Miriam E. Tucker

ATLANTA — The recent measles outbreak in San Diego—started by one child who imported the disease from Switzerland—reinforces the ongoing need to maintain high vaccination coverage, Dr. Jane Seward said at the winter meeting of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

The unvaccinated 7-year-old boy, who had rash onset 12 days after returning to the United States, infected at least 11 additional children ranging in age from 10 months to 9 years. Four were infected in the pediatrician's office that the child had visited the day before he was taken to a hospital emergency department for high fever and generalized rash. Another two cases were the boy's siblings, while five attended his school.

One infant was hospitalized for 2 days for dehydration, and another traveled by plane to Hawaii while infectious, necessitating “quite a response” by public health authorities in that state, Dr. Seward noted.

All cases were unvaccinated, including eight whose parents had claimed personal belief exemptions. In fact, 10% of the 350 children in the index child's school—kindergarten through 9th grade—were unimmunized because of these sorts of such exemptions, said Dr. Seward, acting deputy director of the CDC's division of viral diseases, National Center for Immunizations and Respiratory Diseases. The other four children were unimmunized because three were less than 12 months of age and therefore too young to be vaccinated and the fourth had received her routine vaccination 6 days after the unrecognized exposure.

At the time of publication in the CDC's Morbidity and Mortality Weekly Report, the episode had necessitated quarantine of 70 children who lacked evidence of immunity (MMWR 2008;57:[early release]1–4).

In the 1950s, 3 million to 4 million cases of measles occurred annually in the United States, causing 4,000 cases of encephalitis, 150,000 respiratory complications, 48,000 hospitalizations, and 450 deaths. Since the implementation of a two-dose immunization schedule in the early 1990s, measles is no longer endemic in the United States. Today, all of the 50 or so U.S. cases reported annually were imported from developed countries including those in Europe and Asia.

There's good and bad news in the San Diego situation, Dr. Seward said. The bad news is that measles is highly infectious and still poses a threat, unimmunized people are still at risk, and many health care providers are not familiar enough with the disease to ensure appropriate infection-control practices in their offices. But on the upside, there were no cases in immunized children. “The wall of immunity held fast. … We need to remember we have an ongoing challenge to sustaining high vaccine coverage to maintain our current [measles] elimination status.”

ATLANTA — The recent measles outbreak in San Diego—started by one child who imported the disease from Switzerland—reinforces the ongoing need to maintain high vaccination coverage, Dr. Jane Seward said at the winter meeting of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

The unvaccinated 7-year-old boy, who had rash onset 12 days after returning to the United States, infected at least 11 additional children ranging in age from 10 months to 9 years. Four were infected in the pediatrician's office that the child had visited the day before he was taken to a hospital emergency department for high fever and generalized rash. Another two cases were the boy's siblings, while five attended his school.

One infant was hospitalized for 2 days for dehydration, and another traveled by plane to Hawaii while infectious, necessitating “quite a response” by public health authorities in that state, Dr. Seward noted.

All cases were unvaccinated, including eight whose parents had claimed personal belief exemptions. In fact, 10% of the 350 children in the index child's school—kindergarten through 9th grade—were unimmunized because of these sorts of such exemptions, said Dr. Seward, acting deputy director of the CDC's division of viral diseases, National Center for Immunizations and Respiratory Diseases. The other four children were unimmunized because three were less than 12 months of age and therefore too young to be vaccinated and the fourth had received her routine vaccination 6 days after the unrecognized exposure.

At the time of publication in the CDC's Morbidity and Mortality Weekly Report, the episode had necessitated quarantine of 70 children who lacked evidence of immunity (MMWR 2008;57:[early release]1–4).

In the 1950s, 3 million to 4 million cases of measles occurred annually in the United States, causing 4,000 cases of encephalitis, 150,000 respiratory complications, 48,000 hospitalizations, and 450 deaths. Since the implementation of a two-dose immunization schedule in the early 1990s, measles is no longer endemic in the United States. Today, all of the 50 or so U.S. cases reported annually were imported from developed countries including those in Europe and Asia.

There's good and bad news in the San Diego situation, Dr. Seward said. The bad news is that measles is highly infectious and still poses a threat, unimmunized people are still at risk, and many health care providers are not familiar enough with the disease to ensure appropriate infection-control practices in their offices. But on the upside, there were no cases in immunized children. “The wall of immunity held fast. … We need to remember we have an ongoing challenge to sustaining high vaccine coverage to maintain our current [measles] elimination status.”

ATLANTA — The recent measles outbreak in San Diego—started by one child who imported the disease from Switzerland—reinforces the ongoing need to maintain high vaccination coverage, Dr. Jane Seward said at the winter meeting of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices.

The unvaccinated 7-year-old boy, who had rash onset 12 days after returning to the United States, infected at least 11 additional children ranging in age from 10 months to 9 years. Four were infected in the pediatrician's office that the child had visited the day before he was taken to a hospital emergency department for high fever and generalized rash. Another two cases were the boy's siblings, while five attended his school.

One infant was hospitalized for 2 days for dehydration, and another traveled by plane to Hawaii while infectious, necessitating “quite a response” by public health authorities in that state, Dr. Seward noted.

All cases were unvaccinated, including eight whose parents had claimed personal belief exemptions. In fact, 10% of the 350 children in the index child's school—kindergarten through 9th grade—were unimmunized because of these sorts of such exemptions, said Dr. Seward, acting deputy director of the CDC's division of viral diseases, National Center for Immunizations and Respiratory Diseases. The other four children were unimmunized because three were less than 12 months of age and therefore too young to be vaccinated and the fourth had received her routine vaccination 6 days after the unrecognized exposure.

At the time of publication in the CDC's Morbidity and Mortality Weekly Report, the episode had necessitated quarantine of 70 children who lacked evidence of immunity (MMWR 2008;57:[early release]1–4).

In the 1950s, 3 million to 4 million cases of measles occurred annually in the United States, causing 4,000 cases of encephalitis, 150,000 respiratory complications, 48,000 hospitalizations, and 450 deaths. Since the implementation of a two-dose immunization schedule in the early 1990s, measles is no longer endemic in the United States. Today, all of the 50 or so U.S. cases reported annually were imported from developed countries including those in Europe and Asia.

There's good and bad news in the San Diego situation, Dr. Seward said. The bad news is that measles is highly infectious and still poses a threat, unimmunized people are still at risk, and many health care providers are not familiar enough with the disease to ensure appropriate infection-control practices in their offices. But on the upside, there were no cases in immunized children. “The wall of immunity held fast. … We need to remember we have an ongoing challenge to sustaining high vaccine coverage to maintain our current [measles] elimination status.”

ATLANTA — Routine use of the conjugate meningococcal vaccine is not recommended for children aged 2–10 years, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention decided at its winter meeting.

Currently recommended for routine use in adolescents aged 11–18 years, the quadrivalent meningococcal conjugate vaccine (MCV4) (Sanofi Pasteur Inc.'s Menactra) was approved by the Food and Drug Administration for use in children aged 2–10 years on Oct. 17, 2007. Prior to that, it had been licensed for use in persons aged 11–55 years. Also in October, the ACIP recommended MCV4 instead of the old meningococcal polysaccharide vaccine (Sanofi Pasteur's Menomune) for children aged 2–10 years who are at high risk for meningococcal disease. These include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement component deficiencies, and children who have anatomic or functional asplenia (MMWR 2007;56:1265–6).

After considering data on the burden of disease, population impact, economic analysis, and other factors, an ACIP working group determined that routine vaccination against meningococcal disease in children aged 2–10 years should not be recommended at this time, other than for the children at high risk.

However, if providers or parents choose to vaccinate children in that age group, MCV4 is preferred over the polysaccharide vaccine. After hearing an outline of the rationale for this recommendation, the full committee voted unanimously (with one abstention) to support it.

Dr. Amanda Cohn of the CDC's National Center for Immunization and Respiratory Diseases' Division of Bacterial Diseases presented the working group's conclusions. Overall, the incidence of meningococcal disease is at a “historic low,” having decreased or remained stable each year for the last decade.

In the year 2006, the most recent for which data are available, the overall incidence in the population was 0.3/100,000, compared with 1.3/100,000 10 years earlier. “Being at this nadir did impact the working group's decision,” she said.

In most studies, young children have a low prevalence of Neisseria meningitidis carriage, compared with adolescents. While the current recommendation to give the vaccine to children aged 11–18 years is expected to protect them before they enter college, a time of high risk/incidence, giving the vaccine to 2-year-olds would be “catching the downslope.” Moreover, the proportion of disease caused by the serogroups contained in the vaccine—A, C, Y, and W-135—is just 59% in 2- to 10-year-olds, compared with 75% of the disease in adolescents.

An estimated 160 cases per year of meningococcal disease caused by serotypes A, C, Y, and W-135 occur among 2- to 10-year-olds, of which the majority (50%) are in children aged 2–4 years. Among 11- to 19-year-olds, approximately 250 cases occur annually, she said.

Cost-effectiveness analyses place the cost per quality-adjusted life-year (QALY) of giving MCV4 to all 2-year-olds at $160,000, compared with $90,000/QALY for the current adolescent immunization strategy, assuming the same duration of immunity. On top of that, there are currently no vaccines recommended to be given at the 2-year-old well-child visit, so such a recommendation would add programmatic concerns as well, Dr. Cohn pointed out.

Dr. Cohn suggested—and several panel members agreed—that it would be best to wait for the licensure of meningococcal vaccines for infants and/or toddlers, who have the highest meningococcal disease rates in the population (3.9/100,000). Several companies are working on this, and data thus far are positive (JAMA 2008;299:173–84).

Meanwhile, for those who still choose to immunize 2- to 10-year-olds, data do support the use of MCV4 rather than the polysaccharide vaccine (Pediatr. Infect. Dis. J. 2005;24:57–62).

ATLANTA — Routine use of the conjugate meningococcal vaccine is not recommended for children aged 2–10 years, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention decided at its winter meeting.

Currently recommended for routine use in adolescents aged 11–18 years, the quadrivalent meningococcal conjugate vaccine (MCV4) (Sanofi Pasteur Inc.'s Menactra) was approved by the Food and Drug Administration for use in children aged 2–10 years on Oct. 17, 2007. Prior to that, it had been licensed for use in persons aged 11–55 years. Also in October, the ACIP recommended MCV4 instead of the old meningococcal polysaccharide vaccine (Sanofi Pasteur's Menomune) for children aged 2–10 years who are at high risk for meningococcal disease. These include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement component deficiencies, and children who have anatomic or functional asplenia (MMWR 2007;56:1265–6).

After considering data on the burden of disease, population impact, economic analysis, and other factors, an ACIP working group determined that routine vaccination against meningococcal disease in children aged 2–10 years should not be recommended at this time, other than for the children at high risk.

However, if providers or parents choose to vaccinate children in that age group, MCV4 is preferred over the polysaccharide vaccine. After hearing an outline of the rationale for this recommendation, the full committee voted unanimously (with one abstention) to support it.

Dr. Amanda Cohn of the CDC's National Center for Immunization and Respiratory Diseases' Division of Bacterial Diseases presented the working group's conclusions. Overall, the incidence of meningococcal disease is at a “historic low,” having decreased or remained stable each year for the last decade.

In the year 2006, the most recent for which data are available, the overall incidence in the population was 0.3/100,000, compared with 1.3/100,000 10 years earlier. “Being at this nadir did impact the working group's decision,” she said.

In most studies, young children have a low prevalence of Neisseria meningitidis carriage, compared with adolescents. While the current recommendation to give the vaccine to children aged 11–18 years is expected to protect them before they enter college, a time of high risk/incidence, giving the vaccine to 2-year-olds would be “catching the downslope.” Moreover, the proportion of disease caused by the serogroups contained in the vaccine—A, C, Y, and W-135—is just 59% in 2- to 10-year-olds, compared with 75% of the disease in adolescents.

An estimated 160 cases per year of meningococcal disease caused by serotypes A, C, Y, and W-135 occur among 2- to 10-year-olds, of which the majority (50%) are in children aged 2–4 years. Among 11- to 19-year-olds, approximately 250 cases occur annually, she said.

