of a 2005 report linking community-acquired MRSA to 14 cases of necrotizing fasciitis in the Los Angeles area, Dr. Young and her colleagues retrospectively evaluated the prevalence of MRSA in patients treated for necrotizing fasciitis over a 2-year period at the Denver Health Medical Center, where community-acquired MRSA accounts for more than half of the community S. aureus clinical isolates.

The investigators reviewed the pathologic records and diagnostic codes of patients treated at the medical center for necrotizing fasciitis between January 2004 and February 2006 and determined that 5 of the 30 cases diagnosed were caused by MRSA. All five cases involved the extremities, and in all five cases, the patients' MRSA isolates were susceptible within 12 hours to the empiric antibiotics that were given. The patients required a median of six surgeries (range 2–7) to remove infected tissue. “None of them needed an amputation, and all five survived,” Dr. Young said.

Three of the five patients, whose ages ranged from 28 to 55 years, experienced “a spider bite lesion” 2 or 3 days prior to admission. One patient was an alcoholic, one was a diabetic, and the remaining three were healthy.

Pathology results showed that the MRSA isolates had the USA300 DNA banding pattern. This strain of community-acquired MRSA produces the Panton Valentine leukocidin cytotoxin, which has been associated with serious necrotizing infections, Dr. Young explained. The increasing prevalence in recent years of these isolates, which differ from other S. aureus clones, might be a result of antibiotic overuse, she noted.

With respect to clinical management of suspected necrotizing fasciitis, “in areas of high prevalence [of MRSA], do not wait for cultures before beginning empiric treatment with antibiotic therapy that is effective against MRSA,” Dr. Young advised. The organism is highly aggressive and virulent, so treatment delays or the use of ineffective therapies “could lead to severe tissue damage or amputation,” she said.

Dr. Young reported having no financial disclosures related to her presentation.

TORONTO—Early, empiric antimicrobial therapy for possible necrotizing fasciitis should include coverage for methicillin-resistant Staphylococcus aureus in regions of the United States where the bacteria are endemic, according to Dr. Lisa S. Young of the University of Colorado Health Sciences Center, Denver.

Although the severe soft tissue infection continues to be rare, “community-acquired MRSA is on the rise and clinicians need to be aware of the potential association [with necrotizing fasciitis], especially in areas with high or increasing rates of community-acquired MSRA,” Dr. Young said at the annual meeting of the Infectious Diseases Society of America.

In the wake of a 2005 report linking community-acquired MRSA to 14 cases of necrotizing fasciitis in the Los Angeles area, Dr. Young and her colleagues retrospectively evaluated the prevalence of MRSA in patients treated for necrotizing fasciitis over a 2-year period at the Denver Health Medical Center, where community-acquired MRSA accounts for more than half of the community S. aureus clinical isolates.

The investigators reviewed the pathologic records and diagnostic codes of patients treated at the medical center for necrotizing fasciitis between January 2004 and February 2006 and determined that 5 of the 30 cases diagnosed were caused by MRSA. All five cases involved the extremities, and in all five cases, the patients' MRSA isolates were susceptible within 12 hours to the empiric antibiotics that were given. The patients required a median of six surgeries (range 2–7) to remove infected tissue. “None of them needed an amputation, and all five survived,” Dr. Young said.

Three of the five patients, whose ages ranged from 28 to 55 years, experienced “a spider bite lesion” 2 or 3 days prior to admission. One patient was an alcoholic, one was a diabetic, and the remaining three were healthy.

Pathology results showed that the MRSA isolates had the USA300 DNA banding pattern. This strain of community-acquired MRSA produces the Panton Valentine leukocidin cytotoxin, which has been associated with serious necrotizing infections, Dr. Young explained. The increasing prevalence in recent years of these isolates, which differ from other S. aureus clones, might be a result of antibiotic overuse, she noted.

With respect to clinical management of suspected necrotizing fasciitis, “in areas of high prevalence [of MRSA], do not wait for cultures before beginning empiric treatment with antibiotic therapy that is effective against MRSA,” Dr. Young advised. The organism is highly aggressive and virulent, so treatment delays or the use of ineffective therapies “could lead to severe tissue damage or amputation,” she said.

Dr. Young reported having no financial disclosures related to her presentation.

TORONTO—Early, empiric antimicrobial therapy for possible necrotizing fasciitis should include coverage for methicillin-resistant Staphylococcus aureus in regions of the United States where the bacteria are endemic, according to Dr. Lisa S. Young of the University of Colorado Health Sciences Center, Denver.

Although the severe soft tissue infection continues to be rare, “community-acquired MRSA is on the rise and clinicians need to be aware of the potential association [with necrotizing fasciitis], especially in areas with high or increasing rates of community-acquired MSRA,” Dr. Young said at the annual meeting of the Infectious Diseases Society of America.

In the wake of a 2005 report linking community-acquired MRSA to 14 cases of necrotizing fasciitis in the Los Angeles area, Dr. Young and her colleagues retrospectively evaluated the prevalence of MRSA in patients treated for necrotizing fasciitis over a 2-year period at the Denver Health Medical Center, where community-acquired MRSA accounts for more than half of the community S. aureus clinical isolates.

The investigators reviewed the pathologic records and diagnostic codes of patients treated at the medical center for necrotizing fasciitis between January 2004 and February 2006 and determined that 5 of the 30 cases diagnosed were caused by MRSA. All five cases involved the extremities, and in all five cases, the patients' MRSA isolates were susceptible within 12 hours to the empiric antibiotics that were given. The patients required a median of six surgeries (range 2–7) to remove infected tissue. “None of them needed an amputation, and all five survived,” Dr. Young said.

Three of the five patients, whose ages ranged from 28 to 55 years, experienced “a spider bite lesion” 2 or 3 days prior to admission. One patient was an alcoholic, one was a diabetic, and the remaining three were healthy.

Pathology results showed that the MRSA isolates had the USA300 DNA banding pattern. This strain of community-acquired MRSA produces the Panton Valentine leukocidin cytotoxin, which has been associated with serious necrotizing infections, Dr. Young explained. The increasing prevalence in recent years of these isolates, which differ from other S. aureus clones, might be a result of antibiotic overuse, she noted.

With respect to clinical management of suspected necrotizing fasciitis, “in areas of high prevalence [of MRSA], do not wait for cultures before beginning empiric treatment with antibiotic therapy that is effective against MRSA,” Dr. Young advised. The organism is highly aggressive and virulent, so treatment delays or the use of ineffective therapies “could lead to severe tissue damage or amputation,” she said.

Dr. Young reported having no financial disclosures related to her presentation.

BOSTON—Prophylaxis with pegylated interferon plus ribavirin is relatively safe and well tolerated following liver transplantation for hepatitis C, a study has shown.

Preliminary findings from the first randomized control trial of antiviral prophylaxis for the prevention of recurrent hepatitis C infection in orthotopic liver-transplant (OLT) patients suggest that although adverse events are common during prophylactic treatment with peginterferon α-2a (Pegasys) plus ribavirin (Copegus), only a small percentage of those adverse events necessitate treatment withdrawal, Dr. Natalie H. Bzowej said at the annual meeting of the American Association for the Study of Liver Diseases.

Because recurrent infection with the hepatitis C virus (HCV) can cause graft failure and death following liver transplantation, preemptive antiviral therapy has been suggested as a way to enhance viral clearance. However, safety concerns—particularly regarding anemia, neutropenia, and acute cellular rejection—have limited its use, said Dr. Bzowej of California Pacific Medical Center in San Francisco.

To assess the safety and efficacy of preemptive antiviral therapy following liver transplant and to compare the outcomes of patients undergoing prophylactic treatment to those of patients who don't receive treatment until recurrent hepatitis has become established in the graft, Dr. Bzowej and her colleagues in the ongoing Phoenix study out of the Mayo Clinic to date have randomized 115 post-liver transplant patients to either a prophylaxis or an observation arm. Dr. Bzowej presented data on the first 60 randomized patients.

