Immunology

Primary care providers must intervene more assertively to get patients to adopt healthier lifestyles, directly targeting smoking, obesity, poor diet, and physical inactivity, according to an American Heart Association science advisory published online Oct. 7 in Circulation.

Alexander Raths/Fotolia.com

The investigators termed this science advisory "a call to action" for clinicians, citing their vital role in fostering healthier behaviors. They added that system-wide changes also are necessary "to shift the majority of the public toward the next level of improved cardiovascular health," and so also called on "the health care system, insurance companies, employers, and educational institutions" to do so.

The science advisory urged physicians to follow "the 5 As" – a comprehensive, validated treatment algorithm of counseling steps to facilitate patient behavior change that can be completed within the constraints of the typical medical visit. These include Assessing the risk behavior; Advising change, Agreeing on goals and an action plan; Assisting with treatment; and Arranging follow-up.

Most clinicians easily follow the first A, assessing and tracking health behaviors such as smoking habits, weight gain, diet, and exercise over time.

However, "many providers say they omit the last three As because they perceive them as time consuming," and they also feel they lack the necessary counseling skills.

But even taking a single step toward that goal can be extremely helpful to patients. Simple use of patient-centered communication is key: that is, avoiding the use of "commanding language" and instead asking open-ended questions and expressing empathy signals that the physician takes an active interest in the patient’s perspective. It also reveals what actions a patient is willing to take, helping him or her to develop a behavior change plan.

Physicians also can enlist the help of many allied health professionals to take this step, including clinical psychologists, dieticians, health educators, and kinesiologists. They also should be prepared to connect patients to community resources such as park or community-center programs, biking trials, and farmers’ markets.

Direct physician intervention "will undoubtedly also take the form of answering patients’ questions about which of an armory of computer programs, applications, sensors, and online communities they should use to support healthy lifestyle changes," said Bonnie Spring, Ph.D., and Judith K. Ockene, Ph.D., cochairs of the AHA committee that issued the report. (Circulation 2013 Oct. 7 [doi:10.1161/01.cir.0000435173.25936.e1]).

On the population level, physicians should advocate for policies and strategies that support a large-scale shift toward healthier behaviors. Chief among these is the reimbursement for the intensive behavioral counseling and the multidisciplinary provider teams that are required for patients whose poor health habits put them at cardiovascular risk, Dr. Spring and Dr. Ockene said.

Copies of "Better Population Health Through Behavior Change in Adults: A Call to Action" are available at my.americanheart.org/statements.

This science advisory was issued on behalf of the AHA’s behavior change committee of the Council on Epidemiology and Prevention, the Council on Lifestyle and Cardiometabolic Health, the Council for High Blood Pressure Research, and the Council on Cardiovascular and Stroke Nursing. The writing panel’s disclosure questionnaires are available from the AHA.

Primary care providers must intervene more assertively to get patients to adopt healthier lifestyles, directly targeting smoking, obesity, poor diet, and physical inactivity, according to an American Heart Association science advisory published online Oct. 7 in Circulation.

Alexander Raths/Fotolia.com

The investigators termed this science advisory "a call to action" for clinicians, citing their vital role in fostering healthier behaviors. They added that system-wide changes also are necessary "to shift the majority of the public toward the next level of improved cardiovascular health," and so also called on "the health care system, insurance companies, employers, and educational institutions" to do so.

The science advisory urged physicians to follow "the 5 As" – a comprehensive, validated treatment algorithm of counseling steps to facilitate patient behavior change that can be completed within the constraints of the typical medical visit. These include Assessing the risk behavior; Advising change, Agreeing on goals and an action plan; Assisting with treatment; and Arranging follow-up.

Most clinicians easily follow the first A, assessing and tracking health behaviors such as smoking habits, weight gain, diet, and exercise over time.

However, "many providers say they omit the last three As because they perceive them as time consuming," and they also feel they lack the necessary counseling skills.

But even taking a single step toward that goal can be extremely helpful to patients. Simple use of patient-centered communication is key: that is, avoiding the use of "commanding language" and instead asking open-ended questions and expressing empathy signals that the physician takes an active interest in the patient’s perspective. It also reveals what actions a patient is willing to take, helping him or her to develop a behavior change plan.

Physicians also can enlist the help of many allied health professionals to take this step, including clinical psychologists, dieticians, health educators, and kinesiologists. They also should be prepared to connect patients to community resources such as park or community-center programs, biking trials, and farmers’ markets.

Direct physician intervention "will undoubtedly also take the form of answering patients’ questions about which of an armory of computer programs, applications, sensors, and online communities they should use to support healthy lifestyle changes," said Bonnie Spring, Ph.D., and Judith K. Ockene, Ph.D., cochairs of the AHA committee that issued the report. (Circulation 2013 Oct. 7 [doi:10.1161/01.cir.0000435173.25936.e1]).

On the population level, physicians should advocate for policies and strategies that support a large-scale shift toward healthier behaviors. Chief among these is the reimbursement for the intensive behavioral counseling and the multidisciplinary provider teams that are required for patients whose poor health habits put them at cardiovascular risk, Dr. Spring and Dr. Ockene said.

Copies of "Better Population Health Through Behavior Change in Adults: A Call to Action" are available at my.americanheart.org/statements.

This science advisory was issued on behalf of the AHA’s behavior change committee of the Council on Epidemiology and Prevention, the Council on Lifestyle and Cardiometabolic Health, the Council for High Blood Pressure Research, and the Council on Cardiovascular and Stroke Nursing. The writing panel’s disclosure questionnaires are available from the AHA.

Primary care providers must intervene more assertively to get patients to adopt healthier lifestyles, directly targeting smoking, obesity, poor diet, and physical inactivity, according to an American Heart Association science advisory published online Oct. 7 in Circulation.

Alexander Raths/Fotolia.com

The investigators termed this science advisory "a call to action" for clinicians, citing their vital role in fostering healthier behaviors. They added that system-wide changes also are necessary "to shift the majority of the public toward the next level of improved cardiovascular health," and so also called on "the health care system, insurance companies, employers, and educational institutions" to do so.

The science advisory urged physicians to follow "the 5 As" – a comprehensive, validated treatment algorithm of counseling steps to facilitate patient behavior change that can be completed within the constraints of the typical medical visit. These include Assessing the risk behavior; Advising change, Agreeing on goals and an action plan; Assisting with treatment; and Arranging follow-up.

Most clinicians easily follow the first A, assessing and tracking health behaviors such as smoking habits, weight gain, diet, and exercise over time.

However, "many providers say they omit the last three As because they perceive them as time consuming," and they also feel they lack the necessary counseling skills.

But even taking a single step toward that goal can be extremely helpful to patients. Simple use of patient-centered communication is key: that is, avoiding the use of "commanding language" and instead asking open-ended questions and expressing empathy signals that the physician takes an active interest in the patient’s perspective. It also reveals what actions a patient is willing to take, helping him or her to develop a behavior change plan.

Physicians also can enlist the help of many allied health professionals to take this step, including clinical psychologists, dieticians, health educators, and kinesiologists. They also should be prepared to connect patients to community resources such as park or community-center programs, biking trials, and farmers’ markets.

Direct physician intervention "will undoubtedly also take the form of answering patients’ questions about which of an armory of computer programs, applications, sensors, and online communities they should use to support healthy lifestyle changes," said Bonnie Spring, Ph.D., and Judith K. Ockene, Ph.D., cochairs of the AHA committee that issued the report. (Circulation 2013 Oct. 7 [doi:10.1161/01.cir.0000435173.25936.e1]).

On the population level, physicians should advocate for policies and strategies that support a large-scale shift toward healthier behaviors. Chief among these is the reimbursement for the intensive behavioral counseling and the multidisciplinary provider teams that are required for patients whose poor health habits put them at cardiovascular risk, Dr. Spring and Dr. Ockene said.

Copies of "Better Population Health Through Behavior Change in Adults: A Call to Action" are available at my.americanheart.org/statements.

This science advisory was issued on behalf of the AHA’s behavior change committee of the Council on Epidemiology and Prevention, the Council on Lifestyle and Cardiometabolic Health, the Council for High Blood Pressure Research, and the Council on Cardiovascular and Stroke Nursing. The writing panel’s disclosure questionnaires are available from the AHA.

Each year in late summer, the CDC publishes its recommendations for the prevention of influenza for the upcoming season. The severity of each influenza season varies and is difficult to predict—underscoring the need to provide maximal vaccine coverage for at-risk patient populations.

Hoping for the best, planning for the worst.

Over the past several decades, the annual number of influenza-related hospitalizations has varied from approximately 55,000 to 431,000,¹ and the number of deaths from influenza has been as low as 3,349 and as high as 48,614.² Infection rates are usually highest in children.

Complications, hospitalizations, and deaths are highest in adults ≥ 65, children < 2 years, and patients with medical conditions known to increase risk for influenza complications. Those at high risk of complications appear in Table 1.³

The main recommendations for this coming year are the same as those for last year, including vaccinating everyone ≥ 6 months of age without a contraindication, starting vaccinations as soon as vaccine is available, and continuing throughout the influenza season for those who need it.

What’s new this year

An increasing number of influenza vaccine products are available; although to date, their effectiveness (which was determined to be 56% for all vaccines used last influenza season)⁴ remains below what we would hope for. The CDC’s recommendations address these new types of vaccines, including ones that have four antigens instead of three, and use new terminology to describe the vaccines.³

New terminology reflects changing vaccine formulations.

Last influenza season there were two major categories of influenza vaccines: live-attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV). All products were produced using egg-culture methods and contained two influenza A antigen subtypes and oneB subtype.

Several products this year include four antigens (two A subtypes and two B subtypes), and some are now produced with non–egg-culture methods. This has led to a new system of classification, with the term inactivated influenza vaccine (IIV) replacing TIV. Table 2 lists the influenza vaccine categories and abbreviations. Table 3³ lists the contraindications for the different vaccine types.

The new products include Flumist Quadrivalent (MedImmune), a quadrivalent LAIV (LAIV4); Fluarix Quadrivalent (GlaxoSmithKline), a quadrivalent IIV (IIV4); Flucelvax (Novartis Vaccines and Diagnostics), a cell culture-based trivalent IIV (ccIIV3); and FluBlok (Protein Sciences), a trivalent recombinant hemagglutinin influenza vaccine (RIV3). Fluzone (Sanofi Pasteur), introduced last season in a trivalent formulation, is also available this season as a quadrivalent IIV (IIV4).

As a group, influenza vaccine products now offer three routes of administration: intramuscular, subcutaneous, and intranasal. There is currently no evidence that any route offers an advantage over another, and the CDC states no preference for any particular product or route of administration.

Mercury content is not a problem

Even though there is no scientific controversy over the safety of the mercury-containing preservative thimerosal, some patients still have doubts and may ask for a thimerosal-free product. The only influenza products that contain any thimerosal are those that come in multidose vials. A description of each influenza vaccine product, including thimerosal content, indicated ages, and routes of administration, can be found on the CDC’s Web site (www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm).³

Options for those with egg allergy

There is now a product, RIV3 (FluBlok), that is manufactured without the use of eggs. It can be used in those 18 to 49 years of age with a history of egg allergy of any severity. Since 2011, the Advisory Committee on Immunization Practices (ACIP) has recommended that individuals with a history of mild egg allergy (those who experience only hives after egg exposure) may receive IIV, with additional safety precautions. Do not delay vaccination for these individuals if RIV is unavailable. Because of a lack of data demonstrating safety of LAIV for individuals with egg allergy, those allergic to eggs should receive RIV or IIV rather than LAIV.

Though the new ccIIV product, Flucelvax, is manufactured without the use of eggs, the seed viruses used to create the vaccine have been processed in eggs. The egg protein content in the vaccine is extremely low (< 50 femto­grams [5 × 10^-14 g] per 0.5-mL dose), but the CDC does not consider it egg free. Figure 1 (see page 32) de­picts the recommendations for those with a history of egg allergy.³

Other interventions for influenza prevention

Vaccination is only one tool available to prevent morbidity and mortality from influenza. Antiviral chemoprevention and treatment and infection control practices can also be effective.

Antiviral chemoprevention is available for both pre- and post-exposure administration. In the past few years, the CDC has de-emphasized such use of antivirals for these indications out of concern for the supply of these agents and for the possibility that their use might lead to increased rates of viral resistance. Consider antiviral chemoprevention for those who have conditions that place them at risk for complications, and for those who are unvaccinated if they are at high risk for exposure to influenza (pre-exposure prophylaxis) or have been exposed (postexposure prophylaxis), if the medication can be started within 48 hours of exposure.

Another option for unvaccinated high-risk patients is vigilant symptom monitoring with early treatment for influenza symptoms. Chemoprophylaxis is recommended in addition to vaccination to control influenza outbreaks at institutions that house patients at high risk for complications of influenza. Details on recommended antivirals including doses and duration of treatment can be found in a 2011 issue of Morbidity and Mortality Weekly Report.⁵

Antiviral treatment. The CDC recommends antiviral treatment for anyone with suspected or confirmed influenza who has progressive, severe, or complicated illness or is hospitalized for his or her illness.⁵ Treatment is also recommended for outpatients with suspected or confirmed influenza who are at higher risk for influenza complications. This latter group includes those in Table 1, particularly children 6 to 59 months and adults ≥ 50. Start antiviral treatment within 48 hours of the first symptoms. For hospitalized patients, however, begin treatment at any point, regardless of duration of illness.

Infection control practices can prevent the spread of influenza in the health care setting and in the homes of those with influenza. These practices are also described on the CDC influenza Web site.⁶

References

1. Thompson WW, Shay DK, Weintraub E. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333-1340.

2. CDC. Estimates of deaths associated with seasonal influenza–United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59:1057-1062.

3. CDC. Summary* recommendations: prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United States, 2013-14. www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm. Accessed August 9, 2013.

4. CDC. Interim adjusted estimates of seasonal influenza vaccine effectiveness–United States, February 2013. MMWR Morb Mortal Wkly Rep. 2013;62:119-123.

5. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza. MMWR Recomm Rep. 2011;60(RR01):1-24. www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm. Accessed July 2, 2013.

6. CDC. Infection control in health care facilities. www.cdc.gov/flu/professionals/infectioncontrol/index.htm. Accessed July 2, 2013.

Each year in late summer, the CDC publishes its recommendations for the prevention of influenza for the upcoming season. The severity of each influenza season varies and is difficult to predict—underscoring the need to provide maximal vaccine coverage for at-risk patient populations.

Hoping for the best, planning for the worst.

Over the past several decades, the annual number of influenza-related hospitalizations has varied from approximately 55,000 to 431,000,¹ and the number of deaths from influenza has been as low as 3,349 and as high as 48,614.² Infection rates are usually highest in children.

Complications, hospitalizations, and deaths are highest in adults ≥ 65, children < 2 years, and patients with medical conditions known to increase risk for influenza complications. Those at high risk of complications appear in Table 1.³

The main recommendations for this coming year are the same as those for last year, including vaccinating everyone ≥ 6 months of age without a contraindication, starting vaccinations as soon as vaccine is available, and continuing throughout the influenza season for those who need it.

What’s new this year

An increasing number of influenza vaccine products are available; although to date, their effectiveness (which was determined to be 56% for all vaccines used last influenza season)⁴ remains below what we would hope for. The CDC’s recommendations address these new types of vaccines, including ones that have four antigens instead of three, and use new terminology to describe the vaccines.³

New terminology reflects changing vaccine formulations.

Last influenza season there were two major categories of influenza vaccines: live-attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV). All products were produced using egg-culture methods and contained two influenza A antigen subtypes and oneB subtype.

Several products this year include four antigens (two A subtypes and two B subtypes), and some are now produced with non–egg-culture methods. This has led to a new system of classification, with the term inactivated influenza vaccine (IIV) replacing TIV. Table 2 lists the influenza vaccine categories and abbreviations. Table 3³ lists the contraindications for the different vaccine types.

The new products include Flumist Quadrivalent (MedImmune), a quadrivalent LAIV (LAIV4); Fluarix Quadrivalent (GlaxoSmithKline), a quadrivalent IIV (IIV4); Flucelvax (Novartis Vaccines and Diagnostics), a cell culture-based trivalent IIV (ccIIV3); and FluBlok (Protein Sciences), a trivalent recombinant hemagglutinin influenza vaccine (RIV3). Fluzone (Sanofi Pasteur), introduced last season in a trivalent formulation, is also available this season as a quadrivalent IIV (IIV4).

As a group, influenza vaccine products now offer three routes of administration: intramuscular, subcutaneous, and intranasal. There is currently no evidence that any route offers an advantage over another, and the CDC states no preference for any particular product or route of administration.

Mercury content is not a problem

Even though there is no scientific controversy over the safety of the mercury-containing preservative thimerosal, some patients still have doubts and may ask for a thimerosal-free product. The only influenza products that contain any thimerosal are those that come in multidose vials. A description of each influenza vaccine product, including thimerosal content, indicated ages, and routes of administration, can be found on the CDC’s Web site (www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm).³

Options for those with egg allergy

There is now a product, RIV3 (FluBlok), that is manufactured without the use of eggs. It can be used in those 18 to 49 years of age with a history of egg allergy of any severity. Since 2011, the Advisory Committee on Immunization Practices (ACIP) has recommended that individuals with a history of mild egg allergy (those who experience only hives after egg exposure) may receive IIV, with additional safety precautions. Do not delay vaccination for these individuals if RIV is unavailable. Because of a lack of data demonstrating safety of LAIV for individuals with egg allergy, those allergic to eggs should receive RIV or IIV rather than LAIV.

Though the new ccIIV product, Flucelvax, is manufactured without the use of eggs, the seed viruses used to create the vaccine have been processed in eggs. The egg protein content in the vaccine is extremely low (< 50 femto­grams [5 × 10^-14 g] per 0.5-mL dose), but the CDC does not consider it egg free. Figure 1 (see page 32) de­picts the recommendations for those with a history of egg allergy.³

Other interventions for influenza prevention

Vaccination is only one tool available to prevent morbidity and mortality from influenza. Antiviral chemoprevention and treatment and infection control practices can also be effective.

