Mary Ann Moon

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC's Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%. Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more “children are vaccinated with the newly licensed PCV13,” Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. “For clinicians, [this suggests] that current treatment guidelines … targeting the major pathogenic causes are still appropriate.” S. pneumoniae was the most common causative pathogen among adults and children aged 1–11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. “As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease,” they said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification “depends on the diagnostic and therapeutic practices of those caring for patients,” they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, “which may account for up to 40% of cases,” Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen's associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC's Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%. Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more “children are vaccinated with the newly licensed PCV13,” Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. “For clinicians, [this suggests] that current treatment guidelines … targeting the major pathogenic causes are still appropriate.” S. pneumoniae was the most common causative pathogen among adults and children aged 1–11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. “As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease,” they said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification “depends on the diagnostic and therapeutic practices of those caring for patients,” they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, “which may account for up to 40% of cases,” Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen's associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC's Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%. Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more “children are vaccinated with the newly licensed PCV13,” Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. “For clinicians, [this suggests] that current treatment guidelines … targeting the major pathogenic causes are still appropriate.” S. pneumoniae was the most common causative pathogen among adults and children aged 1–11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. “As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease,” they said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification “depends on the diagnostic and therapeutic practices of those caring for patients,” they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, “which may account for up to 40% of cases,” Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen's associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Two measures of fracture risk – bone mineral density T score and FRAX score – are clinically useful in patients with type 2 diabetes, even though they tend to underestimate the increased fracture risk in this patient population, according to the results of a large study reported in the June 1 issue of JAMA.

But to be more accurate for older adults with diabetes, these treatment and diagnostic algorithms should undergo "refinements," said Ann V. Schwartz, Ph.D., of the department of epidemiology and biostatistics, University of California, San Francisco, and her associates (JAMA 2011;305:2184-92).

Type 2 diabetes is known to be associated with a higher bone mineral density (BMD) but, paradoxically, also with a higher risk of fracture. There has been concern that established methods for predicting fractures "may not perform adequately in patients with type 2 diabetes," the researchers said.

In what they described as the first study to prospectively examine the relationship between BMD and fractures in older adults with type 2 diabetes, Dr. Schwartz and her colleagues analyzed data from three large, prospective, observational studies that all used radiology reports and radiographs to confirm fracture diagnoses. The three studies also ascertained subjects’ diabetes status.

The Study of Osteoporotic Fractures (SOF) involved 7,926 white women at four U.S. clinical centers who underwent femoral neck-hip BMD measurement and were followed for the occurrence of fractures from 1988 through 2008. The Osteoporotic Fractures in Men Study (MrOS) involved 5,994 men at six U.S. clinical centers who underwent hip BMD measurement and were followed from 2000 through 2009. And the Health, Aging, and Body Composition (Health ABC) study involved 1,523 women and 1,442 men in their 70s, approximately half of whom were white and half black, who underwent hip BMD measurement and were followed from 1997 through 2007.

The FRAX (Fracture Risk Algorithm) scores were calculated for subjects in the SOF and MrOS studies by the World Health Organization (WHO) Collaborating Center for Metabolic Bone Disease, but not for subjects in the Health ABC study.

Dr. Schwartz and her associates found that both low BMD T score and high FRAX score were predictive of hip and nonspinal fracture in patients with diabetes. "However, for a given T score and age, those adults with diabetes had a higher risk of fracture than those without diabetes," they said.

For example, the risk of hip fracture in a woman with diabetes was equivalent to that of a nondiabetic woman with a T score of about 0.5 units lower.

The subjects with diabetes showed higher rates of fracture at any given FRAX score than did subjects who didn’t have diabetes, they noted.

"Interpretation of T score or FRAX score in an older patient with diabetes must take into account the higher fracture risk associated with diabetes. For example, ... a T score in a woman with diabetes is associated with hip fracture risk equivalent to a woman without diabetes with a T score of approximately 0.5 units lower," the investigators said.

"The FRAX score has been incorporated into U.S. guidelines for prevention and treatment of osteoporosis. The FRAX algorithm does not currently include type 2 diabetes as a risk factor for fracture, and our results indicate that use of the FRAX score in patients with diabetes will likely underestimate risk.

"An adjustment of this algorithm for type 2 diabetes seems justified, given the prevalence of diabetes among older adults," Dr. Schwartz and her associates said.

The reason diabetes raises fracture risk even as it appears to protect against loss of BMD is not understood. "Bone strength may be compromised through changes that are not captured with dual-energy x-ray absorptiometry, such as higher levels of advanced glycation end products in bone collagen. More frequent falls in older adults with diabetes could also increase fracture risk for a given BMD," they said.

This study was funded by an investigator-initiated grant from Amgen to Dr. Schwartz. She and her associates also reported receiving support from Novartis, Merck, Pfizer, Nycomed, and Roche.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Repeated bronchoconstriction alone, without additional inflammation, induces airway remodeling in asthma patients, according to a report in the May 26 issue of the New England Journal of Medicine.