Of the 60 patients, 33 were randomized to prophylaxis with 135 mcg peginterferon α-2a per week for 4 weeks, followed by 180 mcg/week for 44 weeks, plus ribavirin, at an initial dosage of 400 mg/day, escalating to 1,000 mg or 1,200 mg/day over the first 12 weeks, for 48 weeks. The 27 patients randomized to observation received no treatment until histologic recurrence of HCV, Dr. Bzowej reported.

All of the patients in the study were randomized 10–26 weeks post transplant. Previous investigations into preemptive therapy have begun prophylaxis as early as 4 weeks post transplant, “but doing so excludes a number of potential candidates who are still recovering from surgery,” Dr. Bzowej said.

After randomization and before treatment initiation, one patient in the prophylaxis arm and three patients in the observation arm withdrew consent for the study. Of the 32 patients who began treatment in the prophylaxis arm, 7 withdrew. Four of the patients in the observation arm crossed over to treatment because of HCV recurrence.

During the first 12 study weeks, 94% of the prophylaxis arm and 82% of the observation arm experienced one or more adverse events, with a total of 278 and 107 adverse events, respectively. Additionally, 19% of patients in the prophylaxis arm and 15% in the observation arm experienced one or more serious adverse events, with a total of seven and six serious adverse events, respectively.

“The most common treatment-related adverse events were fatigue, anemia, headache, and nausea,” Dr. Bzowej said.

With respect to treatment modifications or interruptions, of the 32 patients assigned to the prophylaxis arm, 6 (19%) withdrew from therapy because of adverse events. Five of the six withdrew from both pegylated interferon α-2a and ribavirin—one for rash and anemia, one for thrombocytopenia, one for increased bilirubin, one for dehydration, and one for neutropenia. The sixth patient withdrew from the ribavirin only because of anemia. None of the four crossover patients in the observation arm withdrew from treatment.

Importantly, “no clinically apparent episodes of acute cellular rejection occurred through week 12,” Dr. Bzowej said. And although adverse events occurred in 94% of the prophylactically treated patients, “only 19% experienced events necessitating therapeutic withdrawal—a figure that compares favorably with other studies, suggesting the regimen is reasonably well tolerated,” she said.

Dr. Bzowej disclosed that she has been a speaker for Schering and Glaxo and that she has served as a consultant for Intarcia. She has also been an investigator on clinical trials supported by numerous companies, including Roche Laboratories, which manufactures Pegasys.

BOSTON—Prophylaxis with pegylated interferon plus ribavirin is relatively safe and well tolerated following liver transplantation for hepatitis C, a study has shown.

Preliminary findings from the first randomized control trial of antiviral prophylaxis for the prevention of recurrent hepatitis C infection in orthotopic liver-transplant (OLT) patients suggest that although adverse events are common during prophylactic treatment with peginterferon α-2a (Pegasys) plus ribavirin (Copegus), only a small percentage of those adverse events necessitate treatment withdrawal, Dr. Natalie H. Bzowej said at the annual meeting of the American Association for the Study of Liver Diseases.

Because recurrent infection with the hepatitis C virus (HCV) can cause graft failure and death following liver transplantation, preemptive antiviral therapy has been suggested as a way to enhance viral clearance. However, safety concerns—particularly regarding anemia, neutropenia, and acute cellular rejection—have limited its use, said Dr. Bzowej of California Pacific Medical Center in San Francisco.

To assess the safety and efficacy of preemptive antiviral therapy following liver transplant and to compare the outcomes of patients undergoing prophylactic treatment to those of patients who don't receive treatment until recurrent hepatitis has become established in the graft, Dr. Bzowej and her colleagues in the ongoing Phoenix study out of the Mayo Clinic to date have randomized 115 post-liver transplant patients to either a prophylaxis or an observation arm. Dr. Bzowej presented data on the first 60 randomized patients.

Of the 60 patients, 33 were randomized to prophylaxis with 135 mcg peginterferon α-2a per week for 4 weeks, followed by 180 mcg/week for 44 weeks, plus ribavirin, at an initial dosage of 400 mg/day, escalating to 1,000 mg or 1,200 mg/day over the first 12 weeks, for 48 weeks. The 27 patients randomized to observation received no treatment until histologic recurrence of HCV, Dr. Bzowej reported.

All of the patients in the study were randomized 10–26 weeks post transplant. Previous investigations into preemptive therapy have begun prophylaxis as early as 4 weeks post transplant, “but doing so excludes a number of potential candidates who are still recovering from surgery,” Dr. Bzowej said.

After randomization and before treatment initiation, one patient in the prophylaxis arm and three patients in the observation arm withdrew consent for the study. Of the 32 patients who began treatment in the prophylaxis arm, 7 withdrew. Four of the patients in the observation arm crossed over to treatment because of HCV recurrence.

During the first 12 study weeks, 94% of the prophylaxis arm and 82% of the observation arm experienced one or more adverse events, with a total of 278 and 107 adverse events, respectively. Additionally, 19% of patients in the prophylaxis arm and 15% in the observation arm experienced one or more serious adverse events, with a total of seven and six serious adverse events, respectively.

“The most common treatment-related adverse events were fatigue, anemia, headache, and nausea,” Dr. Bzowej said.

With respect to treatment modifications or interruptions, of the 32 patients assigned to the prophylaxis arm, 6 (19%) withdrew from therapy because of adverse events. Five of the six withdrew from both pegylated interferon α-2a and ribavirin—one for rash and anemia, one for thrombocytopenia, one for increased bilirubin, one for dehydration, and one for neutropenia. The sixth patient withdrew from the ribavirin only because of anemia. None of the four crossover patients in the observation arm withdrew from treatment.

Importantly, “no clinically apparent episodes of acute cellular rejection occurred through week 12,” Dr. Bzowej said. And although adverse events occurred in 94% of the prophylactically treated patients, “only 19% experienced events necessitating therapeutic withdrawal—a figure that compares favorably with other studies, suggesting the regimen is reasonably well tolerated,” she said.

Dr. Bzowej disclosed that she has been a speaker for Schering and Glaxo and that she has served as a consultant for Intarcia. She has also been an investigator on clinical trials supported by numerous companies, including Roche Laboratories, which manufactures Pegasys.

BOSTON—Prophylaxis with pegylated interferon plus ribavirin is relatively safe and well tolerated following liver transplantation for hepatitis C, a study has shown.

Preliminary findings from the first randomized control trial of antiviral prophylaxis for the prevention of recurrent hepatitis C infection in orthotopic liver-transplant (OLT) patients suggest that although adverse events are common during prophylactic treatment with peginterferon α-2a (Pegasys) plus ribavirin (Copegus), only a small percentage of those adverse events necessitate treatment withdrawal, Dr. Natalie H. Bzowej said at the annual meeting of the American Association for the Study of Liver Diseases.

Because recurrent infection with the hepatitis C virus (HCV) can cause graft failure and death following liver transplantation, preemptive antiviral therapy has been suggested as a way to enhance viral clearance. However, safety concerns—particularly regarding anemia, neutropenia, and acute cellular rejection—have limited its use, said Dr. Bzowej of California Pacific Medical Center in San Francisco.

To assess the safety and efficacy of preemptive antiviral therapy following liver transplant and to compare the outcomes of patients undergoing prophylactic treatment to those of patients who don't receive treatment until recurrent hepatitis has become established in the graft, Dr. Bzowej and her colleagues in the ongoing Phoenix study out of the Mayo Clinic to date have randomized 115 post-liver transplant patients to either a prophylaxis or an observation arm. Dr. Bzowej presented data on the first 60 randomized patients.

Of the 60 patients, 33 were randomized to prophylaxis with 135 mcg peginterferon α-2a per week for 4 weeks, followed by 180 mcg/week for 44 weeks, plus ribavirin, at an initial dosage of 400 mg/day, escalating to 1,000 mg or 1,200 mg/day over the first 12 weeks, for 48 weeks. The 27 patients randomized to observation received no treatment until histologic recurrence of HCV, Dr. Bzowej reported.

All of the patients in the study were randomized 10–26 weeks post transplant. Previous investigations into preemptive therapy have begun prophylaxis as early as 4 weeks post transplant, “but doing so excludes a number of potential candidates who are still recovering from surgery,” Dr. Bzowej said.