Antiviral chemoprevention is available for both pre- and post-exposure administration. In the past few years, the CDC has de-emphasized such use of antivirals for these indications out of concern for the supply of these agents and for the possibility that their use might lead to increased rates of viral resistance. Consider antiviral chemoprevention for those who have conditions that place them at risk for complications, and for those who are unvaccinated if they are at high risk for exposure to influenza (pre-exposure prophylaxis) or have been exposed (postexposure prophylaxis), if the medication can be started within 48 hours of exposure.

Another option for unvaccinated high-risk patients is vigilant symptom monitoring with early treatment for influenza symptoms. Chemoprophylaxis is recommended in addition to vaccination to control influenza outbreaks at institutions that house patients at high risk for complications of influenza. Details on recommended antivirals including doses and duration of treatment can be found in a 2011 issue of Morbidity and Mortality Weekly Report.⁵

Antiviral treatment. The CDC recommends antiviral treatment for anyone with suspected or confirmed influenza who has progressive, severe, or complicated illness or is hospitalized for his or her illness.⁵ Treatment is also recommended for outpatients with suspected or confirmed influenza who are at higher risk for influenza complications. This latter group includes those in Table 1, particularly children 6 to 59 months and adults ≥ 50. Start antiviral treatment within 48 hours of the first symptoms. For hospitalized patients, however, begin treatment at any point, regardless of duration of illness.

Infection control practices can prevent the spread of influenza in the health care setting and in the homes of those with influenza. These practices are also described on the CDC influenza Web site.⁶

References

1. Thompson WW, Shay DK, Weintraub E. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333-1340.

2. CDC. Estimates of deaths associated with seasonal influenza–United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59:1057-1062.

3. CDC. Summary* recommendations: prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United States, 2013-14. www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm. Accessed August 9, 2013.

4. CDC. Interim adjusted estimates of seasonal influenza vaccine effectiveness–United States, February 2013. MMWR Morb Mortal Wkly Rep. 2013;62:119-123.

5. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza. MMWR Recomm Rep. 2011;60(RR01):1-24. www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm. Accessed July 2, 2013.

6. CDC. Infection control in health care facilities. www.cdc.gov/flu/professionals/infectioncontrol/index.htm. Accessed July 2, 2013.

Each year in late summer, the CDC publishes its recommendations for the prevention of influenza for the upcoming season. The severity of each influenza season varies and is difficult to predict—underscoring the need to provide maximal vaccine coverage for at-risk patient populations.

Hoping for the best, planning for the worst.

Over the past several decades, the annual number of influenza-related hospitalizations has varied from approximately 55,000 to 431,000,¹ and the number of deaths from influenza has been as low as 3,349 and as high as 48,614.² Infection rates are usually highest in children.

Complications, hospitalizations, and deaths are highest in adults ≥ 65, children < 2 years, and patients with medical conditions known to increase risk for influenza complications. Those at high risk of complications appear in Table 1.³

The main recommendations for this coming year are the same as those for last year, including vaccinating everyone ≥ 6 months of age without a contraindication, starting vaccinations as soon as vaccine is available, and continuing throughout the influenza season for those who need it.

What’s new this year

An increasing number of influenza vaccine products are available; although to date, their effectiveness (which was determined to be 56% for all vaccines used last influenza season)⁴ remains below what we would hope for. The CDC’s recommendations address these new types of vaccines, including ones that have four antigens instead of three, and use new terminology to describe the vaccines.³

New terminology reflects changing vaccine formulations.

Last influenza season there were two major categories of influenza vaccines: live-attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV). All products were produced using egg-culture methods and contained two influenza A antigen subtypes and oneB subtype.

Several products this year include four antigens (two A subtypes and two B subtypes), and some are now produced with non–egg-culture methods. This has led to a new system of classification, with the term inactivated influenza vaccine (IIV) replacing TIV. Table 2 lists the influenza vaccine categories and abbreviations. Table 3³ lists the contraindications for the different vaccine types.

The new products include Flumist Quadrivalent (MedImmune), a quadrivalent LAIV (LAIV4); Fluarix Quadrivalent (GlaxoSmithKline), a quadrivalent IIV (IIV4); Flucelvax (Novartis Vaccines and Diagnostics), a cell culture-based trivalent IIV (ccIIV3); and FluBlok (Protein Sciences), a trivalent recombinant hemagglutinin influenza vaccine (RIV3). Fluzone (Sanofi Pasteur), introduced last season in a trivalent formulation, is also available this season as a quadrivalent IIV (IIV4).

As a group, influenza vaccine products now offer three routes of administration: intramuscular, subcutaneous, and intranasal. There is currently no evidence that any route offers an advantage over another, and the CDC states no preference for any particular product or route of administration.

Mercury content is not a problem

Even though there is no scientific controversy over the safety of the mercury-containing preservative thimerosal, some patients still have doubts and may ask for a thimerosal-free product. The only influenza products that contain any thimerosal are those that come in multidose vials. A description of each influenza vaccine product, including thimerosal content, indicated ages, and routes of administration, can be found on the CDC’s Web site (www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm).³

Options for those with egg allergy

There is now a product, RIV3 (FluBlok), that is manufactured without the use of eggs. It can be used in those 18 to 49 years of age with a history of egg allergy of any severity. Since 2011, the Advisory Committee on Immunization Practices (ACIP) has recommended that individuals with a history of mild egg allergy (those who experience only hives after egg exposure) may receive IIV, with additional safety precautions. Do not delay vaccination for these individuals if RIV is unavailable. Because of a lack of data demonstrating safety of LAIV for individuals with egg allergy, those allergic to eggs should receive RIV or IIV rather than LAIV.

Though the new ccIIV product, Flucelvax, is manufactured without the use of eggs, the seed viruses used to create the vaccine have been processed in eggs. The egg protein content in the vaccine is extremely low (< 50 femto­grams [5 × 10^-14 g] per 0.5-mL dose), but the CDC does not consider it egg free. Figure 1 (see page 32) de­picts the recommendations for those with a history of egg allergy.³

Other interventions for influenza prevention

Vaccination is only one tool available to prevent morbidity and mortality from influenza. Antiviral chemoprevention and treatment and infection control practices can also be effective.

Antiviral chemoprevention is available for both pre- and post-exposure administration. In the past few years, the CDC has de-emphasized such use of antivirals for these indications out of concern for the supply of these agents and for the possibility that their use might lead to increased rates of viral resistance. Consider antiviral chemoprevention for those who have conditions that place them at risk for complications, and for those who are unvaccinated if they are at high risk for exposure to influenza (pre-exposure prophylaxis) or have been exposed (postexposure prophylaxis), if the medication can be started within 48 hours of exposure.

Another option for unvaccinated high-risk patients is vigilant symptom monitoring with early treatment for influenza symptoms. Chemoprophylaxis is recommended in addition to vaccination to control influenza outbreaks at institutions that house patients at high risk for complications of influenza. Details on recommended antivirals including doses and duration of treatment can be found in a 2011 issue of Morbidity and Mortality Weekly Report.⁵

Antiviral treatment. The CDC recommends antiviral treatment for anyone with suspected or confirmed influenza who has progressive, severe, or complicated illness or is hospitalized for his or her illness.⁵ Treatment is also recommended for outpatients with suspected or confirmed influenza who are at higher risk for influenza complications. This latter group includes those in Table 1, particularly children 6 to 59 months and adults ≥ 50. Start antiviral treatment within 48 hours of the first symptoms. For hospitalized patients, however, begin treatment at any point, regardless of duration of illness.

Infection control practices can prevent the spread of influenza in the health care setting and in the homes of those with influenza. These practices are also described on the CDC influenza Web site.⁶

References

1. Thompson WW, Shay DK, Weintraub E. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333-1340.

2. CDC. Estimates of deaths associated with seasonal influenza–United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59:1057-1062.

3. CDC. Summary* recommendations: prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—(ACIP)—United States, 2013-14. www.cdc.gov/flu/professionals/acip/2013-summary-recommendations.htm. Accessed August 9, 2013.

4. CDC. Interim adjusted estimates of seasonal influenza vaccine effectiveness–United States, February 2013. MMWR Morb Mortal Wkly Rep. 2013;62:119-123.

5. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza. MMWR Recomm Rep. 2011;60(RR01):1-24. www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm. Accessed July 2, 2013.

6. CDC. Infection control in health care facilities. www.cdc.gov/flu/professionals/infectioncontrol/index.htm. Accessed July 2, 2013.

A 5-day course of dexamethasone significantly shortened hospital stays for infants with bronchiolitis who had eczema or close relatives with asthma.

The randomized, placebo-controlled study suggests that a family history of atopy could identify a subset of babies who would benefit from the addition of a corticosteroid to the usual salbutamol therapy for acute bronchiolitis, according to Dr. Khalid Alansari and colleagues. The report was published in the Sept. 16 issue of Pediatrics.

The researchers examined 7-day outcomes in 200 infants with acute bronchiolitis who were at a high risk of asthma, as determined by having at least one first-degree relative with either asthma or eczema. All of the children (mean age 3.5 months) were admitted to a pediatric hospital for treatment, wrote Dr. Alansari of Weill Cornell Medical College, Doha, Qatar, and coauthors. Infants who received dexamethasone were discharged 8 hours earlier than were those receiving standard treatment. The mean duration of symptoms was 4.5 days (Pediatrics 2013 Sept. 13 [doi: 10.1542/peds.2012-3746]).

The study’s primary outcome was time until discharge. Secondary outcomes included the number of patients who needed epinephrine treatment, readmission for a shorter stay in an infirmary site, and revisiting the emergency department or another clinic for the same illness. A study nurse made daily calls to assess the patients after discharge.

Infants in the dexamethasone group were discharged at a mean of 18.6 hours – significantly sooner than those in the control group (27 hours). Epinephrine was necessary for 19 infants in the dexamethasone group and 31 in the placebo group – again a significant difference.

Similar numbers in each group needed readmission and additional outpatient visits in the week after discharge. During the follow-up week, 22% of the dexamethasone group needed infirmary care and the mean stay was 17 hours, compared with 21% of the placebo group with a mean stay of 18 hours.

Nineteen in the dexamethasone group and 11 in the placebo group made a clinic visit (18.6% vs. 11%); this difference was not significant.

The chest radiograph was normal in about 37% of infants studied. About half showed lesser infiltrates; 15% had a lobar collapse or consolidation.

More than 70% had a full sibling with asthma. About 20% had a parent with the disease; in 5%, both parents had it. About 20% of patients had both eczema and first-degree relative with asthma.

All of the infants received 2.5 mg salbutamol nebulization at baseline and at 30, 60, and 120 minutes, and then every 2 hours until discharge. Nebulized epinephrine (0.5 mL/kg with a maximum dose of 5 mL) was available if needed. In addition, they were randomized to either placebo or to a 5-day course of dexamethasone 1 mg/mL, at a rate of 1 mL/kg on day 1, reduced to 0.6 mL/kg for days 2-5.

The study was sponsored by Hamad Medical Corporation. The authors reported no financial conflicts.

[email protected]

A 5-day course of dexamethasone significantly shortened hospital stays for infants with bronchiolitis who had eczema or close relatives with asthma.

The randomized, placebo-controlled study suggests that a family history of atopy could identify a subset of babies who would benefit from the addition of a corticosteroid to the usual salbutamol therapy for acute bronchiolitis, according to Dr. Khalid Alansari and colleagues. The report was published in the Sept. 16 issue of Pediatrics.

The researchers examined 7-day outcomes in 200 infants with acute bronchiolitis who were at a high risk of asthma, as determined by having at least one first-degree relative with either asthma or eczema. All of the children (mean age 3.5 months) were admitted to a pediatric hospital for treatment, wrote Dr. Alansari of Weill Cornell Medical College, Doha, Qatar, and coauthors. Infants who received dexamethasone were discharged 8 hours earlier than were those receiving standard treatment. The mean duration of symptoms was 4.5 days (Pediatrics 2013 Sept. 13 [doi: 10.1542/peds.2012-3746]).

The study’s primary outcome was time until discharge. Secondary outcomes included the number of patients who needed epinephrine treatment, readmission for a shorter stay in an infirmary site, and revisiting the emergency department or another clinic for the same illness. A study nurse made daily calls to assess the patients after discharge.

Infants in the dexamethasone group were discharged at a mean of 18.6 hours – significantly sooner than those in the control group (27 hours). Epinephrine was necessary for 19 infants in the dexamethasone group and 31 in the placebo group – again a significant difference.

Similar numbers in each group needed readmission and additional outpatient visits in the week after discharge. During the follow-up week, 22% of the dexamethasone group needed infirmary care and the mean stay was 17 hours, compared with 21% of the placebo group with a mean stay of 18 hours.

Nineteen in the dexamethasone group and 11 in the placebo group made a clinic visit (18.6% vs. 11%); this difference was not significant.

The chest radiograph was normal in about 37% of infants studied. About half showed lesser infiltrates; 15% had a lobar collapse or consolidation.

More than 70% had a full sibling with asthma. About 20% had a parent with the disease; in 5%, both parents had it. About 20% of patients had both eczema and first-degree relative with asthma.

All of the infants received 2.5 mg salbutamol nebulization at baseline and at 30, 60, and 120 minutes, and then every 2 hours until discharge. Nebulized epinephrine (0.5 mL/kg with a maximum dose of 5 mL) was available if needed. In addition, they were randomized to either placebo or to a 5-day course of dexamethasone 1 mg/mL, at a rate of 1 mL/kg on day 1, reduced to 0.6 mL/kg for days 2-5.

The study was sponsored by Hamad Medical Corporation. The authors reported no financial conflicts.

[email protected]

A 5-day course of dexamethasone significantly shortened hospital stays for infants with bronchiolitis who had eczema or close relatives with asthma.

The randomized, placebo-controlled study suggests that a family history of atopy could identify a subset of babies who would benefit from the addition of a corticosteroid to the usual salbutamol therapy for acute bronchiolitis, according to Dr. Khalid Alansari and colleagues. The report was published in the Sept. 16 issue of Pediatrics.

The researchers examined 7-day outcomes in 200 infants with acute bronchiolitis who were at a high risk of asthma, as determined by having at least one first-degree relative with either asthma or eczema. All of the children (mean age 3.5 months) were admitted to a pediatric hospital for treatment, wrote Dr. Alansari of Weill Cornell Medical College, Doha, Qatar, and coauthors. Infants who received dexamethasone were discharged 8 hours earlier than were those receiving standard treatment. The mean duration of symptoms was 4.5 days (Pediatrics 2013 Sept. 13 [doi: 10.1542/peds.2012-3746]).

The study’s primary outcome was time until discharge. Secondary outcomes included the number of patients who needed epinephrine treatment, readmission for a shorter stay in an infirmary site, and revisiting the emergency department or another clinic for the same illness. A study nurse made daily calls to assess the patients after discharge.

Infants in the dexamethasone group were discharged at a mean of 18.6 hours – significantly sooner than those in the control group (27 hours). Epinephrine was necessary for 19 infants in the dexamethasone group and 31 in the placebo group – again a significant difference.

Similar numbers in each group needed readmission and additional outpatient visits in the week after discharge. During the follow-up week, 22% of the dexamethasone group needed infirmary care and the mean stay was 17 hours, compared with 21% of the placebo group with a mean stay of 18 hours.

Nineteen in the dexamethasone group and 11 in the placebo group made a clinic visit (18.6% vs. 11%); this difference was not significant.

The chest radiograph was normal in about 37% of infants studied. About half showed lesser infiltrates; 15% had a lobar collapse or consolidation.

More than 70% had a full sibling with asthma. About 20% had a parent with the disease; in 5%, both parents had it. About 20% of patients had both eczema and first-degree relative with asthma.

All of the infants received 2.5 mg salbutamol nebulization at baseline and at 30, 60, and 120 minutes, and then every 2 hours until discharge. Nebulized epinephrine (0.5 mL/kg with a maximum dose of 5 mL) was available if needed. In addition, they were randomized to either placebo or to a 5-day course of dexamethasone 1 mg/mL, at a rate of 1 mL/kg on day 1, reduced to 0.6 mL/kg for days 2-5.

The study was sponsored by Hamad Medical Corporation. The authors reported no financial conflicts.

[email protected]

DENVER – Oral vancomycin at a dose of 125 mg four times daily is just as effective as is a dose of 250 mg or higher given at the same frequency in the treatment of diarrhea associated with Clostridium difficile infection, judging from the results from a retrospective study.

Use of the lower dosing regimen has the potential to decrease treatment costs without worsening outcomes, Philip Chung, Pharm.D., said in an interview before the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, where the study was presented.

According to current recommendations, oral vancomycin 125 mg q.i.d. is the treatment of choice for severe uncomplicated C. difficile infection. To date, no studies have shown the use of oral vancomycin doses higher than 125 mg q.i.d. to be more efficacious than the recommended 125 mg q.i.d. in this setting, said Dr. Chung, clinical pharmacy manager of infectious diseases at Montefiore Medical Center, New York.

"Prior to 2008, prescribers at our institution frequently requested vancomycin doses higher than the recommended 125 mg q.i.d. for treatment of [C. difficile infection] despite the absence of data showing added benefits with the higher dosing regimens," he said. "This practice not only increases medication and/or preparation costs, but it may also increase the potential for untoward effects in patients being treated with the higher doses (e.g., increased risks for vancomycin-resistant enterococci colonization or higher likelihood to further alter the GI flora)."

Since the inception of the Antimicrobial Stewardship Program at Montefiore Medical Center in 2008, Dr. Chung and his associates observed a shift in oral vancomycin prescribing practices from a higher dosing regimen to a lower dosing regimen. "Because of this change in practice, we wished to evaluate the efficacy of the different oral vancomycin dosing regimen in order to ensure treatment outcomes remained unchanged at our institution," he said. To do so, the researchers retrospectively reviewed clinical outcomes of 300 adult patients treated with oral vancomycin at the medical center between 2006 and 2010. They looked at clinical parameters, concomitant antibiotics, in-hospital mortality, and 30-day readmission.

The primary endpoint was clinical improvement at 72 hours of oral vancomycin. Secondary endpoints included clinical improvement at end of therapy or discharge, length of stay, in-hospital mortality, and 30-day readmission rate.