Cost-effectiveness analyses place the cost per quality-adjusted life-year (QALY) of giving MCV4 to all 2-year-olds at $160,000, compared with $90,000/QALY for the current adolescent immunization strategy, assuming the same duration of immunity. On top of that, there are currently no vaccines recommended to be given at the 2-year-old well-child visit, so such a recommendation would add programmatic concerns as well, Dr. Cohn pointed out.

Dr. Cohn suggested—and several panel members agreed—that it would be best to wait for the licensure of meningococcal vaccines for infants and/or toddlers, who have the highest meningococcal disease rates in the population (3.9/100,000). Several companies are working on this, and data thus far are positive (JAMA 2008;299:173–84).

Meanwhile, for those who still choose to immunize 2- to 10-year-olds, data do support the use of MCV4 rather than the polysaccharide vaccine (Pediatr. Infect. Dis. J. 2005;24:57–62).

ATLANTA — Routine use of the conjugate meningococcal vaccine is not recommended for children aged 2–10 years, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention decided at its winter meeting.

Currently recommended for routine use in adolescents aged 11–18 years, the quadrivalent meningococcal conjugate vaccine (MCV4) (Sanofi Pasteur Inc.'s Menactra) was approved by the Food and Drug Administration for use in children aged 2–10 years on Oct. 17, 2007. Prior to that, it had been licensed for use in persons aged 11–55 years. Also in October, the ACIP recommended MCV4 instead of the old meningococcal polysaccharide vaccine (Sanofi Pasteur's Menomune) for children aged 2–10 years who are at high risk for meningococcal disease. These include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement component deficiencies, and children who have anatomic or functional asplenia (MMWR 2007;56:1265–6).

After considering data on the burden of disease, population impact, economic analysis, and other factors, an ACIP working group determined that routine vaccination against meningococcal disease in children aged 2–10 years should not be recommended at this time, other than for the children at high risk.

However, if providers or parents choose to vaccinate children in that age group, MCV4 is preferred over the polysaccharide vaccine. After hearing an outline of the rationale for this recommendation, the full committee voted unanimously (with one abstention) to support it.

Dr. Amanda Cohn of the CDC's National Center for Immunization and Respiratory Diseases' Division of Bacterial Diseases presented the working group's conclusions. Overall, the incidence of meningococcal disease is at a “historic low,” having decreased or remained stable each year for the last decade.

In the year 2006, the most recent for which data are available, the overall incidence in the population was 0.3/100,000, compared with 1.3/100,000 10 years earlier. “Being at this nadir did impact the working group's decision,” she said.

In most studies, young children have a low prevalence of Neisseria meningitidis carriage, compared with adolescents. While the current recommendation to give the vaccine to children aged 11–18 years is expected to protect them before they enter college, a time of high risk/incidence, giving the vaccine to 2-year-olds would be “catching the downslope.” Moreover, the proportion of disease caused by the serogroups contained in the vaccine—A, C, Y, and W-135—is just 59% in 2- to 10-year-olds, compared with 75% of the disease in adolescents.

An estimated 160 cases per year of meningococcal disease caused by serotypes A, C, Y, and W-135 occur among 2- to 10-year-olds, of which the majority (50%) are in children aged 2–4 years. Among 11- to 19-year-olds, approximately 250 cases occur annually, she said.

Cost-effectiveness analyses place the cost per quality-adjusted life-year (QALY) of giving MCV4 to all 2-year-olds at $160,000, compared with $90,000/QALY for the current adolescent immunization strategy, assuming the same duration of immunity. On top of that, there are currently no vaccines recommended to be given at the 2-year-old well-child visit, so such a recommendation would add programmatic concerns as well, Dr. Cohn pointed out.

Dr. Cohn suggested—and several panel members agreed—that it would be best to wait for the licensure of meningococcal vaccines for infants and/or toddlers, who have the highest meningococcal disease rates in the population (3.9/100,000). Several companies are working on this, and data thus far are positive (JAMA 2008;299:173–84).

Meanwhile, for those who still choose to immunize 2- to 10-year-olds, data do support the use of MCV4 rather than the polysaccharide vaccine (Pediatr. Infect. Dis. J. 2005;24:57–62).

ATLANTA — Full immunization against influenza is approximately 75% effective in preventing hospitalizations in 6- to 23-month-old children, Dr. David Shay reported at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.

The ACIP's recommendation for annual influenza immunization for all children aged 6–23 months beginning in the 2004–2005 influenza season was based on the burden of disease in that age group and the fact that hospitalization rates among that age group were similar to those among the elderly, for whom annual flu vaccination was already recommended. However, no previous study has assessed the effectiveness of the trivalent inactivated vaccine (TIV) in preventing laboratory-confirmed hospitalizations in that age group, said Dr. Shay of the CDC's National Center for Immunization and Respiratory Diseases, Influenza Division.

Now, a multistate case-control study conducted during the 2005–2006 and 2006–2007 flu seasons has confirmed that TIV indeed prevents influenza-related hospitalizations in 6- to 23-month-olds, but only if they receive “full” immunization.

“Partial immunization was less effective, and not significantly protective, based on two seasons of data. It is critical to ensure that children aged 6–23 months are fully immunized if we seek to prevent influenza-associated hospitalizations among children,” Dr. Shay commented.

The data were analyzed using the 2007 definition of “full” immunization, which is more stringent than it had been during the study period: The child must have received two doses during the current season if he or she had never previously received TIV or if they had received only one dose in the previous season. A child who received just one dose in the current season would be considered “fully” immunized if he or she received two doses in a single prior season or had one dose in two or more prior seasons.

The study population comprised 93 of a total 191 eligible 6- to 23-month-old children who were hospitalized with laboratory-confirmed influenza (85% type A, 12% B, and 3% unknown), identified at eight U.S. state health department surveillance sites, and 334 age-matched controls. Cases and controls also were well matched by gender (56% of cases and 52% of controls were male) and by race (72% and 80% were white, respectively).

During the 2005–2006 season, only 9% of cases were fully immunized, compared with 20% of controls. Sixty-seven percent of cases were not immunized, compared with 55% of controls, while about a quarter of both groups were partially immunized. In 2006–2007, only 13% of cases had been immunized, compared with 32% of controls, while 65% of cases were not immunized vs. 38% of controls. Again, the rates of partial immunization were similar, 23% among cases and 30% among controls. (Cumulative percentages might exceed 100% because of rounding.)

Overall effectiveness of TIV in preventing hospitalization was 74% for full immunization, compared with just 39% for partial immunization. Adjustment for high-risk conditions, very low birth weight, and insurance status did not significantly change the result for full immunization (76%), but it dropped the effectiveness of partial immunization to just 27%, Dr. Shay reported.

Following Dr. Shay's presentation, ACIP member Dr. Carol J. Baker urged meeting participants to “get the message out” to their constituencies about the importance of giving two doses in the 6–23 month age group, even if it means vaccinating late into the season. “Unfortunately, we have created a culture of stopping vaccination in late November, early December. … That mentality must change,” said Dr. Baker, professor of pediatrics, molecular virology, and microbiology at Baylor College of Medicine, Houston.

ATLANTA — Full immunization against influenza is approximately 75% effective in preventing hospitalizations in 6- to 23-month-old children, Dr. David Shay reported at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.

The ACIP's recommendation for annual influenza immunization for all children aged 6–23 months beginning in the 2004–2005 influenza season was based on the burden of disease in that age group and the fact that hospitalization rates among that age group were similar to those among the elderly, for whom annual flu vaccination was already recommended. However, no previous study has assessed the effectiveness of the trivalent inactivated vaccine (TIV) in preventing laboratory-confirmed hospitalizations in that age group, said Dr. Shay of the CDC's National Center for Immunization and Respiratory Diseases, Influenza Division.

Now, a multistate case-control study conducted during the 2005–2006 and 2006–2007 flu seasons has confirmed that TIV indeed prevents influenza-related hospitalizations in 6- to 23-month-olds, but only if they receive “full” immunization.

“Partial immunization was less effective, and not significantly protective, based on two seasons of data. It is critical to ensure that children aged 6–23 months are fully immunized if we seek to prevent influenza-associated hospitalizations among children,” Dr. Shay commented.

The data were analyzed using the 2007 definition of “full” immunization, which is more stringent than it had been during the study period: The child must have received two doses during the current season if he or she had never previously received TIV or if they had received only one dose in the previous season. A child who received just one dose in the current season would be considered “fully” immunized if he or she received two doses in a single prior season or had one dose in two or more prior seasons.

The study population comprised 93 of a total 191 eligible 6- to 23-month-old children who were hospitalized with laboratory-confirmed influenza (85% type A, 12% B, and 3% unknown), identified at eight U.S. state health department surveillance sites, and 334 age-matched controls. Cases and controls also were well matched by gender (56% of cases and 52% of controls were male) and by race (72% and 80% were white, respectively).

During the 2005–2006 season, only 9% of cases were fully immunized, compared with 20% of controls. Sixty-seven percent of cases were not immunized, compared with 55% of controls, while about a quarter of both groups were partially immunized. In 2006–2007, only 13% of cases had been immunized, compared with 32% of controls, while 65% of cases were not immunized vs. 38% of controls. Again, the rates of partial immunization were similar, 23% among cases and 30% among controls. (Cumulative percentages might exceed 100% because of rounding.)

Overall effectiveness of TIV in preventing hospitalization was 74% for full immunization, compared with just 39% for partial immunization. Adjustment for high-risk conditions, very low birth weight, and insurance status did not significantly change the result for full immunization (76%), but it dropped the effectiveness of partial immunization to just 27%, Dr. Shay reported.

Following Dr. Shay's presentation, ACIP member Dr. Carol J. Baker urged meeting participants to “get the message out” to their constituencies about the importance of giving two doses in the 6–23 month age group, even if it means vaccinating late into the season. “Unfortunately, we have created a culture of stopping vaccination in late November, early December. … That mentality must change,” said Dr. Baker, professor of pediatrics, molecular virology, and microbiology at Baylor College of Medicine, Houston.

ATLANTA — Full immunization against influenza is approximately 75% effective in preventing hospitalizations in 6- to 23-month-old children, Dr. David Shay reported at the winter meeting of the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.

The ACIP's recommendation for annual influenza immunization for all children aged 6–23 months beginning in the 2004–2005 influenza season was based on the burden of disease in that age group and the fact that hospitalization rates among that age group were similar to those among the elderly, for whom annual flu vaccination was already recommended. However, no previous study has assessed the effectiveness of the trivalent inactivated vaccine (TIV) in preventing laboratory-confirmed hospitalizations in that age group, said Dr. Shay of the CDC's National Center for Immunization and Respiratory Diseases, Influenza Division.

Now, a multistate case-control study conducted during the 2005–2006 and 2006–2007 flu seasons has confirmed that TIV indeed prevents influenza-related hospitalizations in 6- to 23-month-olds, but only if they receive “full” immunization.

“Partial immunization was less effective, and not significantly protective, based on two seasons of data. It is critical to ensure that children aged 6–23 months are fully immunized if we seek to prevent influenza-associated hospitalizations among children,” Dr. Shay commented.

The data were analyzed using the 2007 definition of “full” immunization, which is more stringent than it had been during the study period: The child must have received two doses during the current season if he or she had never previously received TIV or if they had received only one dose in the previous season. A child who received just one dose in the current season would be considered “fully” immunized if he or she received two doses in a single prior season or had one dose in two or more prior seasons.

The study population comprised 93 of a total 191 eligible 6- to 23-month-old children who were hospitalized with laboratory-confirmed influenza (85% type A, 12% B, and 3% unknown), identified at eight U.S. state health department surveillance sites, and 334 age-matched controls. Cases and controls also were well matched by gender (56% of cases and 52% of controls were male) and by race (72% and 80% were white, respectively).