After randomization and before treatment initiation, one patient in the prophylaxis arm and three patients in the observation arm withdrew consent for the study. Of the 32 patients who began treatment in the prophylaxis arm, 7 withdrew. Four of the patients in the observation arm crossed over to treatment because of HCV recurrence.

During the first 12 study weeks, 94% of the prophylaxis arm and 82% of the observation arm experienced one or more adverse events, with a total of 278 and 107 adverse events, respectively. Additionally, 19% of patients in the prophylaxis arm and 15% in the observation arm experienced one or more serious adverse events, with a total of seven and six serious adverse events, respectively.

“The most common treatment-related adverse events were fatigue, anemia, headache, and nausea,” Dr. Bzowej said.

With respect to treatment modifications or interruptions, of the 32 patients assigned to the prophylaxis arm, 6 (19%) withdrew from therapy because of adverse events. Five of the six withdrew from both pegylated interferon α-2a and ribavirin—one for rash and anemia, one for thrombocytopenia, one for increased bilirubin, one for dehydration, and one for neutropenia. The sixth patient withdrew from the ribavirin only because of anemia. None of the four crossover patients in the observation arm withdrew from treatment.

Importantly, “no clinically apparent episodes of acute cellular rejection occurred through week 12,” Dr. Bzowej said. And although adverse events occurred in 94% of the prophylactically treated patients, “only 19% experienced events necessitating therapeutic withdrawal—a figure that compares favorably with other studies, suggesting the regimen is reasonably well tolerated,” she said.

Dr. Bzowej disclosed that she has been a speaker for Schering and Glaxo and that she has served as a consultant for Intarcia. She has also been an investigator on clinical trials supported by numerous companies, including Roche Laboratories, which manufactures Pegasys.

BOSTON—Combination therapy with peginterferon α-2b and weight-based ribavirin produces consistent rates of sustained virologic response in obese patients with chronic hepatitis C virus in the largest U.S. hepatitis C virus study ever conducted.

In fact, the weight-based dosing regimen “produces sustained virologic response rates among obese patients similar to those seen in normal-weight individuals,” Dr. Ira M. Jacobson reported at the annual meeting of the American Association for the Study of Liver Diseases.

Previous studies have shown that overweight patients with hepatitis C virus (HCV) infection are less likely to achieve a sustained virologic response (SVR) with antiviral therapy than are their normal-weight counterparts. And obese patients—those with a BMI greater than 30 kg/m

Previously reported results from the current study—the WIN-R (Weight-Based Dosing of PEG-Intron and Rebetol) multicenter, prospective, open-label trial—showed that weight-based dosing of ribavirin is important in maximizing SVR rates in patients with chronic hepatitis C.

Across the study population, “SVR rates were significantly higher with peginterferon α-2b plus weight-based ribavirin than with flat-dose ribavirin,” Dr. Jacobson said.

To evaluate the consistency of this effect in obese patients with HCV, Dr. Jacobson and his colleagues conducted a subanalysis of data from the 4,900-patient WIN-R trial, looking specifically at the outcomes of 51 chronic HCV patients in the study with a body weight of 125 kg or more.

All of the patients in the study were 18–70 years of age, were treatment naive, had elevated ALT levels within 6 months of study enrollment, had liver biopsy findings consistent with chronic HCV within 36 months of study enrollment, and had compensated liver disease. Patients who tested positive for hepatitis B surface antigen or HIV were excluded.

Patients were randomly assigned to receive subcutaneous peginterferon α-2b (PEG-Intron) at a dosage of 1.5 mcg/kg per week and either flat-dose (800 mg/day) or weight-based oral ribavirin (Rebetol) daily. The weight-based dosing was 800 mg/day for patients weighing less than 65 kg, 1,000 mg/day for patients weighing from 65 to 85 kg, 1,200 mg/day for patients weighing from 85 to 105 kg, and 1,400 mg/day for patients weighing more than 105 kg.

Patients infected with HCV genotype 1 were treated for 48 weeks, and patients infected with HCV genotype 2/3 were treated for 24 or 48 weeks. All patients were monitored for 24 weeks after treatment.

Of the 51 patients included in the subanalysis, 23 received flat-dose ribavirin, and 28 received weight-based doses. The mean body weight in the cohort was 131.2 kg, and the mean BMI was 41.0 kg/m

Overall, 31of the 51 patients in the subanalysis responded to the treatment by the end of the study period, and SVR—defined as undetectable serum HCV RNA (less than 29 IU/mL) 24 weeks after treatment—was achieved by 25 patients (49%), Dr. Jacobson reported. The overall SVR rate for the WIN-R population was 44.3%, he said.

As with the general WIN-R trial population, “patients weighing more than 125 kg had a significantly increased probability of achieving an SVR with weight-based ribavirin than with flat-dose [ribavirin],” said Dr. Jacobson, noting that patients who received weight-based dosing were 3.5 times more likely to achieve SVR than were those on the flat-dose regimen. The differences in SVR rates between flat-dose and weight-based ribavirin were greater in patients in the subanalysis than they were in the WIN-R study population as a whole, he said.

In the subanalysis, 6% of patients had hemoglobin levels below 10 g/dL, and 6% had absolute neutrophil cell counts lower than 750/mm3. In the larger study, the respective rates for these adverse events were 16% and 19%, said Dr. Jacobson.

The findings of this study suggest “that severe obesity should not preclude consideration of antiviral therapy for patients with chronic HCV,” said Dr. Jacobson, who reported receiving research support for this study from Schering-Plough, manufacturer of PEG-Intron.

BOSTON—Combination therapy with peginterferon α-2b and weight-based ribavirin produces consistent rates of sustained virologic response in obese patients with chronic hepatitis C virus in the largest U.S. hepatitis C virus study ever conducted.

In fact, the weight-based dosing regimen “produces sustained virologic response rates among obese patients similar to those seen in normal-weight individuals,” Dr. Ira M. Jacobson reported at the annual meeting of the American Association for the Study of Liver Diseases.

Previous studies have shown that overweight patients with hepatitis C virus (HCV) infection are less likely to achieve a sustained virologic response (SVR) with antiviral therapy than are their normal-weight counterparts. And obese patients—those with a BMI greater than 30 kg/m

Previously reported results from the current study—the WIN-R (Weight-Based Dosing of PEG-Intron and Rebetol) multicenter, prospective, open-label trial—showed that weight-based dosing of ribavirin is important in maximizing SVR rates in patients with chronic hepatitis C.

Across the study population, “SVR rates were significantly higher with peginterferon α-2b plus weight-based ribavirin than with flat-dose ribavirin,” Dr. Jacobson said.

To evaluate the consistency of this effect in obese patients with HCV, Dr. Jacobson and his colleagues conducted a subanalysis of data from the 4,900-patient WIN-R trial, looking specifically at the outcomes of 51 chronic HCV patients in the study with a body weight of 125 kg or more.

All of the patients in the study were 18–70 years of age, were treatment naive, had elevated ALT levels within 6 months of study enrollment, had liver biopsy findings consistent with chronic HCV within 36 months of study enrollment, and had compensated liver disease. Patients who tested positive for hepatitis B surface antigen or HIV were excluded.

Patients were randomly assigned to receive subcutaneous peginterferon α-2b (PEG-Intron) at a dosage of 1.5 mcg/kg per week and either flat-dose (800 mg/day) or weight-based oral ribavirin (Rebetol) daily. The weight-based dosing was 800 mg/day for patients weighing less than 65 kg, 1,000 mg/day for patients weighing from 65 to 85 kg, 1,200 mg/day for patients weighing from 85 to 105 kg, and 1,400 mg/day for patients weighing more than 105 kg.

Patients infected with HCV genotype 1 were treated for 48 weeks, and patients infected with HCV genotype 2/3 were treated for 24 or 48 weeks. All patients were monitored for 24 weeks after treatment.

Of the 51 patients included in the subanalysis, 23 received flat-dose ribavirin, and 28 received weight-based doses. The mean body weight in the cohort was 131.2 kg, and the mean BMI was 41.0 kg/m

Overall, 31of the 51 patients in the subanalysis responded to the treatment by the end of the study period, and SVR—defined as undetectable serum HCV RNA (less than 29 IU/mL) 24 weeks after treatment—was achieved by 25 patients (49%), Dr. Jacobson reported. The overall SVR rate for the WIN-R population was 44.3%, he said.