Of the 300 patients, 197 were prescribed oral vancomycin 125 mg q.i.d. (low-dose group) and 103 patients were prescribed 250 mg or higher q.i.d. (high-dose group). Dr. Chung and his associates reported that clinical improvement assessed 72 hours after starting oral vancomycin therapy was observed in 85% and 86% of patients in the low- and high-dose groups, respectively (P less than 0.05). Rates of clinical improvement at end of therapy or time of hospital discharge between the two groups were also found to be similar (93% vs. 96%), as were total length of hospital stay (20 days vs. 19 days), in-hospital mortality (15% vs. 23%), and rates of 30-day readmission (34% vs. 24%).

"The finding that oral vancomycin 125 mg q.i.d. works as well as higher doses for severe uncomplicated C. difficile infection for the most part is not a surprise to us, as some evidence already exists in the literature," said Dr. Chung, also of Albert Einstein College of Medicine in New York. "Our finding only confirmed what is already known."

Limitations include the fact that this is a single-center study, and that it is subject to selection bias because of its retrospective design, Dr. Chung said. "However, we took steps to ensure that all patients treated with oral vancomycin who had laboratory-confirmed [C. difficile infection] and symptoms consistent with [C. difficile infection] were included in the study," he said.

Dr. Chung said that he had no relevant financial conflicts to disclose.

[email protected]

DENVER – Oral vancomycin at a dose of 125 mg four times daily is just as effective as is a dose of 250 mg or higher given at the same frequency in the treatment of diarrhea associated with Clostridium difficile infection, judging from the results from a retrospective study.

Use of the lower dosing regimen has the potential to decrease treatment costs without worsening outcomes, Philip Chung, Pharm.D., said in an interview before the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, where the study was presented.

According to current recommendations, oral vancomycin 125 mg q.i.d. is the treatment of choice for severe uncomplicated C. difficile infection. To date, no studies have shown the use of oral vancomycin doses higher than 125 mg q.i.d. to be more efficacious than the recommended 125 mg q.i.d. in this setting, said Dr. Chung, clinical pharmacy manager of infectious diseases at Montefiore Medical Center, New York.

"Prior to 2008, prescribers at our institution frequently requested vancomycin doses higher than the recommended 125 mg q.i.d. for treatment of [C. difficile infection] despite the absence of data showing added benefits with the higher dosing regimens," he said. "This practice not only increases medication and/or preparation costs, but it may also increase the potential for untoward effects in patients being treated with the higher doses (e.g., increased risks for vancomycin-resistant enterococci colonization or higher likelihood to further alter the GI flora)."

Since the inception of the Antimicrobial Stewardship Program at Montefiore Medical Center in 2008, Dr. Chung and his associates observed a shift in oral vancomycin prescribing practices from a higher dosing regimen to a lower dosing regimen. "Because of this change in practice, we wished to evaluate the efficacy of the different oral vancomycin dosing regimen in order to ensure treatment outcomes remained unchanged at our institution," he said. To do so, the researchers retrospectively reviewed clinical outcomes of 300 adult patients treated with oral vancomycin at the medical center between 2006 and 2010. They looked at clinical parameters, concomitant antibiotics, in-hospital mortality, and 30-day readmission.

The primary endpoint was clinical improvement at 72 hours of oral vancomycin. Secondary endpoints included clinical improvement at end of therapy or discharge, length of stay, in-hospital mortality, and 30-day readmission rate.

Of the 300 patients, 197 were prescribed oral vancomycin 125 mg q.i.d. (low-dose group) and 103 patients were prescribed 250 mg or higher q.i.d. (high-dose group). Dr. Chung and his associates reported that clinical improvement assessed 72 hours after starting oral vancomycin therapy was observed in 85% and 86% of patients in the low- and high-dose groups, respectively (P less than 0.05). Rates of clinical improvement at end of therapy or time of hospital discharge between the two groups were also found to be similar (93% vs. 96%), as were total length of hospital stay (20 days vs. 19 days), in-hospital mortality (15% vs. 23%), and rates of 30-day readmission (34% vs. 24%).

"The finding that oral vancomycin 125 mg q.i.d. works as well as higher doses for severe uncomplicated C. difficile infection for the most part is not a surprise to us, as some evidence already exists in the literature," said Dr. Chung, also of Albert Einstein College of Medicine in New York. "Our finding only confirmed what is already known."

Limitations include the fact that this is a single-center study, and that it is subject to selection bias because of its retrospective design, Dr. Chung said. "However, we took steps to ensure that all patients treated with oral vancomycin who had laboratory-confirmed [C. difficile infection] and symptoms consistent with [C. difficile infection] were included in the study," he said.

Dr. Chung said that he had no relevant financial conflicts to disclose.

[email protected]

DENVER – Oral vancomycin at a dose of 125 mg four times daily is just as effective as is a dose of 250 mg or higher given at the same frequency in the treatment of diarrhea associated with Clostridium difficile infection, judging from the results from a retrospective study.

Use of the lower dosing regimen has the potential to decrease treatment costs without worsening outcomes, Philip Chung, Pharm.D., said in an interview before the annual Interscience Conference on Antimicrobial Agents and Chemotherapy, where the study was presented.

According to current recommendations, oral vancomycin 125 mg q.i.d. is the treatment of choice for severe uncomplicated C. difficile infection. To date, no studies have shown the use of oral vancomycin doses higher than 125 mg q.i.d. to be more efficacious than the recommended 125 mg q.i.d. in this setting, said Dr. Chung, clinical pharmacy manager of infectious diseases at Montefiore Medical Center, New York.

"Prior to 2008, prescribers at our institution frequently requested vancomycin doses higher than the recommended 125 mg q.i.d. for treatment of [C. difficile infection] despite the absence of data showing added benefits with the higher dosing regimens," he said. "This practice not only increases medication and/or preparation costs, but it may also increase the potential for untoward effects in patients being treated with the higher doses (e.g., increased risks for vancomycin-resistant enterococci colonization or higher likelihood to further alter the GI flora)."

Since the inception of the Antimicrobial Stewardship Program at Montefiore Medical Center in 2008, Dr. Chung and his associates observed a shift in oral vancomycin prescribing practices from a higher dosing regimen to a lower dosing regimen. "Because of this change in practice, we wished to evaluate the efficacy of the different oral vancomycin dosing regimen in order to ensure treatment outcomes remained unchanged at our institution," he said. To do so, the researchers retrospectively reviewed clinical outcomes of 300 adult patients treated with oral vancomycin at the medical center between 2006 and 2010. They looked at clinical parameters, concomitant antibiotics, in-hospital mortality, and 30-day readmission.

The primary endpoint was clinical improvement at 72 hours of oral vancomycin. Secondary endpoints included clinical improvement at end of therapy or discharge, length of stay, in-hospital mortality, and 30-day readmission rate.

Of the 300 patients, 197 were prescribed oral vancomycin 125 mg q.i.d. (low-dose group) and 103 patients were prescribed 250 mg or higher q.i.d. (high-dose group). Dr. Chung and his associates reported that clinical improvement assessed 72 hours after starting oral vancomycin therapy was observed in 85% and 86% of patients in the low- and high-dose groups, respectively (P less than 0.05). Rates of clinical improvement at end of therapy or time of hospital discharge between the two groups were also found to be similar (93% vs. 96%), as were total length of hospital stay (20 days vs. 19 days), in-hospital mortality (15% vs. 23%), and rates of 30-day readmission (34% vs. 24%).

"The finding that oral vancomycin 125 mg q.i.d. works as well as higher doses for severe uncomplicated C. difficile infection for the most part is not a surprise to us, as some evidence already exists in the literature," said Dr. Chung, also of Albert Einstein College of Medicine in New York. "Our finding only confirmed what is already known."

Limitations include the fact that this is a single-center study, and that it is subject to selection bias because of its retrospective design, Dr. Chung said. "However, we took steps to ensure that all patients treated with oral vancomycin who had laboratory-confirmed [C. difficile infection] and symptoms consistent with [C. difficile infection] were included in the study," he said.

Dr. Chung said that he had no relevant financial conflicts to disclose.

[email protected]

VAIL, COLO. – One of the most useful signs that a young infant with an afebrile coughing illness has pertussis is the combination of an elevated white blood cell count of 20,000 cells/mcL or more plus a lymphocyte count of at least 10,000 cells/mcL.

"This is a pediatric pearl. It’s really a poor man’s way of diagnosing pertussis. It’s an effect of the pertussis toxin spreading throughout the neonate’s body, causing a very high white cell count with absolute lymphocytosis," Dr. Ann-Christine Nyquist said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

This clinical pearl is part of a highly useful algorithm put forth by the Global Pertussis Initiative in an effort to update and standardize the case definitions of pertussis. Existing case definitions were developed more than 40 years ago and have numerous shortcomings.

The group developed a three-pronged, age-based algorithm, reflecting an understanding that the key manifestations of pertussis are different in infants aged 0-3 months, children aged 4 months to 9 years, and adolescents or adults.

According to the algorithm, the presence of an elevated WBC count with absolute lymphocytosis in an infant up to 3 months old with an afebrile illness and a cough of less than 3 weeks’ duration that’s increasing in frequency and severity is "virtually diagnostic" of pertussis (Clin. Infect. Dis. 2012;54:1756-64).

Another key feature of pertussis – and this one applies across the age spectrum, from infants to adults – is that the coryza remains watery and doesn’t become purulent, unlike in most viral respiratory infections.

"That green snotty nose doesn’t usually happen when kids have pertussis," explained Dr. Nyquist, professor of pediatrics at the University of Colorado, Denver.

Similarly, in patients of all ages the pertussis cough, even as it worsens, does not become truly productive.

To help nail down the diagnosis of pertussis in infants, the key question to ask parents is, "Is there an adult or adolescent in your family who’s had the most severe cough in their life?" Most infants with pertussis will have had close exposure to an older family member with a prolonged afebrile coughing illness, Dr. Nyquist noted.

In the 4-month to 9-year-old age group, the cough becomes more paroxysmal. The key indicators of pertussis in this age group, according to the Global Pertussis Initiative algorithm, are worsening paroxysmal nonproductive cough of at least 7 days’ duration in an afebrile child with nonpurulent coryza.

This same triad – worsening paroxysmal nonproductive cough, afebrile illness, and nonpurulent coryza – also has high sensitivity and good specificity for the clinical diagnosis of pertussis in adolescents and adults. In addition, the algorithm highlights another useful clue to the diagnosis in patients in this age range: the occurrence of sweating episodes between coughing paroxysms.

In terms of laboratory diagnostics, real-time PCR and culture of nasopharyngeal mucus are most useful in the first 3 weeks after illness onset. Serology is a challenge because the results are influenced by the effects of vaccination; it shouldn’t be used to diagnose pertussis within 1 year following inoculation with any pertussis vaccine because it’s impossible to tell if a positive result represents a response to the vaccine or to infection.

Also, serology can’t distinguish between Bordetella pertussis and B. parapertussis infection. Most PCR tests can. It’s an important distinction because B. parapertussis turns out to be the pathogen in roughly 15% of cases of coughing illnesses similar to pertussis. B. parapertussis infection isn’t vaccine preventable, and its treatment hasn’t been well studied.

The expert consensus is that direct fluorescent antibody testing should be discouraged as a tool to diagnose pertussis because of its unreliable sensitivity and specificity. IgG anti–pertussis toxin ELISA testing is superior to IgA anti–pertussis toxin ELISA, which has a high false-negative rate, Dr. Nyquist observed.

She reported having no financial relationships with any commercial interests.

VAIL, COLO. – One of the most useful signs that a young infant with an afebrile coughing illness has pertussis is the combination of an elevated white blood cell count of 20,000 cells/mcL or more plus a lymphocyte count of at least 10,000 cells/mcL.

"This is a pediatric pearl. It’s really a poor man’s way of diagnosing pertussis. It’s an effect of the pertussis toxin spreading throughout the neonate’s body, causing a very high white cell count with absolute lymphocytosis," Dr. Ann-Christine Nyquist said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

This clinical pearl is part of a highly useful algorithm put forth by the Global Pertussis Initiative in an effort to update and standardize the case definitions of pertussis. Existing case definitions were developed more than 40 years ago and have numerous shortcomings.

The group developed a three-pronged, age-based algorithm, reflecting an understanding that the key manifestations of pertussis are different in infants aged 0-3 months, children aged 4 months to 9 years, and adolescents or adults.

According to the algorithm, the presence of an elevated WBC count with absolute lymphocytosis in an infant up to 3 months old with an afebrile illness and a cough of less than 3 weeks’ duration that’s increasing in frequency and severity is "virtually diagnostic" of pertussis (Clin. Infect. Dis. 2012;54:1756-64).

Another key feature of pertussis – and this one applies across the age spectrum, from infants to adults – is that the coryza remains watery and doesn’t become purulent, unlike in most viral respiratory infections.

"That green snotty nose doesn’t usually happen when kids have pertussis," explained Dr. Nyquist, professor of pediatrics at the University of Colorado, Denver.

Similarly, in patients of all ages the pertussis cough, even as it worsens, does not become truly productive.

To help nail down the diagnosis of pertussis in infants, the key question to ask parents is, "Is there an adult or adolescent in your family who’s had the most severe cough in their life?" Most infants with pertussis will have had close exposure to an older family member with a prolonged afebrile coughing illness, Dr. Nyquist noted.

In the 4-month to 9-year-old age group, the cough becomes more paroxysmal. The key indicators of pertussis in this age group, according to the Global Pertussis Initiative algorithm, are worsening paroxysmal nonproductive cough of at least 7 days’ duration in an afebrile child with nonpurulent coryza.

This same triad – worsening paroxysmal nonproductive cough, afebrile illness, and nonpurulent coryza – also has high sensitivity and good specificity for the clinical diagnosis of pertussis in adolescents and adults. In addition, the algorithm highlights another useful clue to the diagnosis in patients in this age range: the occurrence of sweating episodes between coughing paroxysms.

In terms of laboratory diagnostics, real-time PCR and culture of nasopharyngeal mucus are most useful in the first 3 weeks after illness onset. Serology is a challenge because the results are influenced by the effects of vaccination; it shouldn’t be used to diagnose pertussis within 1 year following inoculation with any pertussis vaccine because it’s impossible to tell if a positive result represents a response to the vaccine or to infection.

Also, serology can’t distinguish between Bordetella pertussis and B. parapertussis infection. Most PCR tests can. It’s an important distinction because B. parapertussis turns out to be the pathogen in roughly 15% of cases of coughing illnesses similar to pertussis. B. parapertussis infection isn’t vaccine preventable, and its treatment hasn’t been well studied.

The expert consensus is that direct fluorescent antibody testing should be discouraged as a tool to diagnose pertussis because of its unreliable sensitivity and specificity. IgG anti–pertussis toxin ELISA testing is superior to IgA anti–pertussis toxin ELISA, which has a high false-negative rate, Dr. Nyquist observed.

She reported having no financial relationships with any commercial interests.

VAIL, COLO. – One of the most useful signs that a young infant with an afebrile coughing illness has pertussis is the combination of an elevated white blood cell count of 20,000 cells/mcL or more plus a lymphocyte count of at least 10,000 cells/mcL.

"This is a pediatric pearl. It’s really a poor man’s way of diagnosing pertussis. It’s an effect of the pertussis toxin spreading throughout the neonate’s body, causing a very high white cell count with absolute lymphocytosis," Dr. Ann-Christine Nyquist said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

This clinical pearl is part of a highly useful algorithm put forth by the Global Pertussis Initiative in an effort to update and standardize the case definitions of pertussis. Existing case definitions were developed more than 40 years ago and have numerous shortcomings.

The group developed a three-pronged, age-based algorithm, reflecting an understanding that the key manifestations of pertussis are different in infants aged 0-3 months, children aged 4 months to 9 years, and adolescents or adults.

According to the algorithm, the presence of an elevated WBC count with absolute lymphocytosis in an infant up to 3 months old with an afebrile illness and a cough of less than 3 weeks’ duration that’s increasing in frequency and severity is "virtually diagnostic" of pertussis (Clin. Infect. Dis. 2012;54:1756-64).

Another key feature of pertussis – and this one applies across the age spectrum, from infants to adults – is that the coryza remains watery and doesn’t become purulent, unlike in most viral respiratory infections.

"That green snotty nose doesn’t usually happen when kids have pertussis," explained Dr. Nyquist, professor of pediatrics at the University of Colorado, Denver.

Similarly, in patients of all ages the pertussis cough, even as it worsens, does not become truly productive.

To help nail down the diagnosis of pertussis in infants, the key question to ask parents is, "Is there an adult or adolescent in your family who’s had the most severe cough in their life?" Most infants with pertussis will have had close exposure to an older family member with a prolonged afebrile coughing illness, Dr. Nyquist noted.

In the 4-month to 9-year-old age group, the cough becomes more paroxysmal. The key indicators of pertussis in this age group, according to the Global Pertussis Initiative algorithm, are worsening paroxysmal nonproductive cough of at least 7 days’ duration in an afebrile child with nonpurulent coryza.

This same triad – worsening paroxysmal nonproductive cough, afebrile illness, and nonpurulent coryza – also has high sensitivity and good specificity for the clinical diagnosis of pertussis in adolescents and adults. In addition, the algorithm highlights another useful clue to the diagnosis in patients in this age range: the occurrence of sweating episodes between coughing paroxysms.

In terms of laboratory diagnostics, real-time PCR and culture of nasopharyngeal mucus are most useful in the first 3 weeks after illness onset. Serology is a challenge because the results are influenced by the effects of vaccination; it shouldn’t be used to diagnose pertussis within 1 year following inoculation with any pertussis vaccine because it’s impossible to tell if a positive result represents a response to the vaccine or to infection.

Also, serology can’t distinguish between Bordetella pertussis and B. parapertussis infection. Most PCR tests can. It’s an important distinction because B. parapertussis turns out to be the pathogen in roughly 15% of cases of coughing illnesses similar to pertussis. B. parapertussis infection isn’t vaccine preventable, and its treatment hasn’t been well studied.

The expert consensus is that direct fluorescent antibody testing should be discouraged as a tool to diagnose pertussis because of its unreliable sensitivity and specificity. IgG anti–pertussis toxin ELISA testing is superior to IgA anti–pertussis toxin ELISA, which has a high false-negative rate, Dr. Nyquist observed.

She reported having no financial relationships with any commercial interests.

VAIL, COLO. – A universal influenza vaccine is not a pipe dream.