During the 2005–2006 season, only 9% of cases were fully immunized, compared with 20% of controls. Sixty-seven percent of cases were not immunized, compared with 55% of controls, while about a quarter of both groups were partially immunized. In 2006–2007, only 13% of cases had been immunized, compared with 32% of controls, while 65% of cases were not immunized vs. 38% of controls. Again, the rates of partial immunization were similar, 23% among cases and 30% among controls. (Cumulative percentages might exceed 100% because of rounding.)

Overall effectiveness of TIV in preventing hospitalization was 74% for full immunization, compared with just 39% for partial immunization. Adjustment for high-risk conditions, very low birth weight, and insurance status did not significantly change the result for full immunization (76%), but it dropped the effectiveness of partial immunization to just 27%, Dr. Shay reported.

Following Dr. Shay's presentation, ACIP member Dr. Carol J. Baker urged meeting participants to “get the message out” to their constituencies about the importance of giving two doses in the 6–23 month age group, even if it means vaccinating late into the season. “Unfortunately, we have created a culture of stopping vaccination in late November, early December. … That mentality must change,” said Dr. Baker, professor of pediatrics, molecular virology, and microbiology at Baylor College of Medicine, Houston.

WASHINGTON — Financial assistance is available to patients struggling with costs of the new—and extremely expensive—targeted therapies for renal cell carcinoma as well as other advanced cancers, Mr. James Goetz announced at the annual Community Oncology Conference.

As far as the patient is concerned, the approved agents sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus (Torisel) are all in the same cost ballpark, with each resulting in a bill of about $135,000 for a 6-month regimen at St. Luke's Hospital and Health Network in Bethlehem, Pa., where Mr. Goetz is the network administrator of the Oncology Service Line.

“We're seeing more and more patients on Medicare without secondary insurance, those who are underinsured, and who have no insurance. … The onus of these expensive drugs is on the patient,” he said.

But there are places to turn for help, according to Mr. Goetz.

First, all the manufacturers offer patient assistance programs, accessible on their Web sites (www.sutent.comwww.nexavar.comwww.torisel.com

Nonprofit organizations can help fill in the gaps.

A highly recommended resource is the Patient Advocate Foundation (PAF; www.patientadvocate.org

The foundation employs professional case managers and attorneys to assist patients with a wide range of access-to-care issues, including pre-authorization, insurance appeals, and assistance with expedited applications for Social Security disability, Medicare, Medicaid, SCHIP, and other programs.

It also provides assistance with job retention, debt crisis, housing, transportation to medical treatment, and child care. In addition, it offers a “Co-Pay Relief” program for those who are already insured, and an assistance program geared specifically to patients with colorectal cancer.

“The PAF is a great resource that we give to many of our patients,” Mr. Goetz said.

Other potentially helpful nonprofit patient assistance organizations listed by Mr. Goetz include the following:

▸ Patient Access Network Foundation (www.patientaccessnetwork.org

▸ Healthwell Foundation (www.healthwellfoundation.org

▸ Cancer Care (www.cancercare.org

Mr. Goetz declared no financial interest in any of the relevant manufacturers' drugs. The Community Oncology Conference and this newspaper are both produced by Elsevier.

WASHINGTON — Financial assistance is available to patients struggling with costs of the new—and extremely expensive—targeted therapies for renal cell carcinoma as well as other advanced cancers, Mr. James Goetz announced at the annual Community Oncology Conference.

As far as the patient is concerned, the approved agents sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus (Torisel) are all in the same cost ballpark, with each resulting in a bill of about $135,000 for a 6-month regimen at St. Luke's Hospital and Health Network in Bethlehem, Pa., where Mr. Goetz is the network administrator of the Oncology Service Line.

“We're seeing more and more patients on Medicare without secondary insurance, those who are underinsured, and who have no insurance. … The onus of these expensive drugs is on the patient,” he said.

But there are places to turn for help, according to Mr. Goetz.

First, all the manufacturers offer patient assistance programs, accessible on their Web sites (www.sutent.comwww.nexavar.comwww.torisel.com

Nonprofit organizations can help fill in the gaps.

A highly recommended resource is the Patient Advocate Foundation (PAF; www.patientadvocate.org

The foundation employs professional case managers and attorneys to assist patients with a wide range of access-to-care issues, including pre-authorization, insurance appeals, and assistance with expedited applications for Social Security disability, Medicare, Medicaid, SCHIP, and other programs.

It also provides assistance with job retention, debt crisis, housing, transportation to medical treatment, and child care. In addition, it offers a “Co-Pay Relief” program for those who are already insured, and an assistance program geared specifically to patients with colorectal cancer.

“The PAF is a great resource that we give to many of our patients,” Mr. Goetz said.

Other potentially helpful nonprofit patient assistance organizations listed by Mr. Goetz include the following:

▸ Patient Access Network Foundation (www.patientaccessnetwork.org

▸ Healthwell Foundation (www.healthwellfoundation.org

▸ Cancer Care (www.cancercare.org

Mr. Goetz declared no financial interest in any of the relevant manufacturers' drugs. The Community Oncology Conference and this newspaper are both produced by Elsevier.

WASHINGTON — Financial assistance is available to patients struggling with costs of the new—and extremely expensive—targeted therapies for renal cell carcinoma as well as other advanced cancers, Mr. James Goetz announced at the annual Community Oncology Conference.

As far as the patient is concerned, the approved agents sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus (Torisel) are all in the same cost ballpark, with each resulting in a bill of about $135,000 for a 6-month regimen at St. Luke's Hospital and Health Network in Bethlehem, Pa., where Mr. Goetz is the network administrator of the Oncology Service Line.

“We're seeing more and more patients on Medicare without secondary insurance, those who are underinsured, and who have no insurance. … The onus of these expensive drugs is on the patient,” he said.

But there are places to turn for help, according to Mr. Goetz.

First, all the manufacturers offer patient assistance programs, accessible on their Web sites (www.sutent.comwww.nexavar.comwww.torisel.com

Nonprofit organizations can help fill in the gaps.

A highly recommended resource is the Patient Advocate Foundation (PAF; www.patientadvocate.org

The foundation employs professional case managers and attorneys to assist patients with a wide range of access-to-care issues, including pre-authorization, insurance appeals, and assistance with expedited applications for Social Security disability, Medicare, Medicaid, SCHIP, and other programs.

It also provides assistance with job retention, debt crisis, housing, transportation to medical treatment, and child care. In addition, it offers a “Co-Pay Relief” program for those who are already insured, and an assistance program geared specifically to patients with colorectal cancer.

“The PAF is a great resource that we give to many of our patients,” Mr. Goetz said.

Other potentially helpful nonprofit patient assistance organizations listed by Mr. Goetz include the following:

▸ Patient Access Network Foundation (www.patientaccessnetwork.org

▸ Healthwell Foundation (www.healthwellfoundation.org

▸ Cancer Care (www.cancercare.org

Mr. Goetz declared no financial interest in any of the relevant manufacturers' drugs. The Community Oncology Conference and this newspaper are both produced by Elsevier.

WASHINGTON — “You're not going to die of prostate cancer.” That's the first thing Dr. Tanya B. Dorff, a specialist in genitourinary oncology, tells most of the patients with localized prostate cancer who are referred to her.

That simple sentence “opens the mind to receive all the other information and process it to make an informed analytical decision … I tell them we're not talking about death, but their chances of surviving free of PSA,” she said at the annual Community Oncology Conference.

Another clinical pearl: Many patients have had a biopsy done at a community hospital that lacks specialists in prostate pathology. Whenever there is a question or inconsistency, Dr. Dorff sends the specimen for a second opinion pathology review to a center such as Johns Hopkins or Bostwick Laboratories that has expertise in this area, “because so much of what we're telling our patients is based on the Gleason score,” said Dr. Dorff of the Angeles Clinic and Research Institute, Santa Monica, Calif.

Patients at low or intermediate risk for disease progression will often wonder why they're not receiving all the imaging tests that other family members with cancer underwent for disease staging. Simple reassurance will usually suffice here, although there are a couple of situations in which Dr. Dorff does consider imaging in patients who are not at high risk for progression.

Also, for an intermediate or high-risk patient who is undecided about whether to choose surgery or radiation, an MRI can identify whether there is extracapsular extension or seminal vesicle involvement. Such a finding would point to the need for adjuvant radiation along with surgery, in which case he might choose primary radiation with hormone therapy instead.

Indeed, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) are emerging technologies that hold promise for improving prognostic and treatment capabilities in the future.

When it comes to quality of life considerations, simplify the side effects discussion by telling the patient it really comes down to a tradeoff between bowel toxicity—slightly more prevalent with radiation—and urinary toxicity, somewhat more likely with surgery. Impotence isn't part of the equation because that risk isn't decisively different between modalities. “I tell patients that most of them will not end up with these consequences, and their risk is minimized by going to a high-volume urologist and radiation oncologist.”

Low-risk patients can also be given the luxury of time. Data from at least one study suggest that delaying treatment for up to 12 months did not compromise curability, compared with immediate surgery (J. Natl. Cancer Inst. 2006;98:355–7). However, there's a bit more pressure for high-risk patients, who should be encouraged to decide within a few weeks.

One should also discuss plans for surveillance after treatment, the need for bone mineral density and cardiac evaluation for patients on androgen deprivation therapy, screening recommendations for family members, and a review of the patient's lifestyle and dietary habits.

FAMILY PRACTICE NEWS and Community Oncology are published by Elsevier.

WASHINGTON — “You're not going to die of prostate cancer.” That's the first thing Dr. Tanya B. Dorff, a specialist in genitourinary oncology, tells most of the patients with localized prostate cancer who are referred to her.

That simple sentence “opens the mind to receive all the other information and process it to make an informed analytical decision … I tell them we're not talking about death, but their chances of surviving free of PSA,” she said at the annual Community Oncology Conference.

Another clinical pearl: Many patients have had a biopsy done at a community hospital that lacks specialists in prostate pathology. Whenever there is a question or inconsistency, Dr. Dorff sends the specimen for a second opinion pathology review to a center such as Johns Hopkins or Bostwick Laboratories that has expertise in this area, “because so much of what we're telling our patients is based on the Gleason score,” said Dr. Dorff of the Angeles Clinic and Research Institute, Santa Monica, Calif.

Patients at low or intermediate risk for disease progression will often wonder why they're not receiving all the imaging tests that other family members with cancer underwent for disease staging. Simple reassurance will usually suffice here, although there are a couple of situations in which Dr. Dorff does consider imaging in patients who are not at high risk for progression.

Also, for an intermediate or high-risk patient who is undecided about whether to choose surgery or radiation, an MRI can identify whether there is extracapsular extension or seminal vesicle involvement. Such a finding would point to the need for adjuvant radiation along with surgery, in which case he might choose primary radiation with hormone therapy instead.

Indeed, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) are emerging technologies that hold promise for improving prognostic and treatment capabilities in the future.

When it comes to quality of life considerations, simplify the side effects discussion by telling the patient it really comes down to a tradeoff between bowel toxicity—slightly more prevalent with radiation—and urinary toxicity, somewhat more likely with surgery. Impotence isn't part of the equation because that risk isn't decisively different between modalities. “I tell patients that most of them will not end up with these consequences, and their risk is minimized by going to a high-volume urologist and radiation oncologist.”

Low-risk patients can also be given the luxury of time. Data from at least one study suggest that delaying treatment for up to 12 months did not compromise curability, compared with immediate surgery (J. Natl. Cancer Inst. 2006;98:355–7). However, there's a bit more pressure for high-risk patients, who should be encouraged to decide within a few weeks.

One should also discuss plans for surveillance after treatment, the need for bone mineral density and cardiac evaluation for patients on androgen deprivation therapy, screening recommendations for family members, and a review of the patient's lifestyle and dietary habits.

FAMILY PRACTICE NEWS and Community Oncology are published by Elsevier.

WASHINGTON — “You're not going to die of prostate cancer.” That's the first thing Dr. Tanya B. Dorff, a specialist in genitourinary oncology, tells most of the patients with localized prostate cancer who are referred to her.

That simple sentence “opens the mind to receive all the other information and process it to make an informed analytical decision … I tell them we're not talking about death, but their chances of surviving free of PSA,” she said at the annual Community Oncology Conference.