As with the general WIN-R trial population, “patients weighing more than 125 kg had a significantly increased probability of achieving an SVR with weight-based ribavirin than with flat-dose [ribavirin],” said Dr. Jacobson, noting that patients who received weight-based dosing were 3.5 times more likely to achieve SVR than were those on the flat-dose regimen. The differences in SVR rates between flat-dose and weight-based ribavirin were greater in patients in the subanalysis than they were in the WIN-R study population as a whole, he said.

In the subanalysis, 6% of patients had hemoglobin levels below 10 g/dL, and 6% had absolute neutrophil cell counts lower than 750/mm3. In the larger study, the respective rates for these adverse events were 16% and 19%, said Dr. Jacobson.

The findings of this study suggest “that severe obesity should not preclude consideration of antiviral therapy for patients with chronic HCV,” said Dr. Jacobson, who reported receiving research support for this study from Schering-Plough, manufacturer of PEG-Intron.

BOSTON—Combination therapy with peginterferon α-2b and weight-based ribavirin produces consistent rates of sustained virologic response in obese patients with chronic hepatitis C virus in the largest U.S. hepatitis C virus study ever conducted.

In fact, the weight-based dosing regimen “produces sustained virologic response rates among obese patients similar to those seen in normal-weight individuals,” Dr. Ira M. Jacobson reported at the annual meeting of the American Association for the Study of Liver Diseases.

Previous studies have shown that overweight patients with hepatitis C virus (HCV) infection are less likely to achieve a sustained virologic response (SVR) with antiviral therapy than are their normal-weight counterparts. And obese patients—those with a BMI greater than 30 kg/m

Previously reported results from the current study—the WIN-R (Weight-Based Dosing of PEG-Intron and Rebetol) multicenter, prospective, open-label trial—showed that weight-based dosing of ribavirin is important in maximizing SVR rates in patients with chronic hepatitis C.

Across the study population, “SVR rates were significantly higher with peginterferon α-2b plus weight-based ribavirin than with flat-dose ribavirin,” Dr. Jacobson said.

To evaluate the consistency of this effect in obese patients with HCV, Dr. Jacobson and his colleagues conducted a subanalysis of data from the 4,900-patient WIN-R trial, looking specifically at the outcomes of 51 chronic HCV patients in the study with a body weight of 125 kg or more.

All of the patients in the study were 18–70 years of age, were treatment naive, had elevated ALT levels within 6 months of study enrollment, had liver biopsy findings consistent with chronic HCV within 36 months of study enrollment, and had compensated liver disease. Patients who tested positive for hepatitis B surface antigen or HIV were excluded.

Patients were randomly assigned to receive subcutaneous peginterferon α-2b (PEG-Intron) at a dosage of 1.5 mcg/kg per week and either flat-dose (800 mg/day) or weight-based oral ribavirin (Rebetol) daily. The weight-based dosing was 800 mg/day for patients weighing less than 65 kg, 1,000 mg/day for patients weighing from 65 to 85 kg, 1,200 mg/day for patients weighing from 85 to 105 kg, and 1,400 mg/day for patients weighing more than 105 kg.

Patients infected with HCV genotype 1 were treated for 48 weeks, and patients infected with HCV genotype 2/3 were treated for 24 or 48 weeks. All patients were monitored for 24 weeks after treatment.

Of the 51 patients included in the subanalysis, 23 received flat-dose ribavirin, and 28 received weight-based doses. The mean body weight in the cohort was 131.2 kg, and the mean BMI was 41.0 kg/m

Overall, 31of the 51 patients in the subanalysis responded to the treatment by the end of the study period, and SVR—defined as undetectable serum HCV RNA (less than 29 IU/mL) 24 weeks after treatment—was achieved by 25 patients (49%), Dr. Jacobson reported. The overall SVR rate for the WIN-R population was 44.3%, he said.

As with the general WIN-R trial population, “patients weighing more than 125 kg had a significantly increased probability of achieving an SVR with weight-based ribavirin than with flat-dose [ribavirin],” said Dr. Jacobson, noting that patients who received weight-based dosing were 3.5 times more likely to achieve SVR than were those on the flat-dose regimen. The differences in SVR rates between flat-dose and weight-based ribavirin were greater in patients in the subanalysis than they were in the WIN-R study population as a whole, he said.

In the subanalysis, 6% of patients had hemoglobin levels below 10 g/dL, and 6% had absolute neutrophil cell counts lower than 750/mm3. In the larger study, the respective rates for these adverse events were 16% and 19%, said Dr. Jacobson.

The findings of this study suggest “that severe obesity should not preclude consideration of antiviral therapy for patients with chronic HCV,” said Dr. Jacobson, who reported receiving research support for this study from Schering-Plough, manufacturer of PEG-Intron.

TORONTO — Fluconazole prophylaxis for invasive candidiasis in extremely low-birth-weight infants is not associated with the emergence of fluconazole-resistant Candida species, Dr. C. Mary Healy said at the annual meeting of the Infectious Diseases Society of America.

In infants weighing less than 1,000 g at birth, 42 days of fluconazole prophylaxis (FP) has been shown to reduce Candida colonization and invasive candidiasis, “but the possibility that [this regimen] could lead to a resistant Candida species is an ongoing concern,” said Dr. Healy of Baylor College of Medicine in Houston. “The worry is that FP will cause overgrowth and infection by inherently less susceptible species, particularly C. glabrata.”

To evaluate the impact of FP on the incidence of invasive candidiasis (IC), as well as IC-related mortality and fluconazole susceptibility of Candida isolates, Dr. Healy and her colleagues reviewed data from the neonatal intensive care unit (NICU) at the Women's Hospital of Texas in Houston for infants treated both before and after the implementation of an FP strategy in 2002. For the purposes of this investigation, IC was defined as the presence of a Candida species isolated from blood or cerebrospinal fluid in NICU infants.

Since April 2002, as per hospital protocol, extremely low-birth-weight infants younger than 5 days in the NICU of the Women's Hospital of Texas have been eligible to receive intravenous FP at a dose of 3 mg/kg for 6 weeks on a dosing schedule that varies by age: every third day for the first 3 weeks, every second day for the subsequent 2 weeks, and daily for the final 2 weeks, said Dr. Healy.

Using pharmacy and electronic records, Dr. Healy and her colleagues reviewed the demographic, clinical, and laboratory data for all of the NICU infants of any birth weight during the first 4 years of FP implementation and compared it with that of infants who were in the NICU in 2000–2001, before the use of FP.

Between April 2002 and March 2006, 362 extremely low-birth-weight infants in the hospital's NICU received FP, along with 47 infants with a body weight greater than 1,000 g who were started on the preventive therapy at the discretion of the neonatologist. The median body weight of the 409 infants was 775 g, the median gestation was 26 weeks, and the median dose they received was 13 mg/kg over 29 days.

Twenty-nine percent of those infants receiving FP completed the 6-week protocol. Fifty-nine percent discontinued the therapy because IV access was no longer needed, 7% died from non IC-related causes, 2% transferred to other hospitals, 2% had breakthrough infections, and 1% had transient elevation of liver transaminases, which resolved when FP was discontinued, Dr. Healy reported.

Comparing infants who developed IC during the pre- and post-FP time periods showed 19 cases in 2000–2001 and 22 cases in 2002–2006. “Infants [who developed IC] during the FP period were of significantly greater gestational age and had significantly higher birth weight than those who developed it before FP,” said Dr. Healy. “There was also a strong trend toward them being older, although this did not reach significance.” There was no difference in prenatal or perinatal complications, nor were there differences in complications of prematurity.

Among the risk factors for infection in both groups, “there was a strong trend toward more antibiotic use, longer duration of infant vascular catheters, and longer duration of TPN [total parenteral nutrition] in the FP period, but the only risk factor that reaches statistical significance was the use of H₂ blockers,” said Dr. Healy.