"There is a really big push for this now. It’s a major goal," Dr. Wayne Sullender observed at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

The impetus for development of a universal influenza vaccine is that influenza still poses a major public health threat despite the widespread availability of current vaccines. Worldwide, roughly 1.4 million children die of pneumonia each year, more than from malaria, AIDS, and measles combined. It has been estimated that each year up to 112,000 children under age 5 die of influenza-associated acute lower respiratory tract infection, with 99% of the deaths occurring in developing countries.

A universal influenza vaccine could render obsolete the current costly, time-consuming, and uncertainty-ridden process of reformulating flu vaccines from year to year based upon expert consensus as to what the epidemic strains are most likely to be in the next flu season. This is a guessing game, and vaccine efficacy is reduced in seasons where the match isn’t good.

Also, a universal vaccine could conceivably protect against highly pathogenic pandemic influenza viruses, such as the swine flu H3N2 or the even more lethal avian H7N9 influenza virus. And even if a universal influenza vaccine wasn’t fully protective against threatening pandemic strains, it could perhaps prime vaccine recipients so they are no longer immunologically naïve, explained Dr. Sullender, an infectious diseases expert who is a visiting professor of pediatrics at the University of Colorado, Denver.

All of the universal flu vaccines in clinical development employ various highly conserved regions of influenza virus target antigens. In focusing on these targets shared by different influenza virus subtypes, the goal is to develop vaccines that protect against seasonal influenza, even as the viruses engage in their relentless antigenic shift and drift, as well as to provide immunity against emerging pandemic strains having the potential for rapid spread and high mortality throughout the world.

Among the novel strategies for development of a universal influenza vaccine being pursued in laboratories around the world, one of the most promising in Dr. Sullender’s view involves stimulation of anti-M2e antibodies. M2 is a proton-selective ion channel that plays a key role in virus assembly. M2 is found on the surface of virus-infected cells. Its advantage as an antigen is that its sequence is virtually the same in every influenza virus isolated since the 1930s. Natural infection doesn’t stimulate much of an antibody response to M2. Yet even though M2e antibodies are not virus-neutralizing, it appears they are able to kill influenza virus by other mechanisms.

Another active area involves antibody responses to highly conserved epitopes on hemagglutinin. A region of vulnerability has been identified in the stem region of hemagglutinin, the viral spike. If the amino acids in this stem antibody binding site prove to be so important to the structure of hemagglutinin that the virus can’t tolerate change there, then the virus wouldn’t be able to adapt to and mutate away from a vaccine targeting this site via stimulation of neutralizing antibodies. Such a vaccine could very well be a universal influenza vaccine.

In addition, a novel epitope has been identified on the globular head of the H1N1 influenza virus hemagglutinin. Investigators have isolated a human monoclonal antibody that recognizes this epitope and neutralizes many different H1N1 strains. This could eventually lead to production of vaccines that incorporate protection against the severe H1N1 flu.

With regard to the avian-origin H7N9 influenza A virus that emerged last winter in China, Dr. Sullender commented, "This one is pretty scary." First estimates are that one-third of people hospitalized with the infection died. However, less severe cases were probably underrecognized, and it’s unlikely the death rate will remain this high.

The human-to-human transmission rate of H7N9 is low. Still, there are several reasons for concern about this virus. Although the pathogenicity in birds is low, the virus appears to have enhanced replication and virulence in humans. And H7N9 is already resistant to amantadine. Moreover, cases of resistance to oseltamivir and zanamivir have been reported.

The potential for mayhem due to H7N9 is such that vaccine development efforts are already underway. Among infectious respiratory disease experts, all eyes are on the coming flu season in Asia and what role H7N9 will play.

"Time will tell whether this will be just another story that comes and goes with influenza, or it becomes a more long-lasting problem," he said.

Experts all agree that it’s not a matter of "if’" another worldwide, high-mortality flu pandemic such as the one that occurred after the end of World War I will happen, it’s simply a question of "when."

"It might occur in 5 years, or it might not happen during our lifetime," according to Dr. Sullender.

He reported receiving research funding from the Centers for Disease Control and Prevention and has no relevant financial relationships.

[email protected]

VAIL, COLO. – A universal influenza vaccine is not a pipe dream.

"There is a really big push for this now. It’s a major goal," Dr. Wayne Sullender observed at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

The impetus for development of a universal influenza vaccine is that influenza still poses a major public health threat despite the widespread availability of current vaccines. Worldwide, roughly 1.4 million children die of pneumonia each year, more than from malaria, AIDS, and measles combined. It has been estimated that each year up to 112,000 children under age 5 die of influenza-associated acute lower respiratory tract infection, with 99% of the deaths occurring in developing countries.

A universal influenza vaccine could render obsolete the current costly, time-consuming, and uncertainty-ridden process of reformulating flu vaccines from year to year based upon expert consensus as to what the epidemic strains are most likely to be in the next flu season. This is a guessing game, and vaccine efficacy is reduced in seasons where the match isn’t good.

Also, a universal vaccine could conceivably protect against highly pathogenic pandemic influenza viruses, such as the swine flu H3N2 or the even more lethal avian H7N9 influenza virus. And even if a universal influenza vaccine wasn’t fully protective against threatening pandemic strains, it could perhaps prime vaccine recipients so they are no longer immunologically naïve, explained Dr. Sullender, an infectious diseases expert who is a visiting professor of pediatrics at the University of Colorado, Denver.

All of the universal flu vaccines in clinical development employ various highly conserved regions of influenza virus target antigens. In focusing on these targets shared by different influenza virus subtypes, the goal is to develop vaccines that protect against seasonal influenza, even as the viruses engage in their relentless antigenic shift and drift, as well as to provide immunity against emerging pandemic strains having the potential for rapid spread and high mortality throughout the world.

Among the novel strategies for development of a universal influenza vaccine being pursued in laboratories around the world, one of the most promising in Dr. Sullender’s view involves stimulation of anti-M2e antibodies. M2 is a proton-selective ion channel that plays a key role in virus assembly. M2 is found on the surface of virus-infected cells. Its advantage as an antigen is that its sequence is virtually the same in every influenza virus isolated since the 1930s. Natural infection doesn’t stimulate much of an antibody response to M2. Yet even though M2e antibodies are not virus-neutralizing, it appears they are able to kill influenza virus by other mechanisms.

Another active area involves antibody responses to highly conserved epitopes on hemagglutinin. A region of vulnerability has been identified in the stem region of hemagglutinin, the viral spike. If the amino acids in this stem antibody binding site prove to be so important to the structure of hemagglutinin that the virus can’t tolerate change there, then the virus wouldn’t be able to adapt to and mutate away from a vaccine targeting this site via stimulation of neutralizing antibodies. Such a vaccine could very well be a universal influenza vaccine.

In addition, a novel epitope has been identified on the globular head of the H1N1 influenza virus hemagglutinin. Investigators have isolated a human monoclonal antibody that recognizes this epitope and neutralizes many different H1N1 strains. This could eventually lead to production of vaccines that incorporate protection against the severe H1N1 flu.

With regard to the avian-origin H7N9 influenza A virus that emerged last winter in China, Dr. Sullender commented, "This one is pretty scary." First estimates are that one-third of people hospitalized with the infection died. However, less severe cases were probably underrecognized, and it’s unlikely the death rate will remain this high.

The human-to-human transmission rate of H7N9 is low. Still, there are several reasons for concern about this virus. Although the pathogenicity in birds is low, the virus appears to have enhanced replication and virulence in humans. And H7N9 is already resistant to amantadine. Moreover, cases of resistance to oseltamivir and zanamivir have been reported.

The potential for mayhem due to H7N9 is such that vaccine development efforts are already underway. Among infectious respiratory disease experts, all eyes are on the coming flu season in Asia and what role H7N9 will play.

"Time will tell whether this will be just another story that comes and goes with influenza, or it becomes a more long-lasting problem," he said.

Experts all agree that it’s not a matter of "if’" another worldwide, high-mortality flu pandemic such as the one that occurred after the end of World War I will happen, it’s simply a question of "when."

"It might occur in 5 years, or it might not happen during our lifetime," according to Dr. Sullender.

He reported receiving research funding from the Centers for Disease Control and Prevention and has no relevant financial relationships.

[email protected]

VAIL, COLO. – A universal influenza vaccine is not a pipe dream.

"There is a really big push for this now. It’s a major goal," Dr. Wayne Sullender observed at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.

The impetus for development of a universal influenza vaccine is that influenza still poses a major public health threat despite the widespread availability of current vaccines. Worldwide, roughly 1.4 million children die of pneumonia each year, more than from malaria, AIDS, and measles combined. It has been estimated that each year up to 112,000 children under age 5 die of influenza-associated acute lower respiratory tract infection, with 99% of the deaths occurring in developing countries.

A universal influenza vaccine could render obsolete the current costly, time-consuming, and uncertainty-ridden process of reformulating flu vaccines from year to year based upon expert consensus as to what the epidemic strains are most likely to be in the next flu season. This is a guessing game, and vaccine efficacy is reduced in seasons where the match isn’t good.

Also, a universal vaccine could conceivably protect against highly pathogenic pandemic influenza viruses, such as the swine flu H3N2 or the even more lethal avian H7N9 influenza virus. And even if a universal influenza vaccine wasn’t fully protective against threatening pandemic strains, it could perhaps prime vaccine recipients so they are no longer immunologically naïve, explained Dr. Sullender, an infectious diseases expert who is a visiting professor of pediatrics at the University of Colorado, Denver.

All of the universal flu vaccines in clinical development employ various highly conserved regions of influenza virus target antigens. In focusing on these targets shared by different influenza virus subtypes, the goal is to develop vaccines that protect against seasonal influenza, even as the viruses engage in their relentless antigenic shift and drift, as well as to provide immunity against emerging pandemic strains having the potential for rapid spread and high mortality throughout the world.

Among the novel strategies for development of a universal influenza vaccine being pursued in laboratories around the world, one of the most promising in Dr. Sullender’s view involves stimulation of anti-M2e antibodies. M2 is a proton-selective ion channel that plays a key role in virus assembly. M2 is found on the surface of virus-infected cells. Its advantage as an antigen is that its sequence is virtually the same in every influenza virus isolated since the 1930s. Natural infection doesn’t stimulate much of an antibody response to M2. Yet even though M2e antibodies are not virus-neutralizing, it appears they are able to kill influenza virus by other mechanisms.

Another active area involves antibody responses to highly conserved epitopes on hemagglutinin. A region of vulnerability has been identified in the stem region of hemagglutinin, the viral spike. If the amino acids in this stem antibody binding site prove to be so important to the structure of hemagglutinin that the virus can’t tolerate change there, then the virus wouldn’t be able to adapt to and mutate away from a vaccine targeting this site via stimulation of neutralizing antibodies. Such a vaccine could very well be a universal influenza vaccine.

In addition, a novel epitope has been identified on the globular head of the H1N1 influenza virus hemagglutinin. Investigators have isolated a human monoclonal antibody that recognizes this epitope and neutralizes many different H1N1 strains. This could eventually lead to production of vaccines that incorporate protection against the severe H1N1 flu.

With regard to the avian-origin H7N9 influenza A virus that emerged last winter in China, Dr. Sullender commented, "This one is pretty scary." First estimates are that one-third of people hospitalized with the infection died. However, less severe cases were probably underrecognized, and it’s unlikely the death rate will remain this high.

The human-to-human transmission rate of H7N9 is low. Still, there are several reasons for concern about this virus. Although the pathogenicity in birds is low, the virus appears to have enhanced replication and virulence in humans. And H7N9 is already resistant to amantadine. Moreover, cases of resistance to oseltamivir and zanamivir have been reported.

The potential for mayhem due to H7N9 is such that vaccine development efforts are already underway. Among infectious respiratory disease experts, all eyes are on the coming flu season in Asia and what role H7N9 will play.

"Time will tell whether this will be just another story that comes and goes with influenza, or it becomes a more long-lasting problem," he said.

Experts all agree that it’s not a matter of "if’" another worldwide, high-mortality flu pandemic such as the one that occurred after the end of World War I will happen, it’s simply a question of "when."

"It might occur in 5 years, or it might not happen during our lifetime," according to Dr. Sullender.

He reported receiving research funding from the Centers for Disease Control and Prevention and has no relevant financial relationships.

[email protected]

NEW YORK – New guidelines for the diagnosis and treatment of urticaria have been endorsed by 15 professional organizations so far and are now being prepared for publication, according to a consensus meeting participant who summarized key points at the American Academy of Dermatology summer meeting.

The guidelines, developed at an earlier conference held in Berlin attended by experts from 39 countries, are straightforward, relatively simple, "and truly developed for global application," according to Dr. Kiran Godse of Patil Medical College and Hospital, Navi Mumbai, India. The guidelines represent a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF), the American Academy of Allergy, Asthma and Immunology (AAAAI), and the World Allergy Organization (WAO).

The simplicity of the guidelines starts with the definition of urticaria. It consists of three characteristics: "wheals, angioedema, or both." While the definition goes on to specify that these conditions should be differentiated from autoinflammatory syndromes, hereditary angioedema, and other diseases that produce hives or swelling, the new guidelines abandon the term "idiopathic."

"Our understanding of the etiology and pathogenesis has advanced to the point that we can identify the causes in most cases," said Dr. Godse, indicating that classifying cases as "idiopathic" without further investigation is unhelpful when the goal is to find and avoid triggers.

A number of subclassifications, such as spontaneous urticaria, inducible urticaria, acute urticaria, and chronic urticaria, are defined and employed to guide clinical management. In patients with acute urticaria, diagnostic testing beyond a careful history is not recommended, except when avoidance strategies fail and recurrences are common.

Even in chronic urticaria, which is defined as symptoms persisting for at least 6 months, Dr. Godse said that the guidelines recommend "limited" initial diagnostic studies.

By relying on careful patient history rather than clinical tests to differentiate the major forms of this disease, such as cold urticaria, heat urticaria, delayed pressure urticaria, solar urticaria, and symptomatic dermographism, the guidelines in effect propose that underlying etiologies do not usually require an extensive workup. However, the guidelines do advise more extensive tests in individuals with persistent and significant disease, which can be measured with the Chronic Urticaria Quality of Life (CU-QoL) and the Angioedema Quality of Life (Ae-QoL) instruments. Both are strongly recommended for baseline assessment of symptom burden.

The treatment goal of the stepwise management is clear: complete absence of symptoms. "Treat the disease until it is gone," said Dr. Godse, summarizing this recommendation.

If symptoms cannot be eliminated simply by avoiding causes and aggravating factors, the guidelines identify second-generation, nonsedating H₁ antihistamines as the first-line pharmacotherapy. Dr. Godse said that the guidelines specifically recommend continuous rather than on-demand regimens at the lowest effective dose. However, if symptoms persist after 1-4 weeks of therapy, the dosing frequency should be increased before moving to adjunctive use of additional therapies. Adjunctive therapies listed in the guidelines include omalizumab, cyclosporine A, and montelukast. The first two of these options received strong recommendations on the basis of a high level of evidence, but the third was given a weak recommendation on the basis of a low level of evidence.

In those who fail these therapies, the list of alternatives is lengthy and includes a short course of corticosteroids, immunomodulating therapies such as methotrexate, and intravenous immunoglobulins. While any one of these may be useful in an individual patient, the overall evidence of benefit was considered to be of relatively low quality.

Ultimately, the guidelines attempt to define an approach that is uniformly applicable across diverse populations, a full range of possible etiologies, and within different systems of medical care, according to Dr. Godse.

Asked for their opinion after hearing the guidelines explained at the meeting, Dr. Paul Schneiderman and Dr. Aaron Warshawsky said they were favorably impressed. Both thought the guidelines were clear, reasonable, and potentially helpful in clinical practice. Dr. Schneiderman, an associate clinical professor of dermatology at Yale University, New Haven, Conn., who maintains a private practice in Syosset, N.Y., reported that he will be able to better judge the clinical applicability of the new guidelines when he sees the full publication, but both he and Dr. Warshawsky, a dermatologist in private practice in Poughkeepsie, N.Y., agreed that advances in urticaria justify updated guidelines.

Dr. Godse reported no financial disclosures relevant to his presentation.

NEW YORK – New guidelines for the diagnosis and treatment of urticaria have been endorsed by 15 professional organizations so far and are now being prepared for publication, according to a consensus meeting participant who summarized key points at the American Academy of Dermatology summer meeting.

The guidelines, developed at an earlier conference held in Berlin attended by experts from 39 countries, are straightforward, relatively simple, "and truly developed for global application," according to Dr. Kiran Godse of Patil Medical College and Hospital, Navi Mumbai, India. The guidelines represent a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF), the American Academy of Allergy, Asthma and Immunology (AAAAI), and the World Allergy Organization (WAO).

The simplicity of the guidelines starts with the definition of urticaria. It consists of three characteristics: "wheals, angioedema, or both." While the definition goes on to specify that these conditions should be differentiated from autoinflammatory syndromes, hereditary angioedema, and other diseases that produce hives or swelling, the new guidelines abandon the term "idiopathic."

"Our understanding of the etiology and pathogenesis has advanced to the point that we can identify the causes in most cases," said Dr. Godse, indicating that classifying cases as "idiopathic" without further investigation is unhelpful when the goal is to find and avoid triggers.

A number of subclassifications, such as spontaneous urticaria, inducible urticaria, acute urticaria, and chronic urticaria, are defined and employed to guide clinical management. In patients with acute urticaria, diagnostic testing beyond a careful history is not recommended, except when avoidance strategies fail and recurrences are common.

Even in chronic urticaria, which is defined as symptoms persisting for at least 6 months, Dr. Godse said that the guidelines recommend "limited" initial diagnostic studies.

By relying on careful patient history rather than clinical tests to differentiate the major forms of this disease, such as cold urticaria, heat urticaria, delayed pressure urticaria, solar urticaria, and symptomatic dermographism, the guidelines in effect propose that underlying etiologies do not usually require an extensive workup. However, the guidelines do advise more extensive tests in individuals with persistent and significant disease, which can be measured with the Chronic Urticaria Quality of Life (CU-QoL) and the Angioedema Quality of Life (Ae-QoL) instruments. Both are strongly recommended for baseline assessment of symptom burden.

The treatment goal of the stepwise management is clear: complete absence of symptoms. "Treat the disease until it is gone," said Dr. Godse, summarizing this recommendation.