Another clinical pearl: Many patients have had a biopsy done at a community hospital that lacks specialists in prostate pathology. Whenever there is a question or inconsistency, Dr. Dorff sends the specimen for a second opinion pathology review to a center such as Johns Hopkins or Bostwick Laboratories that has expertise in this area, “because so much of what we're telling our patients is based on the Gleason score,” said Dr. Dorff of the Angeles Clinic and Research Institute, Santa Monica, Calif.

Patients at low or intermediate risk for disease progression will often wonder why they're not receiving all the imaging tests that other family members with cancer underwent for disease staging. Simple reassurance will usually suffice here, although there are a couple of situations in which Dr. Dorff does consider imaging in patients who are not at high risk for progression.

Also, for an intermediate or high-risk patient who is undecided about whether to choose surgery or radiation, an MRI can identify whether there is extracapsular extension or seminal vesicle involvement. Such a finding would point to the need for adjuvant radiation along with surgery, in which case he might choose primary radiation with hormone therapy instead.

Indeed, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) are emerging technologies that hold promise for improving prognostic and treatment capabilities in the future.

When it comes to quality of life considerations, simplify the side effects discussion by telling the patient it really comes down to a tradeoff between bowel toxicity—slightly more prevalent with radiation—and urinary toxicity, somewhat more likely with surgery. Impotence isn't part of the equation because that risk isn't decisively different between modalities. “I tell patients that most of them will not end up with these consequences, and their risk is minimized by going to a high-volume urologist and radiation oncologist.”

Low-risk patients can also be given the luxury of time. Data from at least one study suggest that delaying treatment for up to 12 months did not compromise curability, compared with immediate surgery (J. Natl. Cancer Inst. 2006;98:355–7). However, there's a bit more pressure for high-risk patients, who should be encouraged to decide within a few weeks.

One should also discuss plans for surveillance after treatment, the need for bone mineral density and cardiac evaluation for patients on androgen deprivation therapy, screening recommendations for family members, and a review of the patient's lifestyle and dietary habits.

FAMILY PRACTICE NEWS and Community Oncology are published by Elsevier.

Long-term treatment with idraparinux is as effective as vitamin K antagonists for preventing thromboembolism in patients with atrial fibrillation, but it causes significantly more bleeding.

Those results, from the Sanofi Aventis-funded multinational open-label AMADEUS trial, mark the third recent failure to find an acceptable fixed-dose alternative to adjusted-dose vitamin K antagonists for stroke prevention in patients with atrial fibrillation. The study was stopped early after randomization of 4,576 patients because of excess clinically relevant bleeding with the investigational factor X inhibitor idraparinux, compared with vitamin K antagonists (Lancet 2008;371:315–21).

At the time that AMADEUS was halted (mean follow-up of 10.7 months), 2,283 patients had been randomized to subcutaneous idraparinux 2.5 mg/wk and 2,293 to oral adjusted-dose vitamin K antagonists (warfarin or acenocoumarol, target international normalized ratio of 2.0–3.0). All had nonvalvular atrial fibrillation and at least one indication for long-term anticoagulation. They had a mean age of 70 years; almost two-thirds were men.

In the vitamin K antagonist group, the INR was within target range 63% of the time, below target 18% of the time, and higher for 19%. More patients discontinued in the idraparinux group (13% vs. 10%), mainly because of adverse events, Dr. Harry R. Buller of the department of vascular medicine, Academic Medical Centre, Amsterdam, and associates.

Idraparinux was noninferior to vitamin K antagonists in the prevention of all stroke or non-CNS systemic embolism—the primary efficacy outcome—in both the intent-to-treat analysis (0.9 vs. 1.3 per 100 patient-years) and in the per-protocol analysis (0.9 vs. 1.2). However, the idraparinux group had overall excesses of clinically relevant bleeding (19.7 vs. 11.3 per 100 patient-years), nonmajor but clinically relevant bleeding (16.4 vs. 10.3), and intracranial hemorrhage (1.1 vs. 0.4). The differences in bleeding incidence became apparent after about 2 months of treatment.

Hemorrhagic stroke occurred in similar numbers in each group. Despite a higher rate of fatal bleeding with idraparinux (0.7 vs. less than 0.1 per 100 patient-years), overall mortality did not differ significantly between the groups (3.2% vs. 2.9%).

Elderly patients and those with renal insufficiency were at significantly increased risk of clinically relevant bleeding with idraparinux, compared with vitamin K antagonists. And irrespective of treatment allocation, clinically relevant bleeding was more than double in the 971 patients who took aspirin with the anticoagulant and in the 126 who took clopidogrel or ticlopidine than it was in those not taking concurrent platelet inhibitor medication. “This combination should be avoided [when] possible,” the authors said.

Adjusted-dose anticoagulation with vitamin K antagonists lowers the risk of stroke in high-risk patients by about two-thirds, but the complexity of the dose-adjustment regimen makes it difficult to carry out in clinical practice.

But Dr. Alan S. Go of Kaiser Permanente of Northern California, Oakland, and Dr. Daniel E. Singer of Massachusetts General Hospital, Boston, are optimistic an alternative will be found. “On the basis of positive features of recent trial experiences, one or more approaches … will emerge as an alternative to vitamin K antagonists,” they wrote in an accompanying comment. But, “We still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation.”

Bleeding was more than double in those taking warfarin with aspirin or those taking clopidogrel or ticlopidine. DR. BULLER

Long-term treatment with idraparinux is as effective as vitamin K antagonists for preventing thromboembolism in patients with atrial fibrillation, but it causes significantly more bleeding.

Those results, from the Sanofi Aventis-funded multinational open-label AMADEUS trial, mark the third recent failure to find an acceptable fixed-dose alternative to adjusted-dose vitamin K antagonists for stroke prevention in patients with atrial fibrillation. The study was stopped early after randomization of 4,576 patients because of excess clinically relevant bleeding with the investigational factor X inhibitor idraparinux, compared with vitamin K antagonists (Lancet 2008;371:315–21).

At the time that AMADEUS was halted (mean follow-up of 10.7 months), 2,283 patients had been randomized to subcutaneous idraparinux 2.5 mg/wk and 2,293 to oral adjusted-dose vitamin K antagonists (warfarin or acenocoumarol, target international normalized ratio of 2.0–3.0). All had nonvalvular atrial fibrillation and at least one indication for long-term anticoagulation. They had a mean age of 70 years; almost two-thirds were men.

In the vitamin K antagonist group, the INR was within target range 63% of the time, below target 18% of the time, and higher for 19%. More patients discontinued in the idraparinux group (13% vs. 10%), mainly because of adverse events, Dr. Harry R. Buller of the department of vascular medicine, Academic Medical Centre, Amsterdam, and associates.

Idraparinux was noninferior to vitamin K antagonists in the prevention of all stroke or non-CNS systemic embolism—the primary efficacy outcome—in both the intent-to-treat analysis (0.9 vs. 1.3 per 100 patient-years) and in the per-protocol analysis (0.9 vs. 1.2). However, the idraparinux group had overall excesses of clinically relevant bleeding (19.7 vs. 11.3 per 100 patient-years), nonmajor but clinically relevant bleeding (16.4 vs. 10.3), and intracranial hemorrhage (1.1 vs. 0.4). The differences in bleeding incidence became apparent after about 2 months of treatment.

Hemorrhagic stroke occurred in similar numbers in each group. Despite a higher rate of fatal bleeding with idraparinux (0.7 vs. less than 0.1 per 100 patient-years), overall mortality did not differ significantly between the groups (3.2% vs. 2.9%).

Elderly patients and those with renal insufficiency were at significantly increased risk of clinically relevant bleeding with idraparinux, compared with vitamin K antagonists. And irrespective of treatment allocation, clinically relevant bleeding was more than double in the 971 patients who took aspirin with the anticoagulant and in the 126 who took clopidogrel or ticlopidine than it was in those not taking concurrent platelet inhibitor medication. “This combination should be avoided [when] possible,” the authors said.

Adjusted-dose anticoagulation with vitamin K antagonists lowers the risk of stroke in high-risk patients by about two-thirds, but the complexity of the dose-adjustment regimen makes it difficult to carry out in clinical practice.

But Dr. Alan S. Go of Kaiser Permanente of Northern California, Oakland, and Dr. Daniel E. Singer of Massachusetts General Hospital, Boston, are optimistic an alternative will be found. “On the basis of positive features of recent trial experiences, one or more approaches … will emerge as an alternative to vitamin K antagonists,” they wrote in an accompanying comment. But, “We still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation.”

Bleeding was more than double in those taking warfarin with aspirin or those taking clopidogrel or ticlopidine. DR. BULLER

Long-term treatment with idraparinux is as effective as vitamin K antagonists for preventing thromboembolism in patients with atrial fibrillation, but it causes significantly more bleeding.

Those results, from the Sanofi Aventis-funded multinational open-label AMADEUS trial, mark the third recent failure to find an acceptable fixed-dose alternative to adjusted-dose vitamin K antagonists for stroke prevention in patients with atrial fibrillation. The study was stopped early after randomization of 4,576 patients because of excess clinically relevant bleeding with the investigational factor X inhibitor idraparinux, compared with vitamin K antagonists (Lancet 2008;371:315–21).

At the time that AMADEUS was halted (mean follow-up of 10.7 months), 2,283 patients had been randomized to subcutaneous idraparinux 2.5 mg/wk and 2,293 to oral adjusted-dose vitamin K antagonists (warfarin or acenocoumarol, target international normalized ratio of 2.0–3.0). All had nonvalvular atrial fibrillation and at least one indication for long-term anticoagulation. They had a mean age of 70 years; almost two-thirds were men.

In the vitamin K antagonist group, the INR was within target range 63% of the time, below target 18% of the time, and higher for 19%. More patients discontinued in the idraparinux group (13% vs. 10%), mainly because of adverse events, Dr. Harry R. Buller of the department of vascular medicine, Academic Medical Centre, Amsterdam, and associates.

Idraparinux was noninferior to vitamin K antagonists in the prevention of all stroke or non-CNS systemic embolism—the primary efficacy outcome—in both the intent-to-treat analysis (0.9 vs. 1.3 per 100 patient-years) and in the per-protocol analysis (0.9 vs. 1.2). However, the idraparinux group had overall excesses of clinically relevant bleeding (19.7 vs. 11.3 per 100 patient-years), nonmajor but clinically relevant bleeding (16.4 vs. 10.3), and intracranial hemorrhage (1.1 vs. 0.4). The differences in bleeding incidence became apparent after about 2 months of treatment.

Hemorrhagic stroke occurred in similar numbers in each group. Despite a higher rate of fatal bleeding with idraparinux (0.7 vs. less than 0.1 per 100 patient-years), overall mortality did not differ significantly between the groups (3.2% vs. 2.9%).

Elderly patients and those with renal insufficiency were at significantly increased risk of clinically relevant bleeding with idraparinux, compared with vitamin K antagonists. And irrespective of treatment allocation, clinically relevant bleeding was more than double in the 971 patients who took aspirin with the anticoagulant and in the 126 who took clopidogrel or ticlopidine than it was in those not taking concurrent platelet inhibitor medication. “This combination should be avoided [when] possible,” the authors said.

Adjusted-dose anticoagulation with vitamin K antagonists lowers the risk of stroke in high-risk patients by about two-thirds, but the complexity of the dose-adjustment regimen makes it difficult to carry out in clinical practice.

But Dr. Alan S. Go of Kaiser Permanente of Northern California, Oakland, and Dr. Daniel E. Singer of Massachusetts General Hospital, Boston, are optimistic an alternative will be found. “On the basis of positive features of recent trial experiences, one or more approaches … will emerge as an alternative to vitamin K antagonists,” they wrote in an accompanying comment. But, “We still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation.”

Bleeding was more than double in those taking warfarin with aspirin or those taking clopidogrel or ticlopidine. DR. BULLER

WASHINGTON — Thrombolytic therapy has resulted in limb salvage among 18 patients with severe frostbite treated at one Minnesota hospital in the last few years.