With respect to potential resistance, “our findings are reassuring,” said Dr. Healy. “The IC species distribution remained stable both before and after FP implementation. In the IC cases prior to FP, C. albicans was identified in 14 infants, C. parapsilosis in 3, C. tropicalis in 1, and C. glabrata in 1. After FP, the species distribution was C. albicans in 13 infants, C. parapsilosis in 6, C. tropicalis in 1, and C. glabrata in 2. “It's particularly reassuring that C. glabrata is no more common now than it was before FP,” she said.

Similarly, the minimum inhibitory concentrations (MICs) for fluconazole were consistent.

Dr. Healy reported having no conflicts of interest related to this presentation.

TORONTO — Fluconazole prophylaxis for invasive candidiasis in extremely low-birth-weight infants is not associated with the emergence of fluconazole-resistant Candida species, Dr. C. Mary Healy said at the annual meeting of the Infectious Diseases Society of America.

In infants weighing less than 1,000 g at birth, 42 days of fluconazole prophylaxis (FP) has been shown to reduce Candida colonization and invasive candidiasis, “but the possibility that [this regimen] could lead to a resistant Candida species is an ongoing concern,” said Dr. Healy of Baylor College of Medicine in Houston. “The worry is that FP will cause overgrowth and infection by inherently less susceptible species, particularly C. glabrata.”

To evaluate the impact of FP on the incidence of invasive candidiasis (IC), as well as IC-related mortality and fluconazole susceptibility of Candida isolates, Dr. Healy and her colleagues reviewed data from the neonatal intensive care unit (NICU) at the Women's Hospital of Texas in Houston for infants treated both before and after the implementation of an FP strategy in 2002. For the purposes of this investigation, IC was defined as the presence of a Candida species isolated from blood or cerebrospinal fluid in NICU infants.

Since April 2002, as per hospital protocol, extremely low-birth-weight infants younger than 5 days in the NICU of the Women's Hospital of Texas have been eligible to receive intravenous FP at a dose of 3 mg/kg for 6 weeks on a dosing schedule that varies by age: every third day for the first 3 weeks, every second day for the subsequent 2 weeks, and daily for the final 2 weeks, said Dr. Healy.

Using pharmacy and electronic records, Dr. Healy and her colleagues reviewed the demographic, clinical, and laboratory data for all of the NICU infants of any birth weight during the first 4 years of FP implementation and compared it with that of infants who were in the NICU in 2000–2001, before the use of FP.

Between April 2002 and March 2006, 362 extremely low-birth-weight infants in the hospital's NICU received FP, along with 47 infants with a body weight greater than 1,000 g who were started on the preventive therapy at the discretion of the neonatologist. The median body weight of the 409 infants was 775 g, the median gestation was 26 weeks, and the median dose they received was 13 mg/kg over 29 days.

Twenty-nine percent of those infants receiving FP completed the 6-week protocol. Fifty-nine percent discontinued the therapy because IV access was no longer needed, 7% died from non IC-related causes, 2% transferred to other hospitals, 2% had breakthrough infections, and 1% had transient elevation of liver transaminases, which resolved when FP was discontinued, Dr. Healy reported.

Comparing infants who developed IC during the pre- and post-FP time periods showed 19 cases in 2000–2001 and 22 cases in 2002–2006. “Infants [who developed IC] during the FP period were of significantly greater gestational age and had significantly higher birth weight than those who developed it before FP,” said Dr. Healy. “There was also a strong trend toward them being older, although this did not reach significance.” There was no difference in prenatal or perinatal complications, nor were there differences in complications of prematurity.

Among the risk factors for infection in both groups, “there was a strong trend toward more antibiotic use, longer duration of infant vascular catheters, and longer duration of TPN [total parenteral nutrition] in the FP period, but the only risk factor that reaches statistical significance was the use of H₂ blockers,” said Dr. Healy.

With respect to potential resistance, “our findings are reassuring,” said Dr. Healy. “The IC species distribution remained stable both before and after FP implementation. In the IC cases prior to FP, C. albicans was identified in 14 infants, C. parapsilosis in 3, C. tropicalis in 1, and C. glabrata in 1. After FP, the species distribution was C. albicans in 13 infants, C. parapsilosis in 6, C. tropicalis in 1, and C. glabrata in 2. “It's particularly reassuring that C. glabrata is no more common now than it was before FP,” she said.

Similarly, the minimum inhibitory concentrations (MICs) for fluconazole were consistent.

Dr. Healy reported having no conflicts of interest related to this presentation.

TORONTO — Fluconazole prophylaxis for invasive candidiasis in extremely low-birth-weight infants is not associated with the emergence of fluconazole-resistant Candida species, Dr. C. Mary Healy said at the annual meeting of the Infectious Diseases Society of America.

In infants weighing less than 1,000 g at birth, 42 days of fluconazole prophylaxis (FP) has been shown to reduce Candida colonization and invasive candidiasis, “but the possibility that [this regimen] could lead to a resistant Candida species is an ongoing concern,” said Dr. Healy of Baylor College of Medicine in Houston. “The worry is that FP will cause overgrowth and infection by inherently less susceptible species, particularly C. glabrata.”

To evaluate the impact of FP on the incidence of invasive candidiasis (IC), as well as IC-related mortality and fluconazole susceptibility of Candida isolates, Dr. Healy and her colleagues reviewed data from the neonatal intensive care unit (NICU) at the Women's Hospital of Texas in Houston for infants treated both before and after the implementation of an FP strategy in 2002. For the purposes of this investigation, IC was defined as the presence of a Candida species isolated from blood or cerebrospinal fluid in NICU infants.

Since April 2002, as per hospital protocol, extremely low-birth-weight infants younger than 5 days in the NICU of the Women's Hospital of Texas have been eligible to receive intravenous FP at a dose of 3 mg/kg for 6 weeks on a dosing schedule that varies by age: every third day for the first 3 weeks, every second day for the subsequent 2 weeks, and daily for the final 2 weeks, said Dr. Healy.

Using pharmacy and electronic records, Dr. Healy and her colleagues reviewed the demographic, clinical, and laboratory data for all of the NICU infants of any birth weight during the first 4 years of FP implementation and compared it with that of infants who were in the NICU in 2000–2001, before the use of FP.

Between April 2002 and March 2006, 362 extremely low-birth-weight infants in the hospital's NICU received FP, along with 47 infants with a body weight greater than 1,000 g who were started on the preventive therapy at the discretion of the neonatologist. The median body weight of the 409 infants was 775 g, the median gestation was 26 weeks, and the median dose they received was 13 mg/kg over 29 days.

Twenty-nine percent of those infants receiving FP completed the 6-week protocol. Fifty-nine percent discontinued the therapy because IV access was no longer needed, 7% died from non IC-related causes, 2% transferred to other hospitals, 2% had breakthrough infections, and 1% had transient elevation of liver transaminases, which resolved when FP was discontinued, Dr. Healy reported.

Comparing infants who developed IC during the pre- and post-FP time periods showed 19 cases in 2000–2001 and 22 cases in 2002–2006. “Infants [who developed IC] during the FP period were of significantly greater gestational age and had significantly higher birth weight than those who developed it before FP,” said Dr. Healy. “There was also a strong trend toward them being older, although this did not reach significance.” There was no difference in prenatal or perinatal complications, nor were there differences in complications of prematurity.

Among the risk factors for infection in both groups, “there was a strong trend toward more antibiotic use, longer duration of infant vascular catheters, and longer duration of TPN [total parenteral nutrition] in the FP period, but the only risk factor that reaches statistical significance was the use of H₂ blockers,” said Dr. Healy.

With respect to potential resistance, “our findings are reassuring,” said Dr. Healy. “The IC species distribution remained stable both before and after FP implementation. In the IC cases prior to FP, C. albicans was identified in 14 infants, C. parapsilosis in 3, C. tropicalis in 1, and C. glabrata in 1. After FP, the species distribution was C. albicans in 13 infants, C. parapsilosis in 6, C. tropicalis in 1, and C. glabrata in 2. “It's particularly reassuring that C. glabrata is no more common now than it was before FP,” she said.

Similarly, the minimum inhibitory concentrations (MICs) for fluconazole were consistent.

Dr. Healy reported having no conflicts of interest related to this presentation.