If symptoms cannot be eliminated simply by avoiding causes and aggravating factors, the guidelines identify second-generation, nonsedating H₁ antihistamines as the first-line pharmacotherapy. Dr. Godse said that the guidelines specifically recommend continuous rather than on-demand regimens at the lowest effective dose. However, if symptoms persist after 1-4 weeks of therapy, the dosing frequency should be increased before moving to adjunctive use of additional therapies. Adjunctive therapies listed in the guidelines include omalizumab, cyclosporine A, and montelukast. The first two of these options received strong recommendations on the basis of a high level of evidence, but the third was given a weak recommendation on the basis of a low level of evidence.

In those who fail these therapies, the list of alternatives is lengthy and includes a short course of corticosteroids, immunomodulating therapies such as methotrexate, and intravenous immunoglobulins. While any one of these may be useful in an individual patient, the overall evidence of benefit was considered to be of relatively low quality.

Ultimately, the guidelines attempt to define an approach that is uniformly applicable across diverse populations, a full range of possible etiologies, and within different systems of medical care, according to Dr. Godse.

Asked for their opinion after hearing the guidelines explained at the meeting, Dr. Paul Schneiderman and Dr. Aaron Warshawsky said they were favorably impressed. Both thought the guidelines were clear, reasonable, and potentially helpful in clinical practice. Dr. Schneiderman, an associate clinical professor of dermatology at Yale University, New Haven, Conn., who maintains a private practice in Syosset, N.Y., reported that he will be able to better judge the clinical applicability of the new guidelines when he sees the full publication, but both he and Dr. Warshawsky, a dermatologist in private practice in Poughkeepsie, N.Y., agreed that advances in urticaria justify updated guidelines.

Dr. Godse reported no financial disclosures relevant to his presentation.

NEW YORK – New guidelines for the diagnosis and treatment of urticaria have been endorsed by 15 professional organizations so far and are now being prepared for publication, according to a consensus meeting participant who summarized key points at the American Academy of Dermatology summer meeting.

The guidelines, developed at an earlier conference held in Berlin attended by experts from 39 countries, are straightforward, relatively simple, "and truly developed for global application," according to Dr. Kiran Godse of Patil Medical College and Hospital, Navi Mumbai, India. The guidelines represent a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF), the American Academy of Allergy, Asthma and Immunology (AAAAI), and the World Allergy Organization (WAO).

The simplicity of the guidelines starts with the definition of urticaria. It consists of three characteristics: "wheals, angioedema, or both." While the definition goes on to specify that these conditions should be differentiated from autoinflammatory syndromes, hereditary angioedema, and other diseases that produce hives or swelling, the new guidelines abandon the term "idiopathic."

"Our understanding of the etiology and pathogenesis has advanced to the point that we can identify the causes in most cases," said Dr. Godse, indicating that classifying cases as "idiopathic" without further investigation is unhelpful when the goal is to find and avoid triggers.

A number of subclassifications, such as spontaneous urticaria, inducible urticaria, acute urticaria, and chronic urticaria, are defined and employed to guide clinical management. In patients with acute urticaria, diagnostic testing beyond a careful history is not recommended, except when avoidance strategies fail and recurrences are common.

Even in chronic urticaria, which is defined as symptoms persisting for at least 6 months, Dr. Godse said that the guidelines recommend "limited" initial diagnostic studies.

By relying on careful patient history rather than clinical tests to differentiate the major forms of this disease, such as cold urticaria, heat urticaria, delayed pressure urticaria, solar urticaria, and symptomatic dermographism, the guidelines in effect propose that underlying etiologies do not usually require an extensive workup. However, the guidelines do advise more extensive tests in individuals with persistent and significant disease, which can be measured with the Chronic Urticaria Quality of Life (CU-QoL) and the Angioedema Quality of Life (Ae-QoL) instruments. Both are strongly recommended for baseline assessment of symptom burden.

The treatment goal of the stepwise management is clear: complete absence of symptoms. "Treat the disease until it is gone," said Dr. Godse, summarizing this recommendation.

If symptoms cannot be eliminated simply by avoiding causes and aggravating factors, the guidelines identify second-generation, nonsedating H₁ antihistamines as the first-line pharmacotherapy. Dr. Godse said that the guidelines specifically recommend continuous rather than on-demand regimens at the lowest effective dose. However, if symptoms persist after 1-4 weeks of therapy, the dosing frequency should be increased before moving to adjunctive use of additional therapies. Adjunctive therapies listed in the guidelines include omalizumab, cyclosporine A, and montelukast. The first two of these options received strong recommendations on the basis of a high level of evidence, but the third was given a weak recommendation on the basis of a low level of evidence.

In those who fail these therapies, the list of alternatives is lengthy and includes a short course of corticosteroids, immunomodulating therapies such as methotrexate, and intravenous immunoglobulins. While any one of these may be useful in an individual patient, the overall evidence of benefit was considered to be of relatively low quality.

Ultimately, the guidelines attempt to define an approach that is uniformly applicable across diverse populations, a full range of possible etiologies, and within different systems of medical care, according to Dr. Godse.

Asked for their opinion after hearing the guidelines explained at the meeting, Dr. Paul Schneiderman and Dr. Aaron Warshawsky said they were favorably impressed. Both thought the guidelines were clear, reasonable, and potentially helpful in clinical practice. Dr. Schneiderman, an associate clinical professor of dermatology at Yale University, New Haven, Conn., who maintains a private practice in Syosset, N.Y., reported that he will be able to better judge the clinical applicability of the new guidelines when he sees the full publication, but both he and Dr. Warshawsky, a dermatologist in private practice in Poughkeepsie, N.Y., agreed that advances in urticaria justify updated guidelines.

Dr. Godse reported no financial disclosures relevant to his presentation.

CE/CME No: CR-1308

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Explain the etiology of herpes zoster infection (HZ), typical and atypical clinical presentation, and diagnostic confirmation, when needed.
• Describe treatment interventions for acute HZ infection, including topical measures, use of antiviral agents, and pain management options.
• Discuss complications of HZ infection, including risk factors and prevention.
• Explain risks, benefits, contraindications, and other considerations for vaccination use to prevent HZ in at-risk adults.

FACULTY
Emily Jacobsen is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at Oregon Health & Science University (OHSU) in Portland, Oregon; she is a practicing Physician Assistant at OHSU Family Medicine at Richmond in Portland. Claire E. Hull is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at OHSU.


The authors have no significant financial relationships to disclose.

ACCREDITATION STATEMENT

Article begins on next page >>

Herpes zoster (HZ) infection, commonly called shingles, represents a reactivation of the chickenpox virus. Persons older than 50 and those with compromised immune systems are at greatest risk. Most cases resolve spontaneously, but about one-third of patients develop postherpetic neuralgia or other complications, and 1% to 4% require hospitalization. Treatment involves antiviral medications and 
pain management. Vaccination against HZ, which is recommended for adults 60 and older, 
incurs benefits and risks that the clinician must be prepared to explain to eligible patients.

Infection with herpes zoster (HZ) affects approximately one million individuals in the United States each year.^1-3 The disease is caused by a reactivation of the varicella zoster virus (VZV), which causes chickenpox. Once chickenpox has resolved, VZV remains dormant in the dorsal (spinal) root ganglia, trigeminal nerve, and autonomic ganglia of the nervous system.⁴ At some later time, VZV may reactivate, causing an extremely painful vesicular rash along the distribution of one or more sensory dermatomes; the rash (as well as the condition in general) is commonly referred to as shingles.

It has been estimated that 90% or more of US adults older than 40 are infected with VZV.^1,3 Because the virus is so ubiquitous, virtually anyone may be at risk for the reactivation of VZV in the form of shingles. It is estimated that 10% to 20% of the US population will develop HZ in their lifetime,³ with age and immune status the most significant determinants of persons to be affected.^3-6

About half of all cases of shingles in the US occur in persons age 50 or older. Incidence among those older than 75 is approximately 10 cases per 1,000 individuals, compared with about two cases per 1,000 individuals in those younger than 50.³

In addition to age, the integrity of an individual’s immune system plays a key role in the development of shingles. Reactivation of VZV is usually suppressed by the host’s cell-mediated immune response, particularly the T cells.^3,5 Thus, if the cell-mediated immune system is compromised, reactivation and widespread dissemination are more likely to occur. Adults with cancer or HIV infection and those taking immunosuppressive drugs have a significantly increased risk for HZ. Psychological or physical stress and trauma have also been shown to play a role in the development of HZ.⁵ In contrast to chickenpox, HZ has no seasonal predilection.⁷

Since 1995, with the licensing of Varivax (the vaccination to prevent varicella), the incidence of wild-type varicella infection is now quite low in the US. From 2000 to 2010, varicella wild-type infection declined by 82%.⁸ Efforts to further quantify the incidence of varicella have been hampered by the absence of reporting requirements for this infection.

Due to the live nature of the Varivax vaccine, patients who have received it remain at risk for HZ infection by way of reactivation of vaccine-type VZV. A population-based surveillance study conducted in California from 2000 to 2006 showed that the incidence of HZ infection decreased by 55% in children 10 years or younger who were vaccinated against varicella.⁹ This finding, along with similar results in other, older research in immunocompromised hosts, supports the notion that the risk for HZ is substantially reduced among children who have been vaccinated against varicella.¹⁰

Incidence of HZ infection seems to be on the rise, both in the US and worldwide¹; however, the causes for this are a point of controversy. Fears have been expressed that incidence of HZ infection in adults would increase once varicella vaccination in children became commonplace, based on reasoning that exposure to the virus (which is thought to boost cell-mediated immunity and keep the virus from reactivating) would decline. This concern has put a halt to vaccination against varicella in some European countries.¹¹ At least one US researcher considers the evidence strong for a causal link between the increase in incidence of HZ and the widespread implementation of varicella vaccination.¹²

Other research has led to different conclusions. Authors of a nationwide, retrospective review of claims data noted an increase in HZ prior to Varivax licensure but did not find any association between vaccination rates and HZ rates geographically.¹³ Similarly, researchers conducting a case-control study in a Wisconsin clinic found no relationship between HZ and exposure to VZV in the previous 10 years.¹⁴

On the next page: Clinical presentation and laboratory diagnosis >>

CLINICAL PRESENTATION
Identifying HZ infection is primarily a clinical diagnosis and not particularly difficult. Approximately 20% of patients will present with prodromal symptoms of fatigue, headache, malaise, and fever. Paresthesias in the involved dermatome often precede the rash by several days and may be manifested as itching, tingling, burning, or severe pain. Physical examination at this stage may reveal tenderness and hyperesthesia of the skin in the involved dermatome.^3,5,15,16

Pain and abnormal skin sensations are the most common symptoms of HZ. They often precede and usually accompany the rash. The prodromal pain of HZ can mimic a variety of other conditions, including pleurisy, myocardial infarction, peptic ulcer, appendicitis, or biliary or renal colic, prompting some clinicians to undertake an extensive workup and treatment plan.^15,17

Consistent with other herpes infections, the HZ rash initially starts in the form of erythematous papules, which quickly evolve into grouped vesicles or bullae. Within three to four days, these vesicular lesions can become more pustular. In contrast to chickenpox, the rash of shingles is manifested in a dermatomal distribution. The two most commonly affected dermatomes are the first (ophthalmic) division of the trigeminal nerve and the spinal sensory ganglia from T1 to L2.^3,5,15,16 The infection is generally limited to one dermatome in previously healthy hosts but can occasionally affect two or three neighboring dermatomes. Some patients have a few scattered vesicles located some distance away from the involved dermatome.¹⁵

In immunocompetent hosts, the lesions crust over within seven to 10 days and are no longer considered infectious. The development of new lesions more than a week after presentation should raise concerns regarding possible underlying immunodeficiency.^3,5,15,16

LABORATORY DIAGNOSIS
While HZ is generally a clinical diagnosis based on the history and physical exam findings, laboratory testing may be appropriate to confirm the diagnosis when the presentation is atypical, the host is immunocompromised, lesions recur, or serious complications are suspected.^17,18

Several laboratory tests are currently available (see Table 1^17,19). Detection of VZV DNA following amplification of appropriate specimens (most reliably, clear fluid from recently erupted vesicles) by polymerase chain reaction (PCR) is generally recommended if testing is required, because of its high sensitivity and specificity and quick turnaround. However, this test is not available at every laboratory.^17-19

When PCR is not available, a suitable alternative is direct fluorescent antibody (DFA) staining of cellular material from fresh vesicles or prevesicular lesions.¹ This test uses a modified Tzanck technique to view fluorescein-conjugated monoclonal antibodies. DFA staining can differentiate between herpes simplex and herpes zoster.^16,17,20

The original Tzanck smear is inexpensive and may reveal multinucleated giant cells and epithelial cells containing acidophilic intranuclear inclusion bodies.¹⁷ However, this test is not often used to confirm a diagnosis of HZ; rather, it is most helpful for distinguishing herpesvirus infections from vesicular lesions of other etiologies (eg, coxsackievirus, echovirus).^15,17

Serologic tests measuring immunoglobulin M and A titers (IgM, IgA) may be helpful in cases of zoster without rash (zoster sine herpete), but their sensitivity and specificity are low.¹⁵ Positive results may be indicative of primary infection, reinfection, or reactivation.¹

On the next page: Treatment >>

TREATMENT
Treatment of HZ infection is focused on limiting the extent, duration, and severity of pain and rash in the primary dermatome, as well as decreasing the risk for complications.

Topical Therapy
Patients should keep the cutaneous lesions clean and dry to reduce the risk for bacterial superinfection. A sterile, nonocclusive, nonadherent dressing placed over the involved dermatome will protect the lesions from contact with clothing. To hasten the drying of vesicular lesions and alleviate pruritus associated with rash, the application of cool compresses, calamine lotion, cornstarch, or baking soda may be helpful.^16,21

While antipruritic agents may help prevent infections that can develop when the affected area is scratched, there is no evidence that any of these agents have any real therapeutic effect on the HZ rash or lesions. Topical antiviral agents are not effective.^15,18

Antiviral Therapy
Treatment for acute HZ with oral antiviral medication should be considered for any patient who presents within 72 hours of rash onset; antiviral agents initiated within this time frame have been shown to reduce the duration and severity of pain associated with acute HZ.²¹ Antivirals are recommended and should be given routinely to patients older than 50 and those who have moderate to severe symptoms.^15,21

Among patients who present longer than 72 hours after rash onset, antiviral therapy should be considered only for those with new vesicular formation, ophthalmic involvement, or motor or neurologic complications, although evidence is lacking for this recommendation.^15,21 A modest reduction in the duration of rash (by 1 to 3 days) has also been reported in patients treated with antivirals,²¹ most likely because viral replication is slowed within the dorsal root ganglion.^16,22

Acyclovir, valacyclovir, and famciclovir—nucleoside analogs that block viral replication—are the only FDA-approved medications for treatment of HZ.^18,22  When choosing among these agents, the prescribing clinician should be aware of their differences in bioavailability and pharmacokinetics. Acyclovir, for example, is a second-generation antiviral drug with poor pharmacokinetics, which explains the frequent dosing its use generally requires.^22,23 However, the inhibitory dose of acyclovir required for patients with HZ is much lower than that required to treat primary VZV infection.

Valacyclovir and famciclovir, which are third-generation antivirals, feature enhanced absorption from the gastrointestinal tract (77% vs 30% for acyclovir),²⁴ thus improving their bioavailability by three to five times, compared with acyclovir. The superior pharmacokinetics of valacyclovir and famciclovir has been confirmed clinically by researchers who demonstrated median pain duration of 38 days in patients taking valacyclovir, compared with 51 days in those treated with acyclovir.²⁵ In a direct comparison of valacyclovir and famciclovir, resolution of rash and pain times were found comparable.²⁶ Table 2^18,27 summarizes the current recommendations for antiviral therapy in patients with HZ.

Pain Management
Pain is almost universal once the HZ rash appears. Pain associated with the prodromal period is variable but may be present in 70% to 80% of patients.^28,29 The severity of acute pain in HZ is highly variable, ranging from mild to quite severe. Pain can begin weeks or a single day before the rash emerges and persist for several weeks after the rash disappears.

Aggressive pain management is appropriate. A variety of opiate analgesics (eg, hydrocodone, oxycodone, hydromorphone, morphine) and nonopiate analgesics (acetaminophen, NSAIDs) may be effective.^17,28 Drug choices, dosage, and scheduling should be tailored to the patient’s level of pain and disability, with any potential contraindications also taken into account. Mild pain can be treated with as-needed dosing, whereas scheduled dosing is preferred for moderate to severe pain.¹⁶

If acute pain persists, addition of gabapentin, pregabalin, or nortriptyline is reasonable.^17,22,28,30 Although these medications have been studied in the treatment of postherpetic neuralgia (PHN), there is little evidence to support their use for acute zoster pain.^22,30

Additional interventions that have been studied for relief of acute HZ pain include topical lidocaine, acupuncture, and interventional pain injections. However, the evidence is either scant or of poor quality. More research is needed before these modalities can be routinely recommended in the clinical setting.^17,22

Corticosteroids have been used for acute HZ, but conflicting study results make their routine use controversial.^17,31,32 In some studies, corticosteroids reduced acute pain and speeded lesion healing and return to daily activities; others have yielded little evidence to support these findings.^22,33 Corticosteroids may offer the greatest benefit when used in combination with effective antiviral therapy.^18,22,31,32 In one randomized clinical trial comparing acyclovir with acyclovir plus prednisolone (40 mg/d for three weeks, tapered down) combination therapy was associated with a significant decrease in pain during the initial two weeks.³²

Historically, corticosteroids have also been prescribed with the hope that their anti-inflammatory properties might help reduce the risk for PHN. However, a recent Cochrane Review found that these agents do not reliably prevent PHN six months after HZ rash onset.³⁴ Glucocorticoids may improve motor outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, in which compression of affected nerves may contribute to disability.