Thrombolytic therapy has been available for management of frostbite for 10 years and has the potential to reduce the need for some of the amputations. However, use of this protocol has not extended to the rural northern areas where most cases of frostbite are treated.

Severe frostbite results in ischemia and blistering with subsequent demarcation and loss of tissue. Prostaglandins and other chemical mediators are released locally, resulting in intense spasm and blistering. Arterial thrombosis results from injury to endothelial cells that retract to expose subintimal collagen, subsequently triggering acute thrombosis after rewarming.

The worse scenario is a freeze-thaw-refreeze injury in which, upon refreeze, ice crystals form intracellularly and kill the cells, rather than extracellularly as occurs in the initial freeze injury, according to Dr. George R. Edmonson of St. Paul (Minn.) Radiology.

Traditional treatment for frostbite has simply been to rewarm the affected extremity, wait to see how much tissue recovers, then amputate the rest. But over the last couple of decades, investigators have been experimenting with intra-arterial infusion of various thrombolytic and vasodilating agents to dissolve clots and relieve arterial spasm, in attempts to preserve more tissue and salvage more limbs.

At the annual meeting of the Society of Interventional Radiology, Dr. Edmonson described the patient care process used at Regions Hospital, also in St. Paul. Patients are admitted from the emergency department to the burn unit, where surgeons assess the affected limb for severity of injury and blood flow. Diagnostic arteriography is done to assess small vessel occlusion and loss of “distal tuft blush” at the tips of digits. Catheters are positioned for simultaneous infusion of treatment drugs into each affected limb. Blisters and wounds are managed in the burn unit with debridement or amputation as appropriate.

Since the mid-1990s, Dr. Edmonson and his associates have been treating frostbite of the extremities with a variety of combined antithrombotic, antiplatelet, and vasodilating agents. Initially, they used urokinase along with heparin and papaverine, then switched to reteplase, and now have moved to using tenecteplase (TNK) because of its superior plasma stability and higher fibrin specificity compared with reteplase. Tenecteplase is degraded more slowly in the bloodstream during infusion, and binds more firmly to the clot at the target than do similar agents. Because it also affects the normal clotting proteins to a lesser degree, it may therefore reduce the risk of bleeding, he explained.

During three unusually mild Minnesota winters, six patients aged 18–65 years with severe frostbite who were at risk for amputation were treated for up to 72 hours with intra-arterial TNK infusions at 0.25 mg/hour per limb with coaxial papaverine at 30 mg/hour per limb and intravenous heparin at 500 mcg/hour. They were managed in the burn unit with arteriography during the infusion.

Of the six patients, three who had 16 involved digits responded well and required no amputations. The other three (six limbs, 30 digits) had incomplete angiographic responses. Of those, two (four limbs, 20 involved digits) improved noticeably following TNK infusion, but then developed infections and required partial amputations. One patient—who needed intubation for alcohol withdrawal—failed to respond and lost eight fingers, but his thumbs were saved. There were no major bleeds or other periprocedural complications.

Those results were compared with data from 10 surviving patients (aged 14–77 years) of 12 who were treated with the same protocol using various doses of reteplase and papaverine over a 2-year period. Six of the patients recovered with no amputations, four had lost 31 digits at 45 days, and two had amputations but more distally than would have been anticipated without treatment.

More recently, six more frostbite patients were treated with TNK. Five of these patients had complete response and one had no response. To date, 8 out of 12 TNK-treated patients have been saved from amputation.

Response to TNK is more rapid than is response to reteplase, with arteries reopening within an average of 24 hours, compared with 36 for reteplase and 72 for urokinase. However, all of these agents are far better than the traditional wait-and-amputate treatment of the past, Dr. Edmonson said.

In an interview after the meeting, Dr. Edmonson explained that the difference between frostbite and typical peripheral vascular occlusion or thrombosis is that in frostbite, all of the small collateral vessels are thrombosed as well as the primary named arteries. The cut-off of flow is abrupt and complete, rather than an interruption with ischemia and some limited collaterals.

Moreover, the catheter system for drug infusion is proximal above the elbow or knee rather than directly into the clot as is the current standard approach to arterial thrombolysis.

Despite its use at several U.S. centers for the last decade, thrombolysis for frostbite has not yet become the standard of care because there have been no published results until recently, and thus far those have mostly consisted of anecdotal reviews of outcomes with wide-ranging dosages and treatment variations.

“That is why in 2003 I decided to initiate [a Food and Drug Administration-approved] prospective trial with rigid guidelines for treatment. The hope was that more scientific results might encourage others to use this type of treatment. The problem is the disease tends to occur away from the major academic centers on the coasts,” he said.

Future considerations include possibly increasing the heparin dose to reduce rethrombosis (since no bleeding problems have been seen), adding antiplatelet drugs to reduce clot formation, and a possible randomized trial comparing intravenous and intra-arterial administration of the drugs. Two sites have reported some success with high-dose intravenous administration.

Fingers with deep frostbite (left) can be saved from amputation with restored blood flow (right) after treatment with tenecteplase, papaverine, and heparin. Photos courtesy Dr. George R. Edmonson

WASHINGTON — Thrombolytic therapy has resulted in limb salvage among 18 patients with severe frostbite treated at one Minnesota hospital in the last few years.

Thrombolytic therapy has been available for management of frostbite for 10 years and has the potential to reduce the need for some of the amputations. However, use of this protocol has not extended to the rural northern areas where most cases of frostbite are treated.

Severe frostbite results in ischemia and blistering with subsequent demarcation and loss of tissue. Prostaglandins and other chemical mediators are released locally, resulting in intense spasm and blistering. Arterial thrombosis results from injury to endothelial cells that retract to expose subintimal collagen, subsequently triggering acute thrombosis after rewarming.

The worse scenario is a freeze-thaw-refreeze injury in which, upon refreeze, ice crystals form intracellularly and kill the cells, rather than extracellularly as occurs in the initial freeze injury, according to Dr. George R. Edmonson of St. Paul (Minn.) Radiology.

Traditional treatment for frostbite has simply been to rewarm the affected extremity, wait to see how much tissue recovers, then amputate the rest. But over the last couple of decades, investigators have been experimenting with intra-arterial infusion of various thrombolytic and vasodilating agents to dissolve clots and relieve arterial spasm, in attempts to preserve more tissue and salvage more limbs.

At the annual meeting of the Society of Interventional Radiology, Dr. Edmonson described the patient care process used at Regions Hospital, also in St. Paul. Patients are admitted from the emergency department to the burn unit, where surgeons assess the affected limb for severity of injury and blood flow. Diagnostic arteriography is done to assess small vessel occlusion and loss of “distal tuft blush” at the tips of digits. Catheters are positioned for simultaneous infusion of treatment drugs into each affected limb. Blisters and wounds are managed in the burn unit with debridement or amputation as appropriate.

Since the mid-1990s, Dr. Edmonson and his associates have been treating frostbite of the extremities with a variety of combined antithrombotic, antiplatelet, and vasodilating agents. Initially, they used urokinase along with heparin and papaverine, then switched to reteplase, and now have moved to using tenecteplase (TNK) because of its superior plasma stability and higher fibrin specificity compared with reteplase. Tenecteplase is degraded more slowly in the bloodstream during infusion, and binds more firmly to the clot at the target than do similar agents. Because it also affects the normal clotting proteins to a lesser degree, it may therefore reduce the risk of bleeding, he explained.

During three unusually mild Minnesota winters, six patients aged 18–65 years with severe frostbite who were at risk for amputation were treated for up to 72 hours with intra-arterial TNK infusions at 0.25 mg/hour per limb with coaxial papaverine at 30 mg/hour per limb and intravenous heparin at 500 mcg/hour. They were managed in the burn unit with arteriography during the infusion.

Of the six patients, three who had 16 involved digits responded well and required no amputations. The other three (six limbs, 30 digits) had incomplete angiographic responses. Of those, two (four limbs, 20 involved digits) improved noticeably following TNK infusion, but then developed infections and required partial amputations. One patient—who needed intubation for alcohol withdrawal—failed to respond and lost eight fingers, but his thumbs were saved. There were no major bleeds or other periprocedural complications.

Those results were compared with data from 10 surviving patients (aged 14–77 years) of 12 who were treated with the same protocol using various doses of reteplase and papaverine over a 2-year period. Six of the patients recovered with no amputations, four had lost 31 digits at 45 days, and two had amputations but more distally than would have been anticipated without treatment.

More recently, six more frostbite patients were treated with TNK. Five of these patients had complete response and one had no response. To date, 8 out of 12 TNK-treated patients have been saved from amputation.

Response to TNK is more rapid than is response to reteplase, with arteries reopening within an average of 24 hours, compared with 36 for reteplase and 72 for urokinase. However, all of these agents are far better than the traditional wait-and-amputate treatment of the past, Dr. Edmonson said.

In an interview after the meeting, Dr. Edmonson explained that the difference between frostbite and typical peripheral vascular occlusion or thrombosis is that in frostbite, all of the small collateral vessels are thrombosed as well as the primary named arteries. The cut-off of flow is abrupt and complete, rather than an interruption with ischemia and some limited collaterals.

Moreover, the catheter system for drug infusion is proximal above the elbow or knee rather than directly into the clot as is the current standard approach to arterial thrombolysis.

Despite its use at several U.S. centers for the last decade, thrombolysis for frostbite has not yet become the standard of care because there have been no published results until recently, and thus far those have mostly consisted of anecdotal reviews of outcomes with wide-ranging dosages and treatment variations.

“That is why in 2003 I decided to initiate [a Food and Drug Administration-approved] prospective trial with rigid guidelines for treatment. The hope was that more scientific results might encourage others to use this type of treatment. The problem is the disease tends to occur away from the major academic centers on the coasts,” he said.

Future considerations include possibly increasing the heparin dose to reduce rethrombosis (since no bleeding problems have been seen), adding antiplatelet drugs to reduce clot formation, and a possible randomized trial comparing intravenous and intra-arterial administration of the drugs. Two sites have reported some success with high-dose intravenous administration.

Fingers with deep frostbite (left) can be saved from amputation with restored blood flow (right) after treatment with tenecteplase, papaverine, and heparin. Photos courtesy Dr. George R. Edmonson

WASHINGTON — Thrombolytic therapy has resulted in limb salvage among 18 patients with severe frostbite treated at one Minnesota hospital in the last few years.

Thrombolytic therapy has been available for management of frostbite for 10 years and has the potential to reduce the need for some of the amputations. However, use of this protocol has not extended to the rural northern areas where most cases of frostbite are treated.

Severe frostbite results in ischemia and blistering with subsequent demarcation and loss of tissue. Prostaglandins and other chemical mediators are released locally, resulting in intense spasm and blistering. Arterial thrombosis results from injury to endothelial cells that retract to expose subintimal collagen, subsequently triggering acute thrombosis after rewarming.

The worse scenario is a freeze-thaw-refreeze injury in which, upon refreeze, ice crystals form intracellularly and kill the cells, rather than extracellularly as occurs in the initial freeze injury, according to Dr. George R. Edmonson of St. Paul (Minn.) Radiology.

Traditional treatment for frostbite has simply been to rewarm the affected extremity, wait to see how much tissue recovers, then amputate the rest. But over the last couple of decades, investigators have been experimenting with intra-arterial infusion of various thrombolytic and vasodilating agents to dissolve clots and relieve arterial spasm, in attempts to preserve more tissue and salvage more limbs.

At the annual meeting of the Society of Interventional Radiology, Dr. Edmonson described the patient care process used at Regions Hospital, also in St. Paul. Patients are admitted from the emergency department to the burn unit, where surgeons assess the affected limb for severity of injury and blood flow. Diagnostic arteriography is done to assess small vessel occlusion and loss of “distal tuft blush” at the tips of digits. Catheters are positioned for simultaneous infusion of treatment drugs into each affected limb. Blisters and wounds are managed in the burn unit with debridement or amputation as appropriate.