TORONTO — Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

Given the potential for providing less than optimal care by promoting compliance with the current CAP quality indicator, a more feasible target should be established, Dr. Kanwar suggested. “It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient.”

To determine the effect of this recommendation on the diagnosis of CAP and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years who were admitted to their institution through the emergency department both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, intensive care unit (ICU) transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% of patients received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported in a poster presentation.

The increases in both the misdiagnosis in CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes. The increase in blood cultures obtained without indication suggests potential antibiotic use for contaminant-related positive cultures.

Dr. Kanwar reported having no financial disclosures related to this presentation.

TORONTO — Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

Given the potential for providing less than optimal care by promoting compliance with the current CAP quality indicator, a more feasible target should be established, Dr. Kanwar suggested. “It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient.”

To determine the effect of this recommendation on the diagnosis of CAP and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years who were admitted to their institution through the emergency department both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, intensive care unit (ICU) transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% of patients received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported in a poster presentation.

The increases in both the misdiagnosis in CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes. The increase in blood cultures obtained without indication suggests potential antibiotic use for contaminant-related positive cultures.

Dr. Kanwar reported having no financial disclosures related to this presentation.

TORONTO — Adherence to guidelines that recommend early use of antibiotics may lead to inaccurate diagnosis of community-acquired pneumonia and inappropriate use of antibiotics, according to a study presented at the annual meeting of the Infectious Diseases Society of America.

The IDSA guidelines for community-acquired pneumonia (CAP), published in November 2003, recommend the initiation of antibiotics within 4 hours of hospitalization—an indicator that has been linked to incentive compensation of third-party payers to hospitals, said Dr. Manreet K. Kanwar of St. John Hospital and Medical Center in Detroit.

Given the potential for providing less than optimal care by promoting compliance with the current CAP quality indicator, a more feasible target should be established, Dr. Kanwar suggested. “It's possible that prolonging the antibiotic window to 6 hours may be enough time to better evaluate a patient.”

To determine the effect of this recommendation on the diagnosis of CAP and associated antibiotic utilization, Dr. Kanwar and colleagues reviewed the charts for 518 patients older than age 21 years who were admitted to their institution through the emergency department both prior to (January through June 2003) and following (January through June 2005) the publication of the guidelines. They collected data on clinical signs and symptoms at presentation, as well as chest x-ray findings, preantibiotic blood cultures, time to antibiotic administration data, Pneumonia Severity Index (PSI) scores, intensive care unit (ICU) transfer rates, and mortality data.

There were no significant differences between the 199 patients in the preguideline group and the 319 in the postguideline group in age, gender, PSI score, ICU transfer rates, or mortality. In the postguideline group, 66% of patients received antibiotics within 4 hours of triage, compared with 54% of the preguideline patients. The percentage of blood cultures prior to antibiotic administration was higher (70%) in the 2005 group compared with 47% in the 2003 group. But the final diagnosis of CAP dropped significantly, from about 76% in 2003 to 59% in 2005, and the mean antibiotic utilization per patient increased significantly, Dr. Kanwar reported in a poster presentation.

The increases in both the misdiagnosis in CAP and inappropriate antibiotic use as a result of compliance with the 4-hour antibiotic rule suggest that many patients received antibiotics for noninfectious processes. The increase in blood cultures obtained without indication suggests potential antibiotic use for contaminant-related positive cultures.

Dr. Kanwar reported having no financial disclosures related to this presentation.

BOSTON — Recent evidence linking autoantibodies to neuronal damage in systemic lupus erythematosus suggests a new paradigm for explaining the occurrence of cognitive and emotional impairment in patients with the autoimmune disorder, according to Dr. Betty Diamond of Columbia University in New York.

Nearly two-thirds of patients with systemic lupus erythematosus (SLE) experience neurologic and psychiatric symptoms—referred to collectively as neuropsychiatric SLE—ranging from headaches, mild impairment of thinking, or personality changes to stroke, epilepsy, and severe mental disorders. “And as our immunosuppressant therapies and armamentarium of antibiotics has improved and lupus patients are living longer than they used to, we're seeing more of the late sequelae of the disease and learning that cognitive dysfunction and disorders of executive function are major components of disease morbidity,” Dr. Diamond reported at a rheumatology conference sponsored by Harvard Medical School.

The etiology of central nervous system (CNS) involvement in lupus has long eluded investigators, particularly because it occurs without evidence of cerebral vascular disease or telltale inflammation, said Dr. Diamond. In addition, in most studies, the progressive cognitive impairment has not been associated with disease activity or medication.

“When one thinks about the pathogenesis of neuropsychiatric lupus, it's logical to consider vascular occlusion or hemorrhage associated with antiphospholipid antibodies. And one might also consider cytokines, which in vitro can be toxic to neurons and alter neuronal function, but there has yet to be any correlation between any particular cytokine in cerebrospinal fluid (CSF) with any particular disease manifestation,” said Dr. Diamond. Medication, particularly steroids, could also be a contributing factor, although studies in lupus patients haven't found any correlation between either steroid dose or duration with neuropsychiatric lupus, she said.

“Of course, one can't think about lupus without considering autoantibodies as part of the disease process, including the CNS sequelae,” said Dr. Diamond, whose recent research in this arena has borne promising fruit.

Specifically, Dr. Diamond and colleagues have determined that the loss of cognitive function is likely immunologically mediated but only in individuals in whom the blood-brain barrier has been compromised. “We've previously shown that anti-DNA antibodies [which bind to double-stranded DNA and are highly associated with SLE] will cross-react with peptides, including one that is present on subunits of the NMDA [N-methyl-D-aspartate] receptor,” said Dr. Diamond. The NMDA receptor is expressed in neurons throughout the brain and at a particularly high density in regions of the cerebral cortex that are associated with learning and memory functions. The anti-DNA antibodies bind to the NMDA receptors of nerve cells in these regions and produce apoptosis, she said.

However, the damage can only occur if the blood-brain barrier is compromised. In studies with mice, “if the anti-DNA antibodies did not permeate the blood-brain barrier, there were no behavioral or cognitive changes,” said Dr. Diamond. In contrast, when the barrier was broken, the antibodies bound to the areas of the brain involved in the regulation of emotion and memory, leading to cognitive and memory impairment. This finding helps explain why antibody titers in the serum of lupus patients may not correlate with clinical symptoms of neuropsychiatric SLE and why, in the presence of serum antibody, symptoms may not progress, she said.

In separate studies using mice with lupus antibodies, Dr. Diamond and colleagues forced open the blood-brain barrier by injecting the bacterial endotoxin lipopolysaccharide to simulate a mock bacterial infection and by injecting epinephrine to simulate the adrenaline spike associated with stress reactivity. In both cases, the autoantibodies were able to reach the cerebral cortex and cause neurocognitive symptoms.

Of interest, according to Dr. Diamond, was the fact that the simulated infection led to the death of nerve cells in the hippocampus while the simulated stress reaction attacked neurons in the amygdala. The “regional specificity” of neuronal damage might explain variations in the nature and extent of cognitive and emotional changes associated with neuropsychiatric lupus, but it is the breach in the blood-brain barrier that sets the stage for the changes, she said.

The findings of these studies suggest “a new paradigm for an immunologically mediated, noninflammatory loss of cognitive function, not only in SLE but possibly in other [autoimmune] conditions,” said Dr. Diamond.

In terms of clinical relevance, “blocking the brain cell receptor to which the anti-DNA antibodies bind could be a promising therapeutic option for neuropsychiatric SLE,” Dr. Diamond stated. In fact, in both of the aforementioned studies, the investigators demonstrated that immunization with the NMDA agonist memantine (Namenda), which is used to treat Alzheimer's disease, protected the targeted neurons from damage and prevented behavioral alterations, as did immunization with the D-isoform of the consensus peptide.

BOSTON — Recent evidence linking autoantibodies to neuronal damage in systemic lupus erythematosus suggests a new paradigm for explaining the occurrence of cognitive and emotional impairment in patients with the autoimmune disorder, according to Dr. Betty Diamond of Columbia University in New York.