Before prescribing steroids, clinicians must consider contraindications to their use, including diabetes, osteoporosis, hypertension, glaucoma, and gastritis.¹⁶

On the next page: Patient education and complications >>

PATIENT EDUCATION
Patients must be instructed in how to avoid transmitting the HZ virus. The mechanism of transmission was long thought to be restricted to direct contact with lesions; however, molecular studies have shown that the HZ virus can be transmitted via the respiratory route, either through aerosolized virus from skin lesions or from respiratory droplets, as early as 24 to 48 hours before the rash appears.^6,17 The risk of transmission by airborne virus is increased in patients with HZ rash that is disseminated beyond the primary and secondary dermatomes. The rash, patients should be informed, generally persists for two to four weeks.^1,16,20

HZ continues to be contagious until the lesions crust over.¹⁷ Covering the rash greatly reduces patients’ risk for transmitting the virus via airborne or direct contact routes.^15,17 A patient with HZ rash can infect a nonimmune person with primary varicella, causing chickenpox.²⁸ The patient with HZ should be advised to avoid exposure to infants younger than 1 year, unvaccinated older children, anyone who is not immune to varicella (either by vaccination or primary infection), susceptible pregnant women, and potentially susceptible immunocompromised persons.¹⁶

COMPLICATIONS AND SEQUELAE
The majority of cases of shingles resolve without any complications or long-term sequelae. Complications of HZ that do occur may include superimposed skin infections, such as Streptococcus or Staphylococcus. The virus may be reactivated in the nasociliary branch of the trigeminal nerve and, in 10% to 25% of cases, herpes zoster ophthalmicus (HZO) may develop.^17,35 Associated morbidity includes keratitis, corneal ulceration, conjunctivitis, uveitis, episcleritis and scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Patients with HZO should be referred to an ophthalmologist promptly, as this condition can result in permanent loss of vision.³⁵

Other less common complications of HZ include Ramsay Hunt syndrome (facial nerve palsy associated with reactivation in the geniculate ganglion) and zoster paresis (motor weakness in noncranial nerve distributions).^17,36,37 Autonomic dysfunction has also been reported in patients with HZ, leading to colonic pseudo-obstruction and urinary retention. Rare but serious neurologic complications include Guillain-Barré syndrome, myelitis, aseptic meningitis, and meningoencephalitis.^15,17

Postherpetic Neuralgia
By far, the most common complication of shingles is postherpetic neuralgia, a painfully debilitating and difficult-to-treat condition. Of the one million persons affected by HZ each year, between 9% and 34% will develop PHN.^3,7,18 The criteria for diagnosing PHN is variable: While all definitions include the presence of persistent pain after rash resolution, they differ in how long this pain must persist. Some define PHN as pain persisting from 30 days to six months after rash resolution, while others define it as pain continuing three months or longer.^3,17,18 While most patients with PHN experience complete resolution, the pain can endure from weeks to months to years.^3,18,38

The pathophysiology of PHN is thought to involve replication of the VZV in the basal ganglia, damaging the nerves and thereby causing pain in the affected dermatome.²² Other possible factors include axonal and cell body degeneration, atrophy of the dorsal horn of the spinal cord, scarring of the dorsal root ganglion, and loss of epidermal innervations of the dermatome.¹⁷

The risk for PHN increases significantly in patients of advancing age. While PHN is rare in those younger than 50, it complicates HZ in 20% of patients between ages 60 and 65 and in 30% of those 80 and older. Additional risk factors for PHN include female gender, prodromal pain preceding the HZ rash, rash that is moderate to severe, moderate to severe acute pain associated with the rash, and ophthalmic involvement.³⁹

Evidence conflicts regarding the impact of antivirals in patients with HZ on the subsequent development of PHN. Researchers performing a meta-analysis of five randomized clinical trials found no significant difference in the incidence of PHN among patients treated for HZ with oral acyclovir, famciclovir, or placebo.³⁴ In an older, placebo-controlled randomized clinical trial, however, famciclovir-treated patients experienced PHN of reduced duration, compared with controls (63 days vs 119 days, respectively). Six months after development of the HZ rash, 15% of treated patients continued to experience PHN symptoms, compared with 23% of controls.²³ More evidence is needed.

Additional Concerns
Recurrence of HZ is uncommon in immunocompetent persons. Despite its ordinarily benign course, 1% to 4% of people with shingles require hospitalization each year, mostly elderly patients.¹ In a recent study, it was estimated that 96 US deaths are attributable to HZ each year.⁴⁰ Almost all HZ-associated deaths occur in elderly patients with compromised or suppressed immune systems.¹

On the next page: Prevention >>

PREVENTION
The varicella vaccine was licensed for use in children by the FDA in 1995. In June 2006, the Advisory Committee on Immunization Practices (ACIP) recommended a second dose to boost waning immunity.⁴¹

In 2006, the HZ vaccine (Zostavax), a more concentrated formulation of the varicella vaccine, was approved by the FDA for use in adults age 60 or older; in 2011, approval of the vaccine was extended to adults 50 or older.⁴² As of November 2011, ACIP has continued to recommend routine administration of the HZ vaccine for immunocompetent adults 60 and older, citing lack of evidence for long-term protection in patients vaccinated before age 60, as well as concerns about maintaining sufficient vaccine supplies.

Although ACIP does not recommend routine vaccination against HZ in patients age 50 to 59, health care providers may wish to consider it for patients in this age-group, based on the potential for poor tolerance of HZ or PHN symptoms, anticipated difficulty tolerating the required medications used to treat them, and employment-related considerations.⁴³

Use of the HZ Vaccine
Zostavax is a live attenuated vaccine that increases varicella-specific, cell-mediated immunity in immunocompetent persons.^17,42 It should be administered as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm⁴²; a booster dose is not licensed for the vaccine.¹⁷ Adverse effects of the HZ vaccine generally include mild injection-site reactions: pain (54%), erythema (48%), swelling (40%), and pruritus (11%).⁴² According to researchers for the Shingles Prevention Study^38,44 (SPS), these reactions were more common in treated patients than in controls and increasingly common in study participants of advancing age. Less than 2% of patients receiving either the HZ vaccine or placebo experienced serious adverse effects.⁴⁴

The evidence to support vaccination against HZ comes mainly from the original SPS,³⁸ a randomized, double-blind, placebo-controlled trial in which more than 38,500 adults 60 and older were enrolled. The SPS researchers showed that the vaccine reduced the incidence of HZ by 51.3%, reduced the incidence of PHN by 67%, and reduced the HZ-associated burden of illness (ie, its incidence, severity, and duration of associated pain and discomfort) by 61%^2,38,45; they also found vaccination against HZ effective for at least three years.

An ongoing substudy involving 14,270 of the original SPS participants produced data showing that from year 4 to year 5 postvaccination, vaccine efficacy in terms of HZ incidence declined from 51% to 40%, respectively, and its efficacy regarding incidence of PHN, from 67% to 60%.⁴⁶ Since there is no strong evidence that any treatment intervention started after shingles presents can reduce the risk for PHN, perhaps the vaccine’s most valuable attribute is its potential for preventing this debilitating and common complication of shingles.

Who Should or Should Not Be Vaccinated?
According to the ACIP, there is no upper age limit on vaccination against shingles. This judgment is supported by the fact that the incidence of zoster and PHN both continue to increase among patients of advancing age.¹⁷

While vaccination is appropriate for most individuals 60 or older, some contraindications exist (see Table 3^17,22,47,48). In cases of anticipated immunosuppression (as in patients scheduled to undergo chemotherapy), vaccination is recommended one month before the start of therapy. Additionally, the safety and efficacy of vaccination is unknown in patients receiving immune modulators and recombinant human immune mediators (eg, adalimumab, etanercept, infliximab); thus, these patients too should be vaccinated one month before starting these treatments or one month after their completion.⁴⁷

On the next page: Conclusion >>

CONCLUSION
Herpes zoster remains a common disease in the US, despite the availability of an effective vaccine. While most cases of shingles resolve spontaneously, life-threatening and permanent complications can occur. Treatment may shorten the length of illness and prevent these complications. Primary care providers should recommend routine vaccination against HZ for their immunocompetent patients 60 or older.

CE/CME No: CR-1308

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Explain the etiology of herpes zoster infection (HZ), typical and atypical clinical presentation, and diagnostic confirmation, when needed.
• Describe treatment interventions for acute HZ infection, including topical measures, use of antiviral agents, and pain management options.
• Discuss complications of HZ infection, including risk factors and prevention.
• Explain risks, benefits, contraindications, and other considerations for vaccination use to prevent HZ in at-risk adults.

FACULTY
Emily Jacobsen is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at Oregon Health & Science University (OHSU) in Portland, Oregon; she is a practicing Physician Assistant at OHSU Family Medicine at Richmond in Portland. Claire E. Hull is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at OHSU.


The authors have no significant financial relationships to disclose.

ACCREDITATION STATEMENT

Article begins on next page >>

Herpes zoster (HZ) infection, commonly called shingles, represents a reactivation of the chickenpox virus. Persons older than 50 and those with compromised immune systems are at greatest risk. Most cases resolve spontaneously, but about one-third of patients develop postherpetic neuralgia or other complications, and 1% to 4% require hospitalization. Treatment involves antiviral medications and 
pain management. Vaccination against HZ, which is recommended for adults 60 and older, 
incurs benefits and risks that the clinician must be prepared to explain to eligible patients.

Infection with herpes zoster (HZ) affects approximately one million individuals in the United States each year.^1-3 The disease is caused by a reactivation of the varicella zoster virus (VZV), which causes chickenpox. Once chickenpox has resolved, VZV remains dormant in the dorsal (spinal) root ganglia, trigeminal nerve, and autonomic ganglia of the nervous system.⁴ At some later time, VZV may reactivate, causing an extremely painful vesicular rash along the distribution of one or more sensory dermatomes; the rash (as well as the condition in general) is commonly referred to as shingles.

It has been estimated that 90% or more of US adults older than 40 are infected with VZV.^1,3 Because the virus is so ubiquitous, virtually anyone may be at risk for the reactivation of VZV in the form of shingles. It is estimated that 10% to 20% of the US population will develop HZ in their lifetime,³ with age and immune status the most significant determinants of persons to be affected.^3-6

About half of all cases of shingles in the US occur in persons age 50 or older. Incidence among those older than 75 is approximately 10 cases per 1,000 individuals, compared with about two cases per 1,000 individuals in those younger than 50.³

In addition to age, the integrity of an individual’s immune system plays a key role in the development of shingles. Reactivation of VZV is usually suppressed by the host’s cell-mediated immune response, particularly the T cells.^3,5 Thus, if the cell-mediated immune system is compromised, reactivation and widespread dissemination are more likely to occur. Adults with cancer or HIV infection and those taking immunosuppressive drugs have a significantly increased risk for HZ. Psychological or physical stress and trauma have also been shown to play a role in the development of HZ.⁵ In contrast to chickenpox, HZ has no seasonal predilection.⁷

Since 1995, with the licensing of Varivax (the vaccination to prevent varicella), the incidence of wild-type varicella infection is now quite low in the US. From 2000 to 2010, varicella wild-type infection declined by 82%.⁸ Efforts to further quantify the incidence of varicella have been hampered by the absence of reporting requirements for this infection.

Due to the live nature of the Varivax vaccine, patients who have received it remain at risk for HZ infection by way of reactivation of vaccine-type VZV. A population-based surveillance study conducted in California from 2000 to 2006 showed that the incidence of HZ infection decreased by 55% in children 10 years or younger who were vaccinated against varicella.⁹ This finding, along with similar results in other, older research in immunocompromised hosts, supports the notion that the risk for HZ is substantially reduced among children who have been vaccinated against varicella.¹⁰

Incidence of HZ infection seems to be on the rise, both in the US and worldwide¹; however, the causes for this are a point of controversy. Fears have been expressed that incidence of HZ infection in adults would increase once varicella vaccination in children became commonplace, based on reasoning that exposure to the virus (which is thought to boost cell-mediated immunity and keep the virus from reactivating) would decline. This concern has put a halt to vaccination against varicella in some European countries.¹¹ At least one US researcher considers the evidence strong for a causal link between the increase in incidence of HZ and the widespread implementation of varicella vaccination.¹²

Other research has led to different conclusions. Authors of a nationwide, retrospective review of claims data noted an increase in HZ prior to Varivax licensure but did not find any association between vaccination rates and HZ rates geographically.¹³ Similarly, researchers conducting a case-control study in a Wisconsin clinic found no relationship between HZ and exposure to VZV in the previous 10 years.¹⁴

On the next page: Clinical presentation and laboratory diagnosis >>

CLINICAL PRESENTATION
Identifying HZ infection is primarily a clinical diagnosis and not particularly difficult. Approximately 20% of patients will present with prodromal symptoms of fatigue, headache, malaise, and fever. Paresthesias in the involved dermatome often precede the rash by several days and may be manifested as itching, tingling, burning, or severe pain. Physical examination at this stage may reveal tenderness and hyperesthesia of the skin in the involved dermatome.^3,5,15,16

Pain and abnormal skin sensations are the most common symptoms of HZ. They often precede and usually accompany the rash. The prodromal pain of HZ can mimic a variety of other conditions, including pleurisy, myocardial infarction, peptic ulcer, appendicitis, or biliary or renal colic, prompting some clinicians to undertake an extensive workup and treatment plan.^15,17

Consistent with other herpes infections, the HZ rash initially starts in the form of erythematous papules, which quickly evolve into grouped vesicles or bullae. Within three to four days, these vesicular lesions can become more pustular. In contrast to chickenpox, the rash of shingles is manifested in a dermatomal distribution. The two most commonly affected dermatomes are the first (ophthalmic) division of the trigeminal nerve and the spinal sensory ganglia from T1 to L2.^3,5,15,16 The infection is generally limited to one dermatome in previously healthy hosts but can occasionally affect two or three neighboring dermatomes. Some patients have a few scattered vesicles located some distance away from the involved dermatome.¹⁵

In immunocompetent hosts, the lesions crust over within seven to 10 days and are no longer considered infectious. The development of new lesions more than a week after presentation should raise concerns regarding possible underlying immunodeficiency.^3,5,15,16

LABORATORY DIAGNOSIS
While HZ is generally a clinical diagnosis based on the history and physical exam findings, laboratory testing may be appropriate to confirm the diagnosis when the presentation is atypical, the host is immunocompromised, lesions recur, or serious complications are suspected.^17,18

Several laboratory tests are currently available (see Table 1^17,19). Detection of VZV DNA following amplification of appropriate specimens (most reliably, clear fluid from recently erupted vesicles) by polymerase chain reaction (PCR) is generally recommended if testing is required, because of its high sensitivity and specificity and quick turnaround. However, this test is not available at every laboratory.^17-19

When PCR is not available, a suitable alternative is direct fluorescent antibody (DFA) staining of cellular material from fresh vesicles or prevesicular lesions.¹ This test uses a modified Tzanck technique to view fluorescein-conjugated monoclonal antibodies. DFA staining can differentiate between herpes simplex and herpes zoster.^16,17,20

The original Tzanck smear is inexpensive and may reveal multinucleated giant cells and epithelial cells containing acidophilic intranuclear inclusion bodies.¹⁷ However, this test is not often used to confirm a diagnosis of HZ; rather, it is most helpful for distinguishing herpesvirus infections from vesicular lesions of other etiologies (eg, coxsackievirus, echovirus).^15,17

Serologic tests measuring immunoglobulin M and A titers (IgM, IgA) may be helpful in cases of zoster without rash (zoster sine herpete), but their sensitivity and specificity are low.¹⁵ Positive results may be indicative of primary infection, reinfection, or reactivation.¹

On the next page: Treatment >>

TREATMENT
Treatment of HZ infection is focused on limiting the extent, duration, and severity of pain and rash in the primary dermatome, as well as decreasing the risk for complications.

Topical Therapy
Patients should keep the cutaneous lesions clean and dry to reduce the risk for bacterial superinfection. A sterile, nonocclusive, nonadherent dressing placed over the involved dermatome will protect the lesions from contact with clothing. To hasten the drying of vesicular lesions and alleviate pruritus associated with rash, the application of cool compresses, calamine lotion, cornstarch, or baking soda may be helpful.^16,21

While antipruritic agents may help prevent infections that can develop when the affected area is scratched, there is no evidence that any of these agents have any real therapeutic effect on the HZ rash or lesions. Topical antiviral agents are not effective.^15,18

Antiviral Therapy
Treatment for acute HZ with oral antiviral medication should be considered for any patient who presents within 72 hours of rash onset; antiviral agents initiated within this time frame have been shown to reduce the duration and severity of pain associated with acute HZ.²¹ Antivirals are recommended and should be given routinely to patients older than 50 and those who have moderate to severe symptoms.^15,21

Among patients who present longer than 72 hours after rash onset, antiviral therapy should be considered only for those with new vesicular formation, ophthalmic involvement, or motor or neurologic complications, although evidence is lacking for this recommendation.^15,21 A modest reduction in the duration of rash (by 1 to 3 days) has also been reported in patients treated with antivirals,²¹ most likely because viral replication is slowed within the dorsal root ganglion.^16,22

Acyclovir, valacyclovir, and famciclovir—nucleoside analogs that block viral replication—are the only FDA-approved medications for treatment of HZ.^18,22  When choosing among these agents, the prescribing clinician should be aware of their differences in bioavailability and pharmacokinetics. Acyclovir, for example, is a second-generation antiviral drug with poor pharmacokinetics, which explains the frequent dosing its use generally requires.^22,23 However, the inhibitory dose of acyclovir required for patients with HZ is much lower than that required to treat primary VZV infection.

Valacyclovir and famciclovir, which are third-generation antivirals, feature enhanced absorption from the gastrointestinal tract (77% vs 30% for acyclovir),²⁴ thus improving their bioavailability by three to five times, compared with acyclovir. The superior pharmacokinetics of valacyclovir and famciclovir has been confirmed clinically by researchers who demonstrated median pain duration of 38 days in patients taking valacyclovir, compared with 51 days in those treated with acyclovir.²⁵ In a direct comparison of valacyclovir and famciclovir, resolution of rash and pain times were found comparable.²⁶ Table 2^18,27 summarizes the current recommendations for antiviral therapy in patients with HZ.

Pain Management
Pain is almost universal once the HZ rash appears. Pain associated with the prodromal period is variable but may be present in 70% to 80% of patients.^28,29 The severity of acute pain in HZ is highly variable, ranging from mild to quite severe. Pain can begin weeks or a single day before the rash emerges and persist for several weeks after the rash disappears.