Since the mid-1990s, Dr. Edmonson and his associates have been treating frostbite of the extremities with a variety of combined antithrombotic, antiplatelet, and vasodilating agents. Initially, they used urokinase along with heparin and papaverine, then switched to reteplase, and now have moved to using tenecteplase (TNK) because of its superior plasma stability and higher fibrin specificity compared with reteplase. Tenecteplase is degraded more slowly in the bloodstream during infusion, and binds more firmly to the clot at the target than do similar agents. Because it also affects the normal clotting proteins to a lesser degree, it may therefore reduce the risk of bleeding, he explained.

During three unusually mild Minnesota winters, six patients aged 18–65 years with severe frostbite who were at risk for amputation were treated for up to 72 hours with intra-arterial TNK infusions at 0.25 mg/hour per limb with coaxial papaverine at 30 mg/hour per limb and intravenous heparin at 500 mcg/hour. They were managed in the burn unit with arteriography during the infusion.

Of the six patients, three who had 16 involved digits responded well and required no amputations. The other three (six limbs, 30 digits) had incomplete angiographic responses. Of those, two (four limbs, 20 involved digits) improved noticeably following TNK infusion, but then developed infections and required partial amputations. One patient—who needed intubation for alcohol withdrawal—failed to respond and lost eight fingers, but his thumbs were saved. There were no major bleeds or other periprocedural complications.

Those results were compared with data from 10 surviving patients (aged 14–77 years) of 12 who were treated with the same protocol using various doses of reteplase and papaverine over a 2-year period. Six of the patients recovered with no amputations, four had lost 31 digits at 45 days, and two had amputations but more distally than would have been anticipated without treatment.

More recently, six more frostbite patients were treated with TNK. Five of these patients had complete response and one had no response. To date, 8 out of 12 TNK-treated patients have been saved from amputation.

Response to TNK is more rapid than is response to reteplase, with arteries reopening within an average of 24 hours, compared with 36 for reteplase and 72 for urokinase. However, all of these agents are far better than the traditional wait-and-amputate treatment of the past, Dr. Edmonson said.

In an interview after the meeting, Dr. Edmonson explained that the difference between frostbite and typical peripheral vascular occlusion or thrombosis is that in frostbite, all of the small collateral vessels are thrombosed as well as the primary named arteries. The cut-off of flow is abrupt and complete, rather than an interruption with ischemia and some limited collaterals.

Moreover, the catheter system for drug infusion is proximal above the elbow or knee rather than directly into the clot as is the current standard approach to arterial thrombolysis.

Despite its use at several U.S. centers for the last decade, thrombolysis for frostbite has not yet become the standard of care because there have been no published results until recently, and thus far those have mostly consisted of anecdotal reviews of outcomes with wide-ranging dosages and treatment variations.

“That is why in 2003 I decided to initiate [a Food and Drug Administration-approved] prospective trial with rigid guidelines for treatment. The hope was that more scientific results might encourage others to use this type of treatment. The problem is the disease tends to occur away from the major academic centers on the coasts,” he said.

Future considerations include possibly increasing the heparin dose to reduce rethrombosis (since no bleeding problems have been seen), adding antiplatelet drugs to reduce clot formation, and a possible randomized trial comparing intravenous and intra-arterial administration of the drugs. Two sites have reported some success with high-dose intravenous administration.

Fingers with deep frostbite (left) can be saved from amputation with restored blood flow (right) after treatment with tenecteplase, papaverine, and heparin. Photos courtesy Dr. George R. Edmonson

Mild traumatic brain injury occurring among soldiers deployed in Iraq is strongly associated with posttraumatic stress disorder and physical health problems 3-4 months after the soldiers return home, according to survey findings.

Results from a survey of more than 2,000 soldiers who had served in Iraq suggest that the relationship between mild traumatic brain injury and physical health problems is largely mediated by the presence of posttraumatic stress disorder (PTSD) and depression.

“The strong associations between mild traumatic brain injury, PTSD, depression, and physical health symptoms in combat veterans reinforce the need for a multidisciplinary approach centered in primary care,” said Dr. Charles W. Hoge of the division of psychiatry and neuroscience at Walter Reed Army Institute of Research in Silver Spring, Md., and his associates.

A total of 2,714 soldiers completed the questionnaire, mailed in 2006 to soldiers from two U.S. Army combat infantry brigades–one active and one reserve–3-4 months after their return from a yearlong deployment in Iraq. The survey elicited information about whether soldiers had been injured, the nature of the injuries, and about the soldiers' physical and mental health (N. Engl. J. Med. 2008;358:453-63).

After exclusion of 149 for missing data and 40 with head injuries that did not involve loss of consciousness or altered mental status, the study group comprised 2,525 soldiers. Of those, 5% (124) reported an injury with loss of consciousness. The majority of these episodes lasted between a few seconds to 2-3 minutes, but four soldiers reported having been unconscious for more than 30 minutes. Another 10% (260) reported an injury with altered mental status in which they did not lose consciousness. This 15% was defined as having mild traumatic brain injury.

Another 17% (435) reported some other injury during deployment with no loss of consciousness or altered mental status, most commonly resulting from a fall or injury during training.

This spectrum of injury is likely to be representative of all soldiers serving in ground-combat units in Iraq, the investigators said.

Compared with the soldiers who had other injuries, those with mild traumatic brain injury were significantly more likely to report high combat intensity, a blast mechanism of injury, more than one blast exposure, and hospitalization while deployed. They were also significantly younger, more junior in rank, and more often male.

Overall, 44% of the soldiers who reported loss of consciousness met the criteria for PTSD, compared with 28% of those with altered mental status, 16% of those with other injuries, and 9% of those with no injuries. Loss of consciousness and combat intensity were the only two factors that remained significantly associated with PTSD after an analysis that took into account age, military rank, sex, hospitalization status, mechanism of injury, level of combat intensity, single vs. multiple blast exposure, and type of injury (loss of consciousness vs. other injuries).

Those with loss of consciousness were nearly three times as likely to have PTSD (odds ratio 2.98), while the odds ratio for the top vs. the bottom quartile of combat intensity was 11.58, Dr. Hoge and his associates reported, adding that injury with loss of consciousness was also independently associated with major depression (odds ratio 3.67).

Soldiers who had lost consciousness were significantly more likely to report poor general health, more missed work days, and a higher number of medical visits in the past month than were soldiers with other injuries. Those who had lost consciousness also had significantly higher scores on the Patient Health Questionnaire 15-item somatic symptom severity scale (PHQ-15).

However, when PTSD and depression were included in the analysis, the relationship between loss of consciousness and the physical health symptoms listed on the PHQ-15 disappeared (except for headache and heart pounding). Indeed, the high PHQ-15 scores occurred almost exclusively in the soldiers who had PTSD, Dr. Hoge and his associates noted.

These findings are “striking,” Richard A. Bryant, Ph.D., noted in an accompanying editorial. “One must use caution when attributing health problems to mild traumatic brain injury, because associated PTSD and depression may be the primary problem. This is an important point because mild traumatic brain injury typically occurs in the context of a traumatic event, and psychological stress will probably be influential in many cases of mild traumatic brain injury.”

In clinical settings, “impairment observed in the aftermath of mild traumatic brain injury has been attributed incorrectly to neurologic insult, rather than psychological distress,” said Dr. Bryant of the School of Psychology, University of New South Wales, Sydney.

There is debate as to whether postconcussive symptoms–such as problems with memory, balance, light sensitivity, and irritability–are the result of organic or psychological factors, or both. The evidence from this study suggests that psychological factors do play a role and that more effective interventions may involve augmenting educational programs with strategies to reduce PTSD and depression, he said.

However, Dr. Bryant cautioned against informing troops who are currently serving in Iraq or Afghanistan that they have a brain injury that will result in permanent change (N.Engl. J. Med. 2008;358:525-7).

“If troops … are informed about a postconcussive syndrome and persistent problems emerging from mild traumatic brain injury, a new syndrome could arise from the current conflict in which soldiers attribute a range of common stress reactions to the effects of brain injury. This could be damaging to morale and to the person's future mental health, because it could lead to the expectation of poor recovery.

“In contrast, the normalization of many of these reactions and the recognition that stress-related conditions can be managed with evidence-based strategies may minimize the unnecessary attribution of common stress reactions to pathology and facilitate resilience after mild traumatic brain injury.”

Mild traumatic brain injury occurring among soldiers deployed in Iraq is strongly associated with posttraumatic stress disorder and physical health problems 3-4 months after the soldiers return home, according to survey findings.

Results from a survey of more than 2,000 soldiers who had served in Iraq suggest that the relationship between mild traumatic brain injury and physical health problems is largely mediated by the presence of posttraumatic stress disorder (PTSD) and depression.

“The strong associations between mild traumatic brain injury, PTSD, depression, and physical health symptoms in combat veterans reinforce the need for a multidisciplinary approach centered in primary care,” said Dr. Charles W. Hoge of the division of psychiatry and neuroscience at Walter Reed Army Institute of Research in Silver Spring, Md., and his associates.

A total of 2,714 soldiers completed the questionnaire, mailed in 2006 to soldiers from two U.S. Army combat infantry brigades–one active and one reserve–3-4 months after their return from a yearlong deployment in Iraq. The survey elicited information about whether soldiers had been injured, the nature of the injuries, and about the soldiers' physical and mental health (N. Engl. J. Med. 2008;358:453-63).

After exclusion of 149 for missing data and 40 with head injuries that did not involve loss of consciousness or altered mental status, the study group comprised 2,525 soldiers. Of those, 5% (124) reported an injury with loss of consciousness. The majority of these episodes lasted between a few seconds to 2-3 minutes, but four soldiers reported having been unconscious for more than 30 minutes. Another 10% (260) reported an injury with altered mental status in which they did not lose consciousness. This 15% was defined as having mild traumatic brain injury.

Another 17% (435) reported some other injury during deployment with no loss of consciousness or altered mental status, most commonly resulting from a fall or injury during training.

This spectrum of injury is likely to be representative of all soldiers serving in ground-combat units in Iraq, the investigators said.

Compared with the soldiers who had other injuries, those with mild traumatic brain injury were significantly more likely to report high combat intensity, a blast mechanism of injury, more than one blast exposure, and hospitalization while deployed. They were also significantly younger, more junior in rank, and more often male.

Overall, 44% of the soldiers who reported loss of consciousness met the criteria for PTSD, compared with 28% of those with altered mental status, 16% of those with other injuries, and 9% of those with no injuries. Loss of consciousness and combat intensity were the only two factors that remained significantly associated with PTSD after an analysis that took into account age, military rank, sex, hospitalization status, mechanism of injury, level of combat intensity, single vs. multiple blast exposure, and type of injury (loss of consciousness vs. other injuries).

Those with loss of consciousness were nearly three times as likely to have PTSD (odds ratio 2.98), while the odds ratio for the top vs. the bottom quartile of combat intensity was 11.58, Dr. Hoge and his associates reported, adding that injury with loss of consciousness was also independently associated with major depression (odds ratio 3.67).

Soldiers who had lost consciousness were significantly more likely to report poor general health, more missed work days, and a higher number of medical visits in the past month than were soldiers with other injuries. Those who had lost consciousness also had significantly higher scores on the Patient Health Questionnaire 15-item somatic symptom severity scale (PHQ-15).

However, when PTSD and depression were included in the analysis, the relationship between loss of consciousness and the physical health symptoms listed on the PHQ-15 disappeared (except for headache and heart pounding). Indeed, the high PHQ-15 scores occurred almost exclusively in the soldiers who had PTSD, Dr. Hoge and his associates noted.

These findings are “striking,” Richard A. Bryant, Ph.D., noted in an accompanying editorial. “One must use caution when attributing health problems to mild traumatic brain injury, because associated PTSD and depression may be the primary problem. This is an important point because mild traumatic brain injury typically occurs in the context of a traumatic event, and psychological stress will probably be influential in many cases of mild traumatic brain injury.”

In clinical settings, “impairment observed in the aftermath of mild traumatic brain injury has been attributed incorrectly to neurologic insult, rather than psychological distress,” said Dr. Bryant of the School of Psychology, University of New South Wales, Sydney.