Nearly two-thirds of patients with systemic lupus erythematosus (SLE) experience neurologic and psychiatric symptoms—referred to collectively as neuropsychiatric SLE—ranging from headaches, mild impairment of thinking, or personality changes to stroke, epilepsy, and severe mental disorders. “And as our immunosuppressant therapies and armamentarium of antibiotics has improved and lupus patients are living longer than they used to, we're seeing more of the late sequelae of the disease and learning that cognitive dysfunction and disorders of executive function are major components of disease morbidity,” Dr. Diamond reported at a rheumatology conference sponsored by Harvard Medical School.

The etiology of central nervous system (CNS) involvement in lupus has long eluded investigators, particularly because it occurs without evidence of cerebral vascular disease or telltale inflammation, said Dr. Diamond. In addition, in most studies, the progressive cognitive impairment has not been associated with disease activity or medication.

“When one thinks about the pathogenesis of neuropsychiatric lupus, it's logical to consider vascular occlusion or hemorrhage associated with antiphospholipid antibodies. And one might also consider cytokines, which in vitro can be toxic to neurons and alter neuronal function, but there has yet to be any correlation between any particular cytokine in cerebrospinal fluid (CSF) with any particular disease manifestation,” said Dr. Diamond. Medication, particularly steroids, could also be a contributing factor, although studies in lupus patients haven't found any correlation between either steroid dose or duration with neuropsychiatric lupus, she said.

“Of course, one can't think about lupus without considering autoantibodies as part of the disease process, including the CNS sequelae,” said Dr. Diamond, whose recent research in this arena has borne promising fruit.

Specifically, Dr. Diamond and colleagues have determined that the loss of cognitive function is likely immunologically mediated but only in individuals in whom the blood-brain barrier has been compromised. “We've previously shown that anti-DNA antibodies [which bind to double-stranded DNA and are highly associated with SLE] will cross-react with peptides, including one that is present on subunits of the NMDA [N-methyl-D-aspartate] receptor,” said Dr. Diamond. The NMDA receptor is expressed in neurons throughout the brain and at a particularly high density in regions of the cerebral cortex that are associated with learning and memory functions. The anti-DNA antibodies bind to the NMDA receptors of nerve cells in these regions and produce apoptosis, she said.

However, the damage can only occur if the blood-brain barrier is compromised. In studies with mice, “if the anti-DNA antibodies did not permeate the blood-brain barrier, there were no behavioral or cognitive changes,” said Dr. Diamond. In contrast, when the barrier was broken, the antibodies bound to the areas of the brain involved in the regulation of emotion and memory, leading to cognitive and memory impairment. This finding helps explain why antibody titers in the serum of lupus patients may not correlate with clinical symptoms of neuropsychiatric SLE and why, in the presence of serum antibody, symptoms may not progress, she said.

In separate studies using mice with lupus antibodies, Dr. Diamond and colleagues forced open the blood-brain barrier by injecting the bacterial endotoxin lipopolysaccharide to simulate a mock bacterial infection and by injecting epinephrine to simulate the adrenaline spike associated with stress reactivity. In both cases, the autoantibodies were able to reach the cerebral cortex and cause neurocognitive symptoms.

Of interest, according to Dr. Diamond, was the fact that the simulated infection led to the death of nerve cells in the hippocampus while the simulated stress reaction attacked neurons in the amygdala. The “regional specificity” of neuronal damage might explain variations in the nature and extent of cognitive and emotional changes associated with neuropsychiatric lupus, but it is the breach in the blood-brain barrier that sets the stage for the changes, she said.

The findings of these studies suggest “a new paradigm for an immunologically mediated, noninflammatory loss of cognitive function, not only in SLE but possibly in other [autoimmune] conditions,” said Dr. Diamond.

In terms of clinical relevance, “blocking the brain cell receptor to which the anti-DNA antibodies bind could be a promising therapeutic option for neuropsychiatric SLE,” Dr. Diamond stated. In fact, in both of the aforementioned studies, the investigators demonstrated that immunization with the NMDA agonist memantine (Namenda), which is used to treat Alzheimer's disease, protected the targeted neurons from damage and prevented behavioral alterations, as did immunization with the D-isoform of the consensus peptide.

BOSTON — Recent evidence linking autoantibodies to neuronal damage in systemic lupus erythematosus suggests a new paradigm for explaining the occurrence of cognitive and emotional impairment in patients with the autoimmune disorder, according to Dr. Betty Diamond of Columbia University in New York.

Nearly two-thirds of patients with systemic lupus erythematosus (SLE) experience neurologic and psychiatric symptoms—referred to collectively as neuropsychiatric SLE—ranging from headaches, mild impairment of thinking, or personality changes to stroke, epilepsy, and severe mental disorders. “And as our immunosuppressant therapies and armamentarium of antibiotics has improved and lupus patients are living longer than they used to, we're seeing more of the late sequelae of the disease and learning that cognitive dysfunction and disorders of executive function are major components of disease morbidity,” Dr. Diamond reported at a rheumatology conference sponsored by Harvard Medical School.

The etiology of central nervous system (CNS) involvement in lupus has long eluded investigators, particularly because it occurs without evidence of cerebral vascular disease or telltale inflammation, said Dr. Diamond. In addition, in most studies, the progressive cognitive impairment has not been associated with disease activity or medication.

“When one thinks about the pathogenesis of neuropsychiatric lupus, it's logical to consider vascular occlusion or hemorrhage associated with antiphospholipid antibodies. And one might also consider cytokines, which in vitro can be toxic to neurons and alter neuronal function, but there has yet to be any correlation between any particular cytokine in cerebrospinal fluid (CSF) with any particular disease manifestation,” said Dr. Diamond. Medication, particularly steroids, could also be a contributing factor, although studies in lupus patients haven't found any correlation between either steroid dose or duration with neuropsychiatric lupus, she said.

“Of course, one can't think about lupus without considering autoantibodies as part of the disease process, including the CNS sequelae,” said Dr. Diamond, whose recent research in this arena has borne promising fruit.

Specifically, Dr. Diamond and colleagues have determined that the loss of cognitive function is likely immunologically mediated but only in individuals in whom the blood-brain barrier has been compromised. “We've previously shown that anti-DNA antibodies [which bind to double-stranded DNA and are highly associated with SLE] will cross-react with peptides, including one that is present on subunits of the NMDA [N-methyl-D-aspartate] receptor,” said Dr. Diamond. The NMDA receptor is expressed in neurons throughout the brain and at a particularly high density in regions of the cerebral cortex that are associated with learning and memory functions. The anti-DNA antibodies bind to the NMDA receptors of nerve cells in these regions and produce apoptosis, she said.

However, the damage can only occur if the blood-brain barrier is compromised. In studies with mice, “if the anti-DNA antibodies did not permeate the blood-brain barrier, there were no behavioral or cognitive changes,” said Dr. Diamond. In contrast, when the barrier was broken, the antibodies bound to the areas of the brain involved in the regulation of emotion and memory, leading to cognitive and memory impairment. This finding helps explain why antibody titers in the serum of lupus patients may not correlate with clinical symptoms of neuropsychiatric SLE and why, in the presence of serum antibody, symptoms may not progress, she said.

In separate studies using mice with lupus antibodies, Dr. Diamond and colleagues forced open the blood-brain barrier by injecting the bacterial endotoxin lipopolysaccharide to simulate a mock bacterial infection and by injecting epinephrine to simulate the adrenaline spike associated with stress reactivity. In both cases, the autoantibodies were able to reach the cerebral cortex and cause neurocognitive symptoms.

Of interest, according to Dr. Diamond, was the fact that the simulated infection led to the death of nerve cells in the hippocampus while the simulated stress reaction attacked neurons in the amygdala. The “regional specificity” of neuronal damage might explain variations in the nature and extent of cognitive and emotional changes associated with neuropsychiatric lupus, but it is the breach in the blood-brain barrier that sets the stage for the changes, she said.

The findings of these studies suggest “a new paradigm for an immunologically mediated, noninflammatory loss of cognitive function, not only in SLE but possibly in other [autoimmune] conditions,” said Dr. Diamond.