Aggressive pain management is appropriate. A variety of opiate analgesics (eg, hydrocodone, oxycodone, hydromorphone, morphine) and nonopiate analgesics (acetaminophen, NSAIDs) may be effective.^17,28 Drug choices, dosage, and scheduling should be tailored to the patient’s level of pain and disability, with any potential contraindications also taken into account. Mild pain can be treated with as-needed dosing, whereas scheduled dosing is preferred for moderate to severe pain.¹⁶

If acute pain persists, addition of gabapentin, pregabalin, or nortriptyline is reasonable.^17,22,28,30 Although these medications have been studied in the treatment of postherpetic neuralgia (PHN), there is little evidence to support their use for acute zoster pain.^22,30

Additional interventions that have been studied for relief of acute HZ pain include topical lidocaine, acupuncture, and interventional pain injections. However, the evidence is either scant or of poor quality. More research is needed before these modalities can be routinely recommended in the clinical setting.^17,22

Corticosteroids have been used for acute HZ, but conflicting study results make their routine use controversial.^17,31,32 In some studies, corticosteroids reduced acute pain and speeded lesion healing and return to daily activities; others have yielded little evidence to support these findings.^22,33 Corticosteroids may offer the greatest benefit when used in combination with effective antiviral therapy.^18,22,31,32 In one randomized clinical trial comparing acyclovir with acyclovir plus prednisolone (40 mg/d for three weeks, tapered down) combination therapy was associated with a significant decrease in pain during the initial two weeks.³²

Historically, corticosteroids have also been prescribed with the hope that their anti-inflammatory properties might help reduce the risk for PHN. However, a recent Cochrane Review found that these agents do not reliably prevent PHN six months after HZ rash onset.³⁴ Glucocorticoids may improve motor outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, in which compression of affected nerves may contribute to disability.

Before prescribing steroids, clinicians must consider contraindications to their use, including diabetes, osteoporosis, hypertension, glaucoma, and gastritis.¹⁶

On the next page: Patient education and complications >>

PATIENT EDUCATION
Patients must be instructed in how to avoid transmitting the HZ virus. The mechanism of transmission was long thought to be restricted to direct contact with lesions; however, molecular studies have shown that the HZ virus can be transmitted via the respiratory route, either through aerosolized virus from skin lesions or from respiratory droplets, as early as 24 to 48 hours before the rash appears.^6,17 The risk of transmission by airborne virus is increased in patients with HZ rash that is disseminated beyond the primary and secondary dermatomes. The rash, patients should be informed, generally persists for two to four weeks.^1,16,20

HZ continues to be contagious until the lesions crust over.¹⁷ Covering the rash greatly reduces patients’ risk for transmitting the virus via airborne or direct contact routes.^15,17 A patient with HZ rash can infect a nonimmune person with primary varicella, causing chickenpox.²⁸ The patient with HZ should be advised to avoid exposure to infants younger than 1 year, unvaccinated older children, anyone who is not immune to varicella (either by vaccination or primary infection), susceptible pregnant women, and potentially susceptible immunocompromised persons.¹⁶

COMPLICATIONS AND SEQUELAE
The majority of cases of shingles resolve without any complications or long-term sequelae. Complications of HZ that do occur may include superimposed skin infections, such as Streptococcus or Staphylococcus. The virus may be reactivated in the nasociliary branch of the trigeminal nerve and, in 10% to 25% of cases, herpes zoster ophthalmicus (HZO) may develop.^17,35 Associated morbidity includes keratitis, corneal ulceration, conjunctivitis, uveitis, episcleritis and scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Patients with HZO should be referred to an ophthalmologist promptly, as this condition can result in permanent loss of vision.³⁵

Other less common complications of HZ include Ramsay Hunt syndrome (facial nerve palsy associated with reactivation in the geniculate ganglion) and zoster paresis (motor weakness in noncranial nerve distributions).^17,36,37 Autonomic dysfunction has also been reported in patients with HZ, leading to colonic pseudo-obstruction and urinary retention. Rare but serious neurologic complications include Guillain-Barré syndrome, myelitis, aseptic meningitis, and meningoencephalitis.^15,17

Postherpetic Neuralgia
By far, the most common complication of shingles is postherpetic neuralgia, a painfully debilitating and difficult-to-treat condition. Of the one million persons affected by HZ each year, between 9% and 34% will develop PHN.^3,7,18 The criteria for diagnosing PHN is variable: While all definitions include the presence of persistent pain after rash resolution, they differ in how long this pain must persist. Some define PHN as pain persisting from 30 days to six months after rash resolution, while others define it as pain continuing three months or longer.^3,17,18 While most patients with PHN experience complete resolution, the pain can endure from weeks to months to years.^3,18,38

The pathophysiology of PHN is thought to involve replication of the VZV in the basal ganglia, damaging the nerves and thereby causing pain in the affected dermatome.²² Other possible factors include axonal and cell body degeneration, atrophy of the dorsal horn of the spinal cord, scarring of the dorsal root ganglion, and loss of epidermal innervations of the dermatome.¹⁷

The risk for PHN increases significantly in patients of advancing age. While PHN is rare in those younger than 50, it complicates HZ in 20% of patients between ages 60 and 65 and in 30% of those 80 and older. Additional risk factors for PHN include female gender, prodromal pain preceding the HZ rash, rash that is moderate to severe, moderate to severe acute pain associated with the rash, and ophthalmic involvement.³⁹

Evidence conflicts regarding the impact of antivirals in patients with HZ on the subsequent development of PHN. Researchers performing a meta-analysis of five randomized clinical trials found no significant difference in the incidence of PHN among patients treated for HZ with oral acyclovir, famciclovir, or placebo.³⁴ In an older, placebo-controlled randomized clinical trial, however, famciclovir-treated patients experienced PHN of reduced duration, compared with controls (63 days vs 119 days, respectively). Six months after development of the HZ rash, 15% of treated patients continued to experience PHN symptoms, compared with 23% of controls.²³ More evidence is needed.

Additional Concerns
Recurrence of HZ is uncommon in immunocompetent persons. Despite its ordinarily benign course, 1% to 4% of people with shingles require hospitalization each year, mostly elderly patients.¹ In a recent study, it was estimated that 96 US deaths are attributable to HZ each year.⁴⁰ Almost all HZ-associated deaths occur in elderly patients with compromised or suppressed immune systems.¹

On the next page: Prevention >>

PREVENTION
The varicella vaccine was licensed for use in children by the FDA in 1995. In June 2006, the Advisory Committee on Immunization Practices (ACIP) recommended a second dose to boost waning immunity.⁴¹

In 2006, the HZ vaccine (Zostavax), a more concentrated formulation of the varicella vaccine, was approved by the FDA for use in adults age 60 or older; in 2011, approval of the vaccine was extended to adults 50 or older.⁴² As of November 2011, ACIP has continued to recommend routine administration of the HZ vaccine for immunocompetent adults 60 and older, citing lack of evidence for long-term protection in patients vaccinated before age 60, as well as concerns about maintaining sufficient vaccine supplies.

Although ACIP does not recommend routine vaccination against HZ in patients age 50 to 59, health care providers may wish to consider it for patients in this age-group, based on the potential for poor tolerance of HZ or PHN symptoms, anticipated difficulty tolerating the required medications used to treat them, and employment-related considerations.⁴³

Use of the HZ Vaccine
Zostavax is a live attenuated vaccine that increases varicella-specific, cell-mediated immunity in immunocompetent persons.^17,42 It should be administered as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm⁴²; a booster dose is not licensed for the vaccine.¹⁷ Adverse effects of the HZ vaccine generally include mild injection-site reactions: pain (54%), erythema (48%), swelling (40%), and pruritus (11%).⁴² According to researchers for the Shingles Prevention Study^38,44 (SPS), these reactions were more common in treated patients than in controls and increasingly common in study participants of advancing age. Less than 2% of patients receiving either the HZ vaccine or placebo experienced serious adverse effects.⁴⁴

The evidence to support vaccination against HZ comes mainly from the original SPS,³⁸ a randomized, double-blind, placebo-controlled trial in which more than 38,500 adults 60 and older were enrolled. The SPS researchers showed that the vaccine reduced the incidence of HZ by 51.3%, reduced the incidence of PHN by 67%, and reduced the HZ-associated burden of illness (ie, its incidence, severity, and duration of associated pain and discomfort) by 61%^2,38,45; they also found vaccination against HZ effective for at least three years.

An ongoing substudy involving 14,270 of the original SPS participants produced data showing that from year 4 to year 5 postvaccination, vaccine efficacy in terms of HZ incidence declined from 51% to 40%, respectively, and its efficacy regarding incidence of PHN, from 67% to 60%.⁴⁶ Since there is no strong evidence that any treatment intervention started after shingles presents can reduce the risk for PHN, perhaps the vaccine’s most valuable attribute is its potential for preventing this debilitating and common complication of shingles.

Who Should or Should Not Be Vaccinated?
According to the ACIP, there is no upper age limit on vaccination against shingles. This judgment is supported by the fact that the incidence of zoster and PHN both continue to increase among patients of advancing age.¹⁷

While vaccination is appropriate for most individuals 60 or older, some contraindications exist (see Table 3^17,22,47,48). In cases of anticipated immunosuppression (as in patients scheduled to undergo chemotherapy), vaccination is recommended one month before the start of therapy. Additionally, the safety and efficacy of vaccination is unknown in patients receiving immune modulators and recombinant human immune mediators (eg, adalimumab, etanercept, infliximab); thus, these patients too should be vaccinated one month before starting these treatments or one month after their completion.⁴⁷

On the next page: Conclusion >>

CONCLUSION
Herpes zoster remains a common disease in the US, despite the availability of an effective vaccine. While most cases of shingles resolve spontaneously, life-threatening and permanent complications can occur. Treatment may shorten the length of illness and prevent these complications. Primary care providers should recommend routine vaccination against HZ for their immunocompetent patients 60 or older.

CE/CME No: CR-1308

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Explain the etiology of herpes zoster infection (HZ), typical and atypical clinical presentation, and diagnostic confirmation, when needed.
• Describe treatment interventions for acute HZ infection, including topical measures, use of antiviral agents, and pain management options.
• Discuss complications of HZ infection, including risk factors and prevention.
• Explain risks, benefits, contraindications, and other considerations for vaccination use to prevent HZ in at-risk adults.

FACULTY
Emily Jacobsen is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at Oregon Health & Science University (OHSU) in Portland, Oregon; she is a practicing Physician Assistant at OHSU Family Medicine at Richmond in Portland. Claire E. Hull is an Assistant Professor in the Department of Family Medicine and in the Division of Physician Assistant Education at OHSU.


The authors have no significant financial relationships to disclose.

ACCREDITATION STATEMENT

Article begins on next page >>

Herpes zoster (HZ) infection, commonly called shingles, represents a reactivation of the chickenpox virus. Persons older than 50 and those with compromised immune systems are at greatest risk. Most cases resolve spontaneously, but about one-third of patients develop postherpetic neuralgia or other complications, and 1% to 4% require hospitalization. Treatment involves antiviral medications and 
pain management. Vaccination against HZ, which is recommended for adults 60 and older, 
incurs benefits and risks that the clinician must be prepared to explain to eligible patients.

Infection with herpes zoster (HZ) affects approximately one million individuals in the United States each year.^1-3 The disease is caused by a reactivation of the varicella zoster virus (VZV), which causes chickenpox. Once chickenpox has resolved, VZV remains dormant in the dorsal (spinal) root ganglia, trigeminal nerve, and autonomic ganglia of the nervous system.⁴ At some later time, VZV may reactivate, causing an extremely painful vesicular rash along the distribution of one or more sensory dermatomes; the rash (as well as the condition in general) is commonly referred to as shingles.

It has been estimated that 90% or more of US adults older than 40 are infected with VZV.^1,3 Because the virus is so ubiquitous, virtually anyone may be at risk for the reactivation of VZV in the form of shingles. It is estimated that 10% to 20% of the US population will develop HZ in their lifetime,³ with age and immune status the most significant determinants of persons to be affected.^3-6

About half of all cases of shingles in the US occur in persons age 50 or older. Incidence among those older than 75 is approximately 10 cases per 1,000 individuals, compared with about two cases per 1,000 individuals in those younger than 50.³

In addition to age, the integrity of an individual’s immune system plays a key role in the development of shingles. Reactivation of VZV is usually suppressed by the host’s cell-mediated immune response, particularly the T cells.^3,5 Thus, if the cell-mediated immune system is compromised, reactivation and widespread dissemination are more likely to occur. Adults with cancer or HIV infection and those taking immunosuppressive drugs have a significantly increased risk for HZ. Psychological or physical stress and trauma have also been shown to play a role in the development of HZ.⁵ In contrast to chickenpox, HZ has no seasonal predilection.⁷

Since 1995, with the licensing of Varivax (the vaccination to prevent varicella), the incidence of wild-type varicella infection is now quite low in the US. From 2000 to 2010, varicella wild-type infection declined by 82%.⁸ Efforts to further quantify the incidence of varicella have been hampered by the absence of reporting requirements for this infection.

Due to the live nature of the Varivax vaccine, patients who have received it remain at risk for HZ infection by way of reactivation of vaccine-type VZV. A population-based surveillance study conducted in California from 2000 to 2006 showed that the incidence of HZ infection decreased by 55% in children 10 years or younger who were vaccinated against varicella.⁹ This finding, along with similar results in other, older research in immunocompromised hosts, supports the notion that the risk for HZ is substantially reduced among children who have been vaccinated against varicella.¹⁰

Incidence of HZ infection seems to be on the rise, both in the US and worldwide¹; however, the causes for this are a point of controversy. Fears have been expressed that incidence of HZ infection in adults would increase once varicella vaccination in children became commonplace, based on reasoning that exposure to the virus (which is thought to boost cell-mediated immunity and keep the virus from reactivating) would decline. This concern has put a halt to vaccination against varicella in some European countries.¹¹ At least one US researcher considers the evidence strong for a causal link between the increase in incidence of HZ and the widespread implementation of varicella vaccination.¹²

Other research has led to different conclusions. Authors of a nationwide, retrospective review of claims data noted an increase in HZ prior to Varivax licensure but did not find any association between vaccination rates and HZ rates geographically.¹³ Similarly, researchers conducting a case-control study in a Wisconsin clinic found no relationship between HZ and exposure to VZV in the previous 10 years.¹⁴

On the next page: Clinical presentation and laboratory diagnosis >>

CLINICAL PRESENTATION
Identifying HZ infection is primarily a clinical diagnosis and not particularly difficult. Approximately 20% of patients will present with prodromal symptoms of fatigue, headache, malaise, and fever. Paresthesias in the involved dermatome often precede the rash by several days and may be manifested as itching, tingling, burning, or severe pain. Physical examination at this stage may reveal tenderness and hyperesthesia of the skin in the involved dermatome.^3,5,15,16

Pain and abnormal skin sensations are the most common symptoms of HZ. They often precede and usually accompany the rash. The prodromal pain of HZ can mimic a variety of other conditions, including pleurisy, myocardial infarction, peptic ulcer, appendicitis, or biliary or renal colic, prompting some clinicians to undertake an extensive workup and treatment plan.^15,17

Consistent with other herpes infections, the HZ rash initially starts in the form of erythematous papules, which quickly evolve into grouped vesicles or bullae. Within three to four days, these vesicular lesions can become more pustular. In contrast to chickenpox, the rash of shingles is manifested in a dermatomal distribution. The two most commonly affected dermatomes are the first (ophthalmic) division of the trigeminal nerve and the spinal sensory ganglia from T1 to L2.^3,5,15,16 The infection is generally limited to one dermatome in previously healthy hosts but can occasionally affect two or three neighboring dermatomes. Some patients have a few scattered vesicles located some distance away from the involved dermatome.¹⁵

In immunocompetent hosts, the lesions crust over within seven to 10 days and are no longer considered infectious. The development of new lesions more than a week after presentation should raise concerns regarding possible underlying immunodeficiency.^3,5,15,16

LABORATORY DIAGNOSIS
While HZ is generally a clinical diagnosis based on the history and physical exam findings, laboratory testing may be appropriate to confirm the diagnosis when the presentation is atypical, the host is immunocompromised, lesions recur, or serious complications are suspected.^17,18

Several laboratory tests are currently available (see Table 1^17,19). Detection of VZV DNA following amplification of appropriate specimens (most reliably, clear fluid from recently erupted vesicles) by polymerase chain reaction (PCR) is generally recommended if testing is required, because of its high sensitivity and specificity and quick turnaround. However, this test is not available at every laboratory.^17-19

When PCR is not available, a suitable alternative is direct fluorescent antibody (DFA) staining of cellular material from fresh vesicles or prevesicular lesions.¹ This test uses a modified Tzanck technique to view fluorescein-conjugated monoclonal antibodies. DFA staining can differentiate between herpes simplex and herpes zoster.^16,17,20

The original Tzanck smear is inexpensive and may reveal multinucleated giant cells and epithelial cells containing acidophilic intranuclear inclusion bodies.¹⁷ However, this test is not often used to confirm a diagnosis of HZ; rather, it is most helpful for distinguishing herpesvirus infections from vesicular lesions of other etiologies (eg, coxsackievirus, echovirus).^15,17

Serologic tests measuring immunoglobulin M and A titers (IgM, IgA) may be helpful in cases of zoster without rash (zoster sine herpete), but their sensitivity and specificity are low.¹⁵ Positive results may be indicative of primary infection, reinfection, or reactivation.¹

On the next page: Treatment >>

TREATMENT
Treatment of HZ infection is focused on limiting the extent, duration, and severity of pain and rash in the primary dermatome, as well as decreasing the risk for complications.