There is debate as to whether postconcussive symptoms–such as problems with memory, balance, light sensitivity, and irritability–are the result of organic or psychological factors, or both. The evidence from this study suggests that psychological factors do play a role and that more effective interventions may involve augmenting educational programs with strategies to reduce PTSD and depression, he said.

However, Dr. Bryant cautioned against informing troops who are currently serving in Iraq or Afghanistan that they have a brain injury that will result in permanent change (N.Engl. J. Med. 2008;358:525-7).

“If troops … are informed about a postconcussive syndrome and persistent problems emerging from mild traumatic brain injury, a new syndrome could arise from the current conflict in which soldiers attribute a range of common stress reactions to the effects of brain injury. This could be damaging to morale and to the person's future mental health, because it could lead to the expectation of poor recovery.

“In contrast, the normalization of many of these reactions and the recognition that stress-related conditions can be managed with evidence-based strategies may minimize the unnecessary attribution of common stress reactions to pathology and facilitate resilience after mild traumatic brain injury.”

Mild traumatic brain injury occurring among soldiers deployed in Iraq is strongly associated with posttraumatic stress disorder and physical health problems 3-4 months after the soldiers return home, according to survey findings.

Results from a survey of more than 2,000 soldiers who had served in Iraq suggest that the relationship between mild traumatic brain injury and physical health problems is largely mediated by the presence of posttraumatic stress disorder (PTSD) and depression.

“The strong associations between mild traumatic brain injury, PTSD, depression, and physical health symptoms in combat veterans reinforce the need for a multidisciplinary approach centered in primary care,” said Dr. Charles W. Hoge of the division of psychiatry and neuroscience at Walter Reed Army Institute of Research in Silver Spring, Md., and his associates.

A total of 2,714 soldiers completed the questionnaire, mailed in 2006 to soldiers from two U.S. Army combat infantry brigades–one active and one reserve–3-4 months after their return from a yearlong deployment in Iraq. The survey elicited information about whether soldiers had been injured, the nature of the injuries, and about the soldiers' physical and mental health (N. Engl. J. Med. 2008;358:453-63).

After exclusion of 149 for missing data and 40 with head injuries that did not involve loss of consciousness or altered mental status, the study group comprised 2,525 soldiers. Of those, 5% (124) reported an injury with loss of consciousness. The majority of these episodes lasted between a few seconds to 2-3 minutes, but four soldiers reported having been unconscious for more than 30 minutes. Another 10% (260) reported an injury with altered mental status in which they did not lose consciousness. This 15% was defined as having mild traumatic brain injury.

Another 17% (435) reported some other injury during deployment with no loss of consciousness or altered mental status, most commonly resulting from a fall or injury during training.

This spectrum of injury is likely to be representative of all soldiers serving in ground-combat units in Iraq, the investigators said.

Compared with the soldiers who had other injuries, those with mild traumatic brain injury were significantly more likely to report high combat intensity, a blast mechanism of injury, more than one blast exposure, and hospitalization while deployed. They were also significantly younger, more junior in rank, and more often male.

Overall, 44% of the soldiers who reported loss of consciousness met the criteria for PTSD, compared with 28% of those with altered mental status, 16% of those with other injuries, and 9% of those with no injuries. Loss of consciousness and combat intensity were the only two factors that remained significantly associated with PTSD after an analysis that took into account age, military rank, sex, hospitalization status, mechanism of injury, level of combat intensity, single vs. multiple blast exposure, and type of injury (loss of consciousness vs. other injuries).

Those with loss of consciousness were nearly three times as likely to have PTSD (odds ratio 2.98), while the odds ratio for the top vs. the bottom quartile of combat intensity was 11.58, Dr. Hoge and his associates reported, adding that injury with loss of consciousness was also independently associated with major depression (odds ratio 3.67).

Soldiers who had lost consciousness were significantly more likely to report poor general health, more missed work days, and a higher number of medical visits in the past month than were soldiers with other injuries. Those who had lost consciousness also had significantly higher scores on the Patient Health Questionnaire 15-item somatic symptom severity scale (PHQ-15).

However, when PTSD and depression were included in the analysis, the relationship between loss of consciousness and the physical health symptoms listed on the PHQ-15 disappeared (except for headache and heart pounding). Indeed, the high PHQ-15 scores occurred almost exclusively in the soldiers who had PTSD, Dr. Hoge and his associates noted.

These findings are “striking,” Richard A. Bryant, Ph.D., noted in an accompanying editorial. “One must use caution when attributing health problems to mild traumatic brain injury, because associated PTSD and depression may be the primary problem. This is an important point because mild traumatic brain injury typically occurs in the context of a traumatic event, and psychological stress will probably be influential in many cases of mild traumatic brain injury.”

In clinical settings, “impairment observed in the aftermath of mild traumatic brain injury has been attributed incorrectly to neurologic insult, rather than psychological distress,” said Dr. Bryant of the School of Psychology, University of New South Wales, Sydney.

There is debate as to whether postconcussive symptoms–such as problems with memory, balance, light sensitivity, and irritability–are the result of organic or psychological factors, or both. The evidence from this study suggests that psychological factors do play a role and that more effective interventions may involve augmenting educational programs with strategies to reduce PTSD and depression, he said.

However, Dr. Bryant cautioned against informing troops who are currently serving in Iraq or Afghanistan that they have a brain injury that will result in permanent change (N.Engl. J. Med. 2008;358:525-7).

“If troops … are informed about a postconcussive syndrome and persistent problems emerging from mild traumatic brain injury, a new syndrome could arise from the current conflict in which soldiers attribute a range of common stress reactions to the effects of brain injury. This could be damaging to morale and to the person's future mental health, because it could lead to the expectation of poor recovery.

“In contrast, the normalization of many of these reactions and the recognition that stress-related conditions can be managed with evidence-based strategies may minimize the unnecessary attribution of common stress reactions to pathology and facilitate resilience after mild traumatic brain injury.”

WASHINGTON — Continuous and cyclic administration of oral contraceptives appeared equally effective in preventing recurrent pain in women following laparoscopic endometrioma excision, but continuous administration was associated with significantly higher rates of side effects leading to treatment discontinuation in a prospective, randomized trial.

Evidence from the literature suggests that medical treatment following laparoscopic endometrioma excision can delay, though probably not prevent, recurrence of endometriosis. Although GnRH analogues can be given for 6 months, longer treatment is associated with high cost and significant side effects. Combination oral contraceptives represent a valid cost-effective alternative to GnRH analogues, but the question of whether they should be administered continuously or in a cyclic fashion has not been tested previously in a prospective randomized trial, said Dr. Ludovico Muzii, who presented data from such a trial at the annual meeting of the AAGL.

A total of 57 women who underwent laparoscopic excision of endometriomas by “stripping” were randomized to a 6-month cyclic regimen of monophasic combined ethinyl estradiol 0.020 mg and desogestrel 0.150 mg daily for 21 days followed by a 7-day interval (28 patients) or to a continuous regimen of the same monophasic oral contraceptive combination daily without the interval for 6 months (29), reported Dr. Muzii of Campus Bio-Medico University, Rome.

The two groups were comparable in age (30.3 years for cyclic, 30.6 for continuous), revised American Fertility Society (r-AFS) endometriosis classification (40.4 vs. 42.1), endometriotic cyst diameter (5.0 vs. 5.1 cm), and the proportion of patients with associated superficial implants (23 of 28 cyclic, 24 of 29 continuous). Twelve of the patients randomized to the continuous regimen did not complete the 6-month treatment because of moderate to severe side effects attributable to the OCs, compared with just four patients allocated to the cyclic treatment. The difference in discontinuation rates, 41% vs. 14%, was statistically significant, Dr. Muzzi said.

In a subsequent “intention to treat” analysis at a minimum of 12 months that included all 57 patients, endometriomas recurred in one cyclic (4%) vs. no continuous patients (0%), pain recurred in nine (32%) cyclic vs. five (17%) continuous; and mean time to recurrence was 12 months for cyclic compared with 16 months for continuous. Although none of these differences were statistically significant, they did represent trends that might have reached significance with a larger sample size, Dr. Muzii noted.

Both groups reported significant improvements in quality of life compared with baseline, despite the high dropout rate in the continuous group. This is probably due to a combination of factors: First, it is possible that patients who receive continuous treatment do experience less pain and recurrence—although not significantly—which might counterbalance the negative impact of the side effects, Dr. Muzzi explained in an interview. Also, most of the women who dropped the continuous regimen actually switched to the cyclic regimen, and therefore would still have been evaluated in the intent-to-treat analysis as having “continuous” treatment.

WASHINGTON — Continuous and cyclic administration of oral contraceptives appeared equally effective in preventing recurrent pain in women following laparoscopic endometrioma excision, but continuous administration was associated with significantly higher rates of side effects leading to treatment discontinuation in a prospective, randomized trial.

Evidence from the literature suggests that medical treatment following laparoscopic endometrioma excision can delay, though probably not prevent, recurrence of endometriosis. Although GnRH analogues can be given for 6 months, longer treatment is associated with high cost and significant side effects. Combination oral contraceptives represent a valid cost-effective alternative to GnRH analogues, but the question of whether they should be administered continuously or in a cyclic fashion has not been tested previously in a prospective randomized trial, said Dr. Ludovico Muzii, who presented data from such a trial at the annual meeting of the AAGL.

A total of 57 women who underwent laparoscopic excision of endometriomas by “stripping” were randomized to a 6-month cyclic regimen of monophasic combined ethinyl estradiol 0.020 mg and desogestrel 0.150 mg daily for 21 days followed by a 7-day interval (28 patients) or to a continuous regimen of the same monophasic oral contraceptive combination daily without the interval for 6 months (29), reported Dr. Muzii of Campus Bio-Medico University, Rome.

The two groups were comparable in age (30.3 years for cyclic, 30.6 for continuous), revised American Fertility Society (r-AFS) endometriosis classification (40.4 vs. 42.1), endometriotic cyst diameter (5.0 vs. 5.1 cm), and the proportion of patients with associated superficial implants (23 of 28 cyclic, 24 of 29 continuous). Twelve of the patients randomized to the continuous regimen did not complete the 6-month treatment because of moderate to severe side effects attributable to the OCs, compared with just four patients allocated to the cyclic treatment. The difference in discontinuation rates, 41% vs. 14%, was statistically significant, Dr. Muzzi said.

In a subsequent “intention to treat” analysis at a minimum of 12 months that included all 57 patients, endometriomas recurred in one cyclic (4%) vs. no continuous patients (0%), pain recurred in nine (32%) cyclic vs. five (17%) continuous; and mean time to recurrence was 12 months for cyclic compared with 16 months for continuous. Although none of these differences were statistically significant, they did represent trends that might have reached significance with a larger sample size, Dr. Muzii noted.

Both groups reported significant improvements in quality of life compared with baseline, despite the high dropout rate in the continuous group. This is probably due to a combination of factors: First, it is possible that patients who receive continuous treatment do experience less pain and recurrence—although not significantly—which might counterbalance the negative impact of the side effects, Dr. Muzzi explained in an interview. Also, most of the women who dropped the continuous regimen actually switched to the cyclic regimen, and therefore would still have been evaluated in the intent-to-treat analysis as having “continuous” treatment.

WASHINGTON — Continuous and cyclic administration of oral contraceptives appeared equally effective in preventing recurrent pain in women following laparoscopic endometrioma excision, but continuous administration was associated with significantly higher rates of side effects leading to treatment discontinuation in a prospective, randomized trial.

Evidence from the literature suggests that medical treatment following laparoscopic endometrioma excision can delay, though probably not prevent, recurrence of endometriosis. Although GnRH analogues can be given for 6 months, longer treatment is associated with high cost and significant side effects. Combination oral contraceptives represent a valid cost-effective alternative to GnRH analogues, but the question of whether they should be administered continuously or in a cyclic fashion has not been tested previously in a prospective randomized trial, said Dr. Ludovico Muzii, who presented data from such a trial at the annual meeting of the AAGL.