In terms of clinical relevance, “blocking the brain cell receptor to which the anti-DNA antibodies bind could be a promising therapeutic option for neuropsychiatric SLE,” Dr. Diamond stated. In fact, in both of the aforementioned studies, the investigators demonstrated that immunization with the NMDA agonist memantine (Namenda), which is used to treat Alzheimer's disease, protected the targeted neurons from damage and prevented behavioral alterations, as did immunization with the D-isoform of the consensus peptide.

BOSTON — An exercise program consisting of moderate to vigorous aerobic activity 6 hours per week was associated with reduced incidence of precancerous colon changes in men who participated in a year-long clinical trial looking at the effect of exercise on cancer biomarkers in colon tissue, Kristin Campbell, Ph.D., said at the annual international conference of the American Association for Cancer Research.

The same exercise intervention did not produce comparable results among women, suggesting that physical activity may play a stronger role in colon cancer risk reduction in men than in women, Dr. Campbell noted.

Alterations in the proliferation and apoptosis of colon crypt cells—the highly programmed cells in the indentations, or crypts, of the colon wall—are thought to play a crucial, early role in the development of colorectal neoplasia. In a previous study, Dr. Campbell and colleagues at Seattle's Fred Hutchinson Cancer Research Center showed that colon crypt cell proliferation decreased with exercise in men but not in women.

In the current study, which was funded by the National Cancer Institute and the National Institutes of Health, the investigators sought to determine the effect of an aerobic exercise intervention on both the proliferation and apoptosis of colon crypt cells. To do this, they measured colon cancer biomarkers—the apoptosis-stimulating Bax protein and the apoptosis-inhibiting bcl-2 protein—in 101 men and 98 women aged 40–75 years. Participants were randomized to a usual-lifestyle control group or the exercise intervention comprising 1 hour of aerobic activity 6 days per week.

All of the patients underwent flexible sigmoidoscopy to obtain stained tissue samples from the mucosal lining of the colon at baseline and 12 months.

For analysis purposes, the crypt was divided into three regions: bottom, middle, and top. Cellular proliferation in the bottom region is normal, but overproliferation can occur when apoptosis goes awry and cells are not dying on schedule and instead migrate up the sides of the crypt to the surface. Such overproliferation is linked to the development of precancerous and cancerous growths, said Dr. Campbell.

Among men in the study, significant increases in Bax density at the bottom of the crypt and significant decreases in cellular proliferation in the upper crypt were seen in the exercise group, compared with controls, Dr. Campbell reported. The changes represented “a substantial increase in the potential for cellular apoptosis in the area of the colon most vulnerable to colon cancer,” she said.

Although men who exercised for the full 6 hours per week or more appeared to benefit the most, “even those who worked out an average of 4 or more hours per week, and those with the most robust aerobic fitness levels, demonstrated beneficial changes,” Dr. Campbell said.

In contrast, there were no notable between-group changes in cellular proliferation or apoptosis markers among the women, she said.

It is unclear why female exercisers do not seem to reap the same benefits as men. Dr. Campbell reported having no conflicts of interest with respect to her presentation.

BOSTON — An exercise program consisting of moderate to vigorous aerobic activity 6 hours per week was associated with reduced incidence of precancerous colon changes in men who participated in a year-long clinical trial looking at the effect of exercise on cancer biomarkers in colon tissue, Kristin Campbell, Ph.D., said at the annual international conference of the American Association for Cancer Research.

The same exercise intervention did not produce comparable results among women, suggesting that physical activity may play a stronger role in colon cancer risk reduction in men than in women, Dr. Campbell noted.

Alterations in the proliferation and apoptosis of colon crypt cells—the highly programmed cells in the indentations, or crypts, of the colon wall—are thought to play a crucial, early role in the development of colorectal neoplasia. In a previous study, Dr. Campbell and colleagues at Seattle's Fred Hutchinson Cancer Research Center showed that colon crypt cell proliferation decreased with exercise in men but not in women.

In the current study, which was funded by the National Cancer Institute and the National Institutes of Health, the investigators sought to determine the effect of an aerobic exercise intervention on both the proliferation and apoptosis of colon crypt cells. To do this, they measured colon cancer biomarkers—the apoptosis-stimulating Bax protein and the apoptosis-inhibiting bcl-2 protein—in 101 men and 98 women aged 40–75 years. Participants were randomized to a usual-lifestyle control group or the exercise intervention comprising 1 hour of aerobic activity 6 days per week.

All of the patients underwent flexible sigmoidoscopy to obtain stained tissue samples from the mucosal lining of the colon at baseline and 12 months.

For analysis purposes, the crypt was divided into three regions: bottom, middle, and top. Cellular proliferation in the bottom region is normal, but overproliferation can occur when apoptosis goes awry and cells are not dying on schedule and instead migrate up the sides of the crypt to the surface. Such overproliferation is linked to the development of precancerous and cancerous growths, said Dr. Campbell.

Among men in the study, significant increases in Bax density at the bottom of the crypt and significant decreases in cellular proliferation in the upper crypt were seen in the exercise group, compared with controls, Dr. Campbell reported. The changes represented “a substantial increase in the potential for cellular apoptosis in the area of the colon most vulnerable to colon cancer,” she said.

Although men who exercised for the full 6 hours per week or more appeared to benefit the most, “even those who worked out an average of 4 or more hours per week, and those with the most robust aerobic fitness levels, demonstrated beneficial changes,” Dr. Campbell said.

In contrast, there were no notable between-group changes in cellular proliferation or apoptosis markers among the women, she said.

It is unclear why female exercisers do not seem to reap the same benefits as men. Dr. Campbell reported having no conflicts of interest with respect to her presentation.

BOSTON — An exercise program consisting of moderate to vigorous aerobic activity 6 hours per week was associated with reduced incidence of precancerous colon changes in men who participated in a year-long clinical trial looking at the effect of exercise on cancer biomarkers in colon tissue, Kristin Campbell, Ph.D., said at the annual international conference of the American Association for Cancer Research.

The same exercise intervention did not produce comparable results among women, suggesting that physical activity may play a stronger role in colon cancer risk reduction in men than in women, Dr. Campbell noted.

Alterations in the proliferation and apoptosis of colon crypt cells—the highly programmed cells in the indentations, or crypts, of the colon wall—are thought to play a crucial, early role in the development of colorectal neoplasia. In a previous study, Dr. Campbell and colleagues at Seattle's Fred Hutchinson Cancer Research Center showed that colon crypt cell proliferation decreased with exercise in men but not in women.

In the current study, which was funded by the National Cancer Institute and the National Institutes of Health, the investigators sought to determine the effect of an aerobic exercise intervention on both the proliferation and apoptosis of colon crypt cells. To do this, they measured colon cancer biomarkers—the apoptosis-stimulating Bax protein and the apoptosis-inhibiting bcl-2 protein—in 101 men and 98 women aged 40–75 years. Participants were randomized to a usual-lifestyle control group or the exercise intervention comprising 1 hour of aerobic activity 6 days per week.

All of the patients underwent flexible sigmoidoscopy to obtain stained tissue samples from the mucosal lining of the colon at baseline and 12 months.

For analysis purposes, the crypt was divided into three regions: bottom, middle, and top. Cellular proliferation in the bottom region is normal, but overproliferation can occur when apoptosis goes awry and cells are not dying on schedule and instead migrate up the sides of the crypt to the surface. Such overproliferation is linked to the development of precancerous and cancerous growths, said Dr. Campbell.

Among men in the study, significant increases in Bax density at the bottom of the crypt and significant decreases in cellular proliferation in the upper crypt were seen in the exercise group, compared with controls, Dr. Campbell reported. The changes represented “a substantial increase in the potential for cellular apoptosis in the area of the colon most vulnerable to colon cancer,” she said.

Although men who exercised for the full 6 hours per week or more appeared to benefit the most, “even those who worked out an average of 4 or more hours per week, and those with the most robust aerobic fitness levels, demonstrated beneficial changes,” Dr. Campbell said.

In contrast, there were no notable between-group changes in cellular proliferation or apoptosis markers among the women, she said.

It is unclear why female exercisers do not seem to reap the same benefits as men. Dr. Campbell reported having no conflicts of interest with respect to her presentation.