"Currently, the primary aim of asthma management is to reduce symptoms and control the disease by targeting airway inflammation. The results of this study suggest that an additional target should be to stabilize airway caliber and prevent bronchoconstriction," said Christopher L. Grainge, Ph.D., of the University of Southampton (England) and his associates.

Airway structural changes after an allergen challenge have been attributed to eosinophilic inflammation. But the investigators hypothesized that the mechanical stresses of airway narrowing induced by asthma patients’ exposure to allergens "may itself be a sufficient stimulus for the development of airway remodeling, and that such remodeling is not solely dependent on induced recruitment of airway eosinophils."

They tested the hypothesis by performing repeated inhalation challenges with dust mite allergen (which induces bronchoconstriction with recruitment of eosinophils) or with methacholine (which induces bronchoconstriction alone).

Two control conditions also were tested: repeated inhalation challenges with a saline placebo, and with methacholine after albuterol administration to prevent bronchoconstriction. The latter condition controlled for any nonbronchodilator, receptor-mediated actions of methacholine within the airways.

Twelve adult volunteers with mild atopic asthma were randomly assigned to one of the four study groups. These subjects underwent bronchoscopy at baseline, followed at least 2 weeks later by three consecutive inhalation challenges at 2-day intervals, followed 4 days later by a final bronchoscopy exam. Markers of airway remodeling were assessed in tissue samples from endobronchial biopsy and from bronchoalveolar-lavage fluid obtained at each bronchoscopy exam.

Clear and identical indications of airway remodeling were seen after the inhalation challenges in the groups in which bronchospasm was induced, regardless of the stimulus. The remodeling thus was independent of eosinophil recruitment into the airways, the researchers said (N. Engl. J. Med. 2011;364:2006-15).

Moreover, "since the same degree of allergen-induced or methacholine-induced acute bronchoconstriction produced indistinguishable remodeling changes ... our data suggest that the allergen-induced eosinophil influx in the airway is not crucial for these changes to occur," Dr. Grainge and his colleagues noted.

After the active inhalation challenges, an increase in mucus-secreting cells was seen. This indicates that bronchoconstriction in asthma stimulates excessive mucus production that may contribute further to airway occlusion, they said.

Similarly, after the active inhalation challenges, there was increased expression of proteins that regulate cell proliferation, as well as increased thickness of the sub-basement membrane collagen within the submucosa. These changes point to "compression-induced epithelial damage and ongoing proliferative repair responses," the investigators said.

"We speculate that sustained and safe bronchoprotection in addition to adequate control of inflammation should be the aim in [asthma] patients in order to prevent the long-term adverse consequences of airway remodeling."

The researchers added that the study findings "not only [have] relevance for asthma but may also provide an explanation for the remodeling described in patients with chronic cough."

This study was supported by the U.K. Defence Postgraduate Medical Deanery and the U.K. Medical Research Council. No financial conflicts of interest were reported.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Abiraterone acetate, a selective inhibitor of androgen biosynthesis, prolonged overall survival, reduced mortality risk by 35%, and delayed time to disease progression in men with metastatic castration-resistant prostate cancer who had already undergone chemotherapy, according to a report in the May 26 issue of the New England Journal of Medicine.

"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this [advanced] stage of the disease," wrote Dr. Johann S. de Bono of the Institute of Cancer Research and Royal Marsden Hospital, Sutton (England), and his associates.

Several previous studies have demonstrated that, despite medical or surgical castration, prostate cancers continue to have sufficient levels of androgens, perhaps from synthesis within the tumor itself, to propel tumor growth. In phase I and phase II trials, abiraterone acetate – which potently blocks cytochrome P450 c17 (CYP17), an enzyme critical to testosterone synthesis – has shown promising antitumor activity even in advanced prostate cancer.

Dr. de Bono and his colleagues performed this international phase III randomized double-blind trial at 147 sites to compare daily oral therapy with four 250-mg abiraterone acetate tablets plus low-dose prednisone against placebo plus low-dose prednisone. They enrolled 1,195 men who had previously received docetaxel and showed disease progression despite ongoing androgen deprivation.

The primary end point of the study was overall survival.

At a preplanned interim analysis, active treatment was found to reduce the risk of death by 35%, compared with placebo. Mortality was 42% with active treatment, compared with 55% with placebo. Median overall survival was 14.8 months with abiraterone, compared with 10.9 months with placebo, the investigators reported (N. Engl J. Med. 2011;364:1995-2005).

This survival benefit "was consistent across all subgroups, and ... robust after adjustment for stratification factors in a multivariate analysis," they said.

Based on these findings, the trial was unblinded and patients in the placebo group were allowed to switch to active treatment.

"All the secondary end points analyzed provided support for the superiority of abiraterone acetate over placebo," Dr. de Bono and his associates said. Treatment response was greater with abiraterone whether measured by PSA levels (29% response vs. 6%) or Response Evaluation Criteria in Solid Tumors (RECIST) criteria (14% vs. 3%). Time to PSA progression was longer (10.2 months vs. 6.6 months), as was median progression-free survival on radiography (5.6 vs. 3.6 months).