A total of 57 women who underwent laparoscopic excision of endometriomas by “stripping” were randomized to a 6-month cyclic regimen of monophasic combined ethinyl estradiol 0.020 mg and desogestrel 0.150 mg daily for 21 days followed by a 7-day interval (28 patients) or to a continuous regimen of the same monophasic oral contraceptive combination daily without the interval for 6 months (29), reported Dr. Muzii of Campus Bio-Medico University, Rome.

The two groups were comparable in age (30.3 years for cyclic, 30.6 for continuous), revised American Fertility Society (r-AFS) endometriosis classification (40.4 vs. 42.1), endometriotic cyst diameter (5.0 vs. 5.1 cm), and the proportion of patients with associated superficial implants (23 of 28 cyclic, 24 of 29 continuous). Twelve of the patients randomized to the continuous regimen did not complete the 6-month treatment because of moderate to severe side effects attributable to the OCs, compared with just four patients allocated to the cyclic treatment. The difference in discontinuation rates, 41% vs. 14%, was statistically significant, Dr. Muzzi said.

In a subsequent “intention to treat” analysis at a minimum of 12 months that included all 57 patients, endometriomas recurred in one cyclic (4%) vs. no continuous patients (0%), pain recurred in nine (32%) cyclic vs. five (17%) continuous; and mean time to recurrence was 12 months for cyclic compared with 16 months for continuous. Although none of these differences were statistically significant, they did represent trends that might have reached significance with a larger sample size, Dr. Muzii noted.

Both groups reported significant improvements in quality of life compared with baseline, despite the high dropout rate in the continuous group. This is probably due to a combination of factors: First, it is possible that patients who receive continuous treatment do experience less pain and recurrence—although not significantly—which might counterbalance the negative impact of the side effects, Dr. Muzzi explained in an interview. Also, most of the women who dropped the continuous regimen actually switched to the cyclic regimen, and therefore would still have been evaluated in the intent-to-treat analysis as having “continuous” treatment.

WASHINGTON — Response to hormonal therapy does not accurately predict whether a patient has endometriosis, Dr. Todd R. Jenkins reported at the annual meeting of the AAGL.

Laparoscopy has long been the standard for diagnosing endo-metriosis. But a 1999 paper by Dr. Frank W. Ling questioned the necessity for doing laparoscopy in women with chronic pelvic pain (Obstet. Gynecol. 1999;93:51–8). Findings in that study, sponsored in part by depot leuprolide manufacturer TAP Holdings Inc., suggested that a diagnostic algorithm plus a reduction in symptoms with a 3-month trial of depot leuprolide could noninvasively identify women for whom endometriosis was the cause of pain.

“Our clinical impression has been that many women who failed to respond to hormonal treatment [had] endometriosis. Many women have been told they did not have endometriosis since they did not respond to [the] treatment,” said Dr. Jenkins, director of the division of women's reproductive health care in the department of obstetrics and gynecology at the University of Alabama, Birmingham.

In a retrospective study by Dr. Jenkins and his then-associates at the Chattanooga (Tenn.) Women's Laser Center, chart reviews identified 486 patients at the private endometriosis referral center who had undergone laparoscopy for chronic pelvic pain and who had received at least 3 months of preoperative hormonal therapy.

Of those, 105 met the study criteria, which included complete information on response to treatment and less than 3 months between completion of hormonal therapy and the laparoscopy.

The hormonal treatments were oral contraceptive pills in 80% of the patients and gonadotropin-releasing hormone (GnRH) agonists in 20%. Response to the hormones, defined as either partial or complete symptom relief, was achieved in 46% (48), whereas 54% (57) had no relief of symptoms. Endometriosis was identified subjectively during laparoscopy in 84% (88) of the women, and a pathological diagnosis was made in 67% (70). These findings confirm those of Dr. Ling and others that endometriosis is present in about 80%–85% of women with well-defined chronic pelvic pain.

There was no significant difference in the rate of endometriosis between all hormonal therapy responders and nonresponders, either by subjective impression or pathological diagnosis. Subjective diagnoses of endometriosis were made for 85% of responders and 81% of nonresponders, and pathological diagnoses in 65% and 68%, respectively. Endometriosis rates also did not differ between the 35 responders and 48 nonresponders to oral contraceptives specifically.

Differences were significant for those who took GnRH agonists: Subjective diagnoses of endometriosis were made in 100% (9/9) of responders, compared with just 50% (4/8) of nonresponders, and pathological diagnoses in 89% (8/9) of responders vs. 25% (2/8) of nonresponders. However, the number of cases was too small to be conclusive.

Response to hormonal therapy also did not predict the diagnosis of endometriosis at any specific location except for the anterior bladder wall peritoneum (70% of responders vs. 30% of nonresponders), but only 10 patients had endometriosis at that site. The same was found for pathologically confirmed diagnoses: Only endometriosis of the anterior peritoneum was statistically more likely in responders than nonresponders (85% vs. 15%), and again, the data were limited because the numbers were small.

Dr. Jenkins said the findings should not be interpreted to mean that a trial of GnRH agonists isn't a good idea. “No … diagnosis of endometriosis [should be] based on the response to hormonal therapy without a laparoscopic evaluation. A laparoscopic diagnosis is still the gold standard.”

Laparoscopic evaluation is the gold standard for a diagnosis. ©Elsevier, Katz: Comprehensive Gynecology, 5th ed. Figure 8–9. 2007

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Response to hormonal therapy does not accurately predict whether a patient has endometriosis, Dr. Todd R. Jenkins reported at the annual meeting of the AAGL.

Laparoscopy has long been the standard for diagnosing endo-metriosis. But a 1999 paper by Dr. Frank W. Ling questioned the necessity for doing laparoscopy in women with chronic pelvic pain (Obstet. Gynecol. 1999;93:51–8). Findings in that study, sponsored in part by depot leuprolide manufacturer TAP Holdings Inc., suggested that a diagnostic algorithm plus a reduction in symptoms with a 3-month trial of depot leuprolide could noninvasively identify women for whom endometriosis was the cause of pain.

“Our clinical impression has been that many women who failed to respond to hormonal treatment [had] endometriosis. Many women have been told they did not have endometriosis since they did not respond to [the] treatment,” said Dr. Jenkins, director of the division of women's reproductive health care in the department of obstetrics and gynecology at the University of Alabama, Birmingham.

In a retrospective study by Dr. Jenkins and his then-associates at the Chattanooga (Tenn.) Women's Laser Center, chart reviews identified 486 patients at the private endometriosis referral center who had undergone laparoscopy for chronic pelvic pain and who had received at least 3 months of preoperative hormonal therapy.

Of those, 105 met the study criteria, which included complete information on response to treatment and less than 3 months between completion of hormonal therapy and the laparoscopy.

The hormonal treatments were oral contraceptive pills in 80% of the patients and gonadotropin-releasing hormone (GnRH) agonists in 20%. Response to the hormones, defined as either partial or complete symptom relief, was achieved in 46% (48), whereas 54% (57) had no relief of symptoms. Endometriosis was identified subjectively during laparoscopy in 84% (88) of the women, and a pathological diagnosis was made in 67% (70). These findings confirm those of Dr. Ling and others that endometriosis is present in about 80%–85% of women with well-defined chronic pelvic pain.

There was no significant difference in the rate of endometriosis between all hormonal therapy responders and nonresponders, either by subjective impression or pathological diagnosis. Subjective diagnoses of endometriosis were made for 85% of responders and 81% of nonresponders, and pathological diagnoses in 65% and 68%, respectively. Endometriosis rates also did not differ between the 35 responders and 48 nonresponders to oral contraceptives specifically.

Differences were significant for those who took GnRH agonists: Subjective diagnoses of endometriosis were made in 100% (9/9) of responders, compared with just 50% (4/8) of nonresponders, and pathological diagnoses in 89% (8/9) of responders vs. 25% (2/8) of nonresponders. However, the number of cases was too small to be conclusive.

Response to hormonal therapy also did not predict the diagnosis of endometriosis at any specific location except for the anterior bladder wall peritoneum (70% of responders vs. 30% of nonresponders), but only 10 patients had endometriosis at that site. The same was found for pathologically confirmed diagnoses: Only endometriosis of the anterior peritoneum was statistically more likely in responders than nonresponders (85% vs. 15%), and again, the data were limited because the numbers were small.

Dr. Jenkins said the findings should not be interpreted to mean that a trial of GnRH agonists isn't a good idea. “No … diagnosis of endometriosis [should be] based on the response to hormonal therapy without a laparoscopic evaluation. A laparoscopic diagnosis is still the gold standard.”

Laparoscopic evaluation is the gold standard for a diagnosis. ©Elsevier, Katz: Comprehensive Gynecology, 5th ed. Figure 8–9. 2007

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WASHINGTON — Response to hormonal therapy does not accurately predict whether a patient has endometriosis, Dr. Todd R. Jenkins reported at the annual meeting of the AAGL.

Laparoscopy has long been the standard for diagnosing endo-metriosis. But a 1999 paper by Dr. Frank W. Ling questioned the necessity for doing laparoscopy in women with chronic pelvic pain (Obstet. Gynecol. 1999;93:51–8). Findings in that study, sponsored in part by depot leuprolide manufacturer TAP Holdings Inc., suggested that a diagnostic algorithm plus a reduction in symptoms with a 3-month trial of depot leuprolide could noninvasively identify women for whom endometriosis was the cause of pain.

“Our clinical impression has been that many women who failed to respond to hormonal treatment [had] endometriosis. Many women have been told they did not have endometriosis since they did not respond to [the] treatment,” said Dr. Jenkins, director of the division of women's reproductive health care in the department of obstetrics and gynecology at the University of Alabama, Birmingham.

In a retrospective study by Dr. Jenkins and his then-associates at the Chattanooga (Tenn.) Women's Laser Center, chart reviews identified 486 patients at the private endometriosis referral center who had undergone laparoscopy for chronic pelvic pain and who had received at least 3 months of preoperative hormonal therapy.

Of those, 105 met the study criteria, which included complete information on response to treatment and less than 3 months between completion of hormonal therapy and the laparoscopy.

The hormonal treatments were oral contraceptive pills in 80% of the patients and gonadotropin-releasing hormone (GnRH) agonists in 20%. Response to the hormones, defined as either partial or complete symptom relief, was achieved in 46% (48), whereas 54% (57) had no relief of symptoms. Endometriosis was identified subjectively during laparoscopy in 84% (88) of the women, and a pathological diagnosis was made in 67% (70). These findings confirm those of Dr. Ling and others that endometriosis is present in about 80%–85% of women with well-defined chronic pelvic pain.

There was no significant difference in the rate of endometriosis between all hormonal therapy responders and nonresponders, either by subjective impression or pathological diagnosis. Subjective diagnoses of endometriosis were made for 85% of responders and 81% of nonresponders, and pathological diagnoses in 65% and 68%, respectively. Endometriosis rates also did not differ between the 35 responders and 48 nonresponders to oral contraceptives specifically.

Differences were significant for those who took GnRH agonists: Subjective diagnoses of endometriosis were made in 100% (9/9) of responders, compared with just 50% (4/8) of nonresponders, and pathological diagnoses in 89% (8/9) of responders vs. 25% (2/8) of nonresponders. However, the number of cases was too small to be conclusive.

Response to hormonal therapy also did not predict the diagnosis of endometriosis at any specific location except for the anterior bladder wall peritoneum (70% of responders vs. 30% of nonresponders), but only 10 patients had endometriosis at that site. The same was found for pathologically confirmed diagnoses: Only endometriosis of the anterior peritoneum was statistically more likely in responders than nonresponders (85% vs. 15%), and again, the data were limited because the numbers were small.

Dr. Jenkins said the findings should not be interpreted to mean that a trial of GnRH agonists isn't a good idea. “No … diagnosis of endometriosis [should be] based on the response to hormonal therapy without a laparoscopic evaluation. A laparoscopic diagnosis is still the gold standard.”

Laparoscopic evaluation is the gold standard for a diagnosis. ©Elsevier, Katz: Comprehensive Gynecology, 5th ed. Figure 8–9. 2007

ELSEVIER GLOBAL MEDICAL NEWS