Active treatment reduced the risk of disease progression by 42% when assessed by PSA levels and by 33% when assessed by radiographic imaging.

Exploratory end points, including pain palliation and time to 25% of patients having a skeletal event, also consistently favored abiraterone over placebo.

"This study validates the hypothesis that the biosyntehsis of steroid hormones downstream of CYP17 contributes to progression of castration-resistant prostate cancer in a subgroup of men for whom this disease remains driven by steroid ligands and should not be described as ‘hormone refractory.’ Since these men cannot be identified a priori, continuing to call this disease ‘androgen independent’ or ‘hormone refractory’ is imprecise," Dr. de Bono and his associates said.

"As our study shows, blocking androgen synthesis by inhibiting CYP17 can produce tumor responses in patients who no longer have a response to standard hormonal therapies and who had received docetaxel-based chemotherapy," they added.

Compliance with abiraterone acetate therapy was high, "and side effects were easily manageable and reversible, despite the advanced age and level of frailty of the study population," the investigators said.

Toxic effects included hypokalemia, hypertension, and fluid retention, "which were largely abrogated by the use of low-dose prednisone," they wrote.

The rates of drug discontinuation and dose reduction were low, and therapy "did not appear to increase the risk of metabolic changes or symptoms associated with chronic androgen deprivation. Nevertheless, longer follow-up is warranted to evaluate late toxic effects," they noted.

This study was sponsored by Ortho Biotech Oncology Research and Development, a unit of Cougar Biotechnology, with further support provided by the Medical Research Council of the United Kingdom, the Experimental Cancer Medical Centre, the National Institute for Health Research Biomedical Research Centre, and the Prostate Cancer Foundation. Dr. de Bono is employed by the Institute of Cancer Research, where abiraterone was designed and synthesized, and which has a commercial interest in the drug. He and his associates reported ties to numerous drug and biotechnology companies.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.

Rates of bacterial meningitis dropped markedly among all age groups in the United States during the past decade but have declined most strikingly in children, according to a report in the May 26 issue of the New England Journal of Medicine.

This trend is probably the result of the success of pneumococcal and Hib conjugate vaccines in preventing these infections in early childhood. The epidemiology of bacterial meningitis has shifted, with the most obvious change being the increase in the average patient age at diagnosis, according to Dr. Michael C. Thigpen of the Centers for Disease Control and Prevention, Atlanta, and his associates.

The investigators tracked changes in the epidemiology of bacterial meningitis cases from 1998 through 2007 using data from two surveillance systems, one laboratory based and the other population based, in the CDC’s Emerging Infections Program network. The network covered approximately 17.4 million people residing in eight regions of the country during the study period.

The researchers identified 3,188 cases of bacterial meningitis resulting from the five most common causative organisims: Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis, group B streptococcus, or Listeria monocytogenes. The overall fatality rate was 15%.

The overall incidence of these infections declined from 2.00 cases per 100,000 people to 1.38 per 100,000 – approximately 30%.

Rates of meningitis declined most dramatically among children, probably because of the introduction of the PCV7 vaccine. This decline correlated with a rise in the median age of bacterial meningitis patients, from about 30 years to 42 years.

The incidence of bacterial meningitis also declined among adults aged 65 and older and may decline further in this age group because of reduced exposure as more "children are vaccinated with the newly licensed PCV13," Dr. Thigpen and his colleagues said (N. Engl. J. Med. 2011;364:2016-25).

Nevertheless, the case fatality rate did not change significantly. It was 15.7% in 1998 and 14.3% in 2007.

Although the epidemiology of bacterial meningitis has changed, the ranking of causative organisms has not. "For clinicians, [this suggests] that current treatment guidelines ... targeting the major pathogenic causes are still appropriate."

S. pneumoniae was the most common causative pathogen among adults as well as children aged 1-11 years. Group B strep accounted for most cases among infants, and that rate did not decrease.

The rate of N. meningitidis infection decreased, but that organism still accounted for most cases of bacterial meningitis that developed in adolescents. "As the proportion of children receiving MCV4 continues to increase, we expect additional reductions in the incidence of meningococcal disease," the investigators said.

This study probably underestimates the true burden of bacterial meningitis for three main reasons.

First, the databases only included culture-proven cases, and the accuracy of that identification "depends on the diagnostic and therapeutic practices of those caring for patients," they said.

Second, the databases did not cover all the possible pathogens that cause bacterial meningitis, such as Escherichia coli and some species of staph.

Third, the databases do not routinely collect information on cases acquired in health care settings, "which may account for up to 40% of cases," Dr. Thigpen and his associates said.

The study was supported by the Centers for Disease Control and Prevention. Some of Dr. Thigpen’s associates reported financial ties to Merck, Wyeth, Sanofi Pasteur, Novartis, GlaxoSmithKline, and Pfizer.