Topical Therapy
Patients should keep the cutaneous lesions clean and dry to reduce the risk for bacterial superinfection. A sterile, nonocclusive, nonadherent dressing placed over the involved dermatome will protect the lesions from contact with clothing. To hasten the drying of vesicular lesions and alleviate pruritus associated with rash, the application of cool compresses, calamine lotion, cornstarch, or baking soda may be helpful.^16,21

While antipruritic agents may help prevent infections that can develop when the affected area is scratched, there is no evidence that any of these agents have any real therapeutic effect on the HZ rash or lesions. Topical antiviral agents are not effective.^15,18

Antiviral Therapy
Treatment for acute HZ with oral antiviral medication should be considered for any patient who presents within 72 hours of rash onset; antiviral agents initiated within this time frame have been shown to reduce the duration and severity of pain associated with acute HZ.²¹ Antivirals are recommended and should be given routinely to patients older than 50 and those who have moderate to severe symptoms.^15,21

Among patients who present longer than 72 hours after rash onset, antiviral therapy should be considered only for those with new vesicular formation, ophthalmic involvement, or motor or neurologic complications, although evidence is lacking for this recommendation.^15,21 A modest reduction in the duration of rash (by 1 to 3 days) has also been reported in patients treated with antivirals,²¹ most likely because viral replication is slowed within the dorsal root ganglion.^16,22

Acyclovir, valacyclovir, and famciclovir—nucleoside analogs that block viral replication—are the only FDA-approved medications for treatment of HZ.^18,22  When choosing among these agents, the prescribing clinician should be aware of their differences in bioavailability and pharmacokinetics. Acyclovir, for example, is a second-generation antiviral drug with poor pharmacokinetics, which explains the frequent dosing its use generally requires.^22,23 However, the inhibitory dose of acyclovir required for patients with HZ is much lower than that required to treat primary VZV infection.

Valacyclovir and famciclovir, which are third-generation antivirals, feature enhanced absorption from the gastrointestinal tract (77% vs 30% for acyclovir),²⁴ thus improving their bioavailability by three to five times, compared with acyclovir. The superior pharmacokinetics of valacyclovir and famciclovir has been confirmed clinically by researchers who demonstrated median pain duration of 38 days in patients taking valacyclovir, compared with 51 days in those treated with acyclovir.²⁵ In a direct comparison of valacyclovir and famciclovir, resolution of rash and pain times were found comparable.²⁶ Table 2^18,27 summarizes the current recommendations for antiviral therapy in patients with HZ.

Pain Management
Pain is almost universal once the HZ rash appears. Pain associated with the prodromal period is variable but may be present in 70% to 80% of patients.^28,29 The severity of acute pain in HZ is highly variable, ranging from mild to quite severe. Pain can begin weeks or a single day before the rash emerges and persist for several weeks after the rash disappears.

Aggressive pain management is appropriate. A variety of opiate analgesics (eg, hydrocodone, oxycodone, hydromorphone, morphine) and nonopiate analgesics (acetaminophen, NSAIDs) may be effective.^17,28 Drug choices, dosage, and scheduling should be tailored to the patient’s level of pain and disability, with any potential contraindications also taken into account. Mild pain can be treated with as-needed dosing, whereas scheduled dosing is preferred for moderate to severe pain.¹⁶

If acute pain persists, addition of gabapentin, pregabalin, or nortriptyline is reasonable.^17,22,28,30 Although these medications have been studied in the treatment of postherpetic neuralgia (PHN), there is little evidence to support their use for acute zoster pain.^22,30

Additional interventions that have been studied for relief of acute HZ pain include topical lidocaine, acupuncture, and interventional pain injections. However, the evidence is either scant or of poor quality. More research is needed before these modalities can be routinely recommended in the clinical setting.^17,22

Corticosteroids have been used for acute HZ, but conflicting study results make their routine use controversial.^17,31,32 In some studies, corticosteroids reduced acute pain and speeded lesion healing and return to daily activities; others have yielded little evidence to support these findings.^22,33 Corticosteroids may offer the greatest benefit when used in combination with effective antiviral therapy.^18,22,31,32 In one randomized clinical trial comparing acyclovir with acyclovir plus prednisolone (40 mg/d for three weeks, tapered down) combination therapy was associated with a significant decrease in pain during the initial two weeks.³²

Historically, corticosteroids have also been prescribed with the hope that their anti-inflammatory properties might help reduce the risk for PHN. However, a recent Cochrane Review found that these agents do not reliably prevent PHN six months after HZ rash onset.³⁴ Glucocorticoids may improve motor outcomes and acute pain in VZV-induced facial paralysis and cranial polyneuritis, in which compression of affected nerves may contribute to disability.

Before prescribing steroids, clinicians must consider contraindications to their use, including diabetes, osteoporosis, hypertension, glaucoma, and gastritis.¹⁶

On the next page: Patient education and complications >>

PATIENT EDUCATION
Patients must be instructed in how to avoid transmitting the HZ virus. The mechanism of transmission was long thought to be restricted to direct contact with lesions; however, molecular studies have shown that the HZ virus can be transmitted via the respiratory route, either through aerosolized virus from skin lesions or from respiratory droplets, as early as 24 to 48 hours before the rash appears.^6,17 The risk of transmission by airborne virus is increased in patients with HZ rash that is disseminated beyond the primary and secondary dermatomes. The rash, patients should be informed, generally persists for two to four weeks.^1,16,20

HZ continues to be contagious until the lesions crust over.¹⁷ Covering the rash greatly reduces patients’ risk for transmitting the virus via airborne or direct contact routes.^15,17 A patient with HZ rash can infect a nonimmune person with primary varicella, causing chickenpox.²⁸ The patient with HZ should be advised to avoid exposure to infants younger than 1 year, unvaccinated older children, anyone who is not immune to varicella (either by vaccination or primary infection), susceptible pregnant women, and potentially susceptible immunocompromised persons.¹⁶

COMPLICATIONS AND SEQUELAE
The majority of cases of shingles resolve without any complications or long-term sequelae. Complications of HZ that do occur may include superimposed skin infections, such as Streptococcus or Staphylococcus. The virus may be reactivated in the nasociliary branch of the trigeminal nerve and, in 10% to 25% of cases, herpes zoster ophthalmicus (HZO) may develop.^17,35 Associated morbidity includes keratitis, corneal ulceration, conjunctivitis, uveitis, episcleritis and scleritis, retinitis, choroiditis, optic neuritis, lid retraction, ptosis, and glaucoma. Patients with HZO should be referred to an ophthalmologist promptly, as this condition can result in permanent loss of vision.³⁵

Other less common complications of HZ include Ramsay Hunt syndrome (facial nerve palsy associated with reactivation in the geniculate ganglion) and zoster paresis (motor weakness in noncranial nerve distributions).^17,36,37 Autonomic dysfunction has also been reported in patients with HZ, leading to colonic pseudo-obstruction and urinary retention. Rare but serious neurologic complications include Guillain-Barré syndrome, myelitis, aseptic meningitis, and meningoencephalitis.^15,17

Postherpetic Neuralgia
By far, the most common complication of shingles is postherpetic neuralgia, a painfully debilitating and difficult-to-treat condition. Of the one million persons affected by HZ each year, between 9% and 34% will develop PHN.^3,7,18 The criteria for diagnosing PHN is variable: While all definitions include the presence of persistent pain after rash resolution, they differ in how long this pain must persist. Some define PHN as pain persisting from 30 days to six months after rash resolution, while others define it as pain continuing three months or longer.^3,17,18 While most patients with PHN experience complete resolution, the pain can endure from weeks to months to years.^3,18,38

The pathophysiology of PHN is thought to involve replication of the VZV in the basal ganglia, damaging the nerves and thereby causing pain in the affected dermatome.²² Other possible factors include axonal and cell body degeneration, atrophy of the dorsal horn of the spinal cord, scarring of the dorsal root ganglion, and loss of epidermal innervations of the dermatome.¹⁷

The risk for PHN increases significantly in patients of advancing age. While PHN is rare in those younger than 50, it complicates HZ in 20% of patients between ages 60 and 65 and in 30% of those 80 and older. Additional risk factors for PHN include female gender, prodromal pain preceding the HZ rash, rash that is moderate to severe, moderate to severe acute pain associated with the rash, and ophthalmic involvement.³⁹

Evidence conflicts regarding the impact of antivirals in patients with HZ on the subsequent development of PHN. Researchers performing a meta-analysis of five randomized clinical trials found no significant difference in the incidence of PHN among patients treated for HZ with oral acyclovir, famciclovir, or placebo.³⁴ In an older, placebo-controlled randomized clinical trial, however, famciclovir-treated patients experienced PHN of reduced duration, compared with controls (63 days vs 119 days, respectively). Six months after development of the HZ rash, 15% of treated patients continued to experience PHN symptoms, compared with 23% of controls.²³ More evidence is needed.

Additional Concerns
Recurrence of HZ is uncommon in immunocompetent persons. Despite its ordinarily benign course, 1% to 4% of people with shingles require hospitalization each year, mostly elderly patients.¹ In a recent study, it was estimated that 96 US deaths are attributable to HZ each year.⁴⁰ Almost all HZ-associated deaths occur in elderly patients with compromised or suppressed immune systems.¹

On the next page: Prevention >>

PREVENTION
The varicella vaccine was licensed for use in children by the FDA in 1995. In June 2006, the Advisory Committee on Immunization Practices (ACIP) recommended a second dose to boost waning immunity.⁴¹

In 2006, the HZ vaccine (Zostavax), a more concentrated formulation of the varicella vaccine, was approved by the FDA for use in adults age 60 or older; in 2011, approval of the vaccine was extended to adults 50 or older.⁴² As of November 2011, ACIP has continued to recommend routine administration of the HZ vaccine for immunocompetent adults 60 and older, citing lack of evidence for long-term protection in patients vaccinated before age 60, as well as concerns about maintaining sufficient vaccine supplies.

Although ACIP does not recommend routine vaccination against HZ in patients age 50 to 59, health care providers may wish to consider it for patients in this age-group, based on the potential for poor tolerance of HZ or PHN symptoms, anticipated difficulty tolerating the required medications used to treat them, and employment-related considerations.⁴³

Use of the HZ Vaccine
Zostavax is a live attenuated vaccine that increases varicella-specific, cell-mediated immunity in immunocompetent persons.^17,42 It should be administered as a single 0.65-mL dose subcutaneously in the deltoid region of the upper arm⁴²; a booster dose is not licensed for the vaccine.¹⁷ Adverse effects of the HZ vaccine generally include mild injection-site reactions: pain (54%), erythema (48%), swelling (40%), and pruritus (11%).⁴² According to researchers for the Shingles Prevention Study^38,44 (SPS), these reactions were more common in treated patients than in controls and increasingly common in study participants of advancing age. Less than 2% of patients receiving either the HZ vaccine or placebo experienced serious adverse effects.⁴⁴

The evidence to support vaccination against HZ comes mainly from the original SPS,³⁸ a randomized, double-blind, placebo-controlled trial in which more than 38,500 adults 60 and older were enrolled. The SPS researchers showed that the vaccine reduced the incidence of HZ by 51.3%, reduced the incidence of PHN by 67%, and reduced the HZ-associated burden of illness (ie, its incidence, severity, and duration of associated pain and discomfort) by 61%^2,38,45; they also found vaccination against HZ effective for at least three years.

An ongoing substudy involving 14,270 of the original SPS participants produced data showing that from year 4 to year 5 postvaccination, vaccine efficacy in terms of HZ incidence declined from 51% to 40%, respectively, and its efficacy regarding incidence of PHN, from 67% to 60%.⁴⁶ Since there is no strong evidence that any treatment intervention started after shingles presents can reduce the risk for PHN, perhaps the vaccine’s most valuable attribute is its potential for preventing this debilitating and common complication of shingles.

Who Should or Should Not Be Vaccinated?
According to the ACIP, there is no upper age limit on vaccination against shingles. This judgment is supported by the fact that the incidence of zoster and PHN both continue to increase among patients of advancing age.¹⁷

While vaccination is appropriate for most individuals 60 or older, some contraindications exist (see Table 3^17,22,47,48). In cases of anticipated immunosuppression (as in patients scheduled to undergo chemotherapy), vaccination is recommended one month before the start of therapy. Additionally, the safety and efficacy of vaccination is unknown in patients receiving immune modulators and recombinant human immune mediators (eg, adalimumab, etanercept, infliximab); thus, these patients too should be vaccinated one month before starting these treatments or one month after their completion.⁴⁷

On the next page: Conclusion >>

CONCLUSION
Herpes zoster remains a common disease in the US, despite the availability of an effective vaccine. While most cases of shingles resolve spontaneously, life-threatening and permanent complications can occur. Treatment may shorten the length of illness and prevent these complications. Primary care providers should recommend routine vaccination against HZ for their immunocompetent patients 60 or older.

Between 1995 and 2009, the use of chest x-rays for children with asthma significantly increased in emergency departments overall, but dropped in pediatric emergency departments – findings that have implications for savings in health care costs and safety, according to Dr. Jane F. Knapp and her associates.

Citing factors that include the average cost of a chest x-ray ($370), the average time that obtaining an x-ray adds to an ED visit (27 minutes), and evidence that many children with respiratory illnesses can be treated safely and effectively without an x-ray, the authors pointed out that "reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure." The results of the retrospective study appear in the August issue of Pediatrics (2013;132:245-52).

Dr. Knapp of Children’s Mercy Hospitals and Clinics, Kansas City, Mo., and her coauthors used national survey data on ED visits from a sample of nonfederal, general, and short-stay hospitals in the United States to compare the rates of x-ray use for three groups of children evaluated between 1995 and 2009: those with moderate to severe asthma, aged 2-18 years; children with bronchiolitis, aged 3 months to 1 year; and children with croup, aged 3 months to 6 years.

During this period, the use of x-rays did not change significantly for the groups with bronchiolitis and croup. But the use of x-rays for children with asthma increased every year, about 7% a year (OR, 1.07). Although this annual increase appears small, it added up to a 2.4-fold increase over the period of time studied, the authors said.

"...Reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure."

In pediatric EDs specifically, the use of x-rays significantly decreased during the period studied for all three respiratory illnesses: asthma (OR, 0.44), bronchiolitis (OR, 0.37), and croup (OR, 0.34). A look at trends according to region showed that the use of x-rays in EDs for all three conditions increased significantly in the Midwest and South compared with the Northeast. In the West, use increased significantly for those with asthma and bronchiolitis only.

The increase in x-ray use among the children with asthma could not be explained by changes in the National Asthma Education and Prevention Program guidelines. The researchers speculated that some factors related to parents, patients, and physicians. They cited evidence that physicians are more likely to order antibiotics for a child or an x-ray for a respiratory illness or low back pain when parents or patients expect such measures. "Pressures on ED physicians to practice more aggressively could also be involved," they wrote.

Although the National Heart, Lung, and Blood Institute guidelines on the use of chest x-rays in children with asthma did not change during the study period, "we also believe that they do not provide the criteria that are sufficiently explicit to affect the discretionary use of x-rays," Dr Knapp and her associates said.

 “As we discussed in the article, we need to understand the reasons why more x-rays are being used over time in the ED care of the child with asthma rather than less. The reasons may be multifactorial, but just as we have worked to limit the overuse of antibiotics with guidelines, parental education, and individual and system performance evaluation, we need to find ways to limit the excess radiation and cost associated with the use of x-rays," Dr. Knapp said in an interview.

There are almost 1 million ED visits per year for pediatric asthma, bronchiolitis, and croup, they noted.

The study did not receive external funding and the authors had no disclosures.

[email protected]

This story was updated. 8/5/2013

Between 1995 and 2009, the use of chest x-rays for children with asthma significantly increased in emergency departments overall, but dropped in pediatric emergency departments – findings that have implications for savings in health care costs and safety, according to Dr. Jane F. Knapp and her associates.

Citing factors that include the average cost of a chest x-ray ($370), the average time that obtaining an x-ray adds to an ED visit (27 minutes), and evidence that many children with respiratory illnesses can be treated safely and effectively without an x-ray, the authors pointed out that "reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure." The results of the retrospective study appear in the August issue of Pediatrics (2013;132:245-52).

Dr. Knapp of Children’s Mercy Hospitals and Clinics, Kansas City, Mo., and her coauthors used national survey data on ED visits from a sample of nonfederal, general, and short-stay hospitals in the United States to compare the rates of x-ray use for three groups of children evaluated between 1995 and 2009: those with moderate to severe asthma, aged 2-18 years; children with bronchiolitis, aged 3 months to 1 year; and children with croup, aged 3 months to 6 years.

During this period, the use of x-rays did not change significantly for the groups with bronchiolitis and croup. But the use of x-rays for children with asthma increased every year, about 7% a year (OR, 1.07). Although this annual increase appears small, it added up to a 2.4-fold increase over the period of time studied, the authors said.

"...Reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure."

In pediatric EDs specifically, the use of x-rays significantly decreased during the period studied for all three respiratory illnesses: asthma (OR, 0.44), bronchiolitis (OR, 0.37), and croup (OR, 0.34). A look at trends according to region showed that the use of x-rays in EDs for all three conditions increased significantly in the Midwest and South compared with the Northeast. In the West, use increased significantly for those with asthma and bronchiolitis only.

The increase in x-ray use among the children with asthma could not be explained by changes in the National Asthma Education and Prevention Program guidelines. The researchers speculated that some factors related to parents, patients, and physicians. They cited evidence that physicians are more likely to order antibiotics for a child or an x-ray for a respiratory illness or low back pain when parents or patients expect such measures. "Pressures on ED physicians to practice more aggressively could also be involved," they wrote.

Although the National Heart, Lung, and Blood Institute guidelines on the use of chest x-rays in children with asthma did not change during the study period, "we also believe that they do not provide the criteria that are sufficiently explicit to affect the discretionary use of x-rays," Dr Knapp and her associates said.

 “As we discussed in the article, we need to understand the reasons why more x-rays are being used over time in the ED care of the child with asthma rather than less. The reasons may be multifactorial, but just as we have worked to limit the overuse of antibiotics with guidelines, parental education, and individual and system performance evaluation, we need to find ways to limit the excess radiation and cost associated with the use of x-rays," Dr. Knapp said in an interview.

There are almost 1 million ED visits per year for pediatric asthma, bronchiolitis, and croup, they noted.

The study did not receive external funding and the authors had no disclosures.

[email protected]

This story was updated. 8/5/2013

Between 1995 and 2009, the use of chest x-rays for children with asthma significantly increased in emergency departments overall, but dropped in pediatric emergency departments – findings that have implications for savings in health care costs and safety, according to Dr. Jane F. Knapp and her associates.

Citing factors that include the average cost of a chest x-ray ($370), the average time that obtaining an x-ray adds to an ED visit (27 minutes), and evidence that many children with respiratory illnesses can be treated safely and effectively without an x-ray, the authors pointed out that "reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure." The results of the retrospective study appear in the August issue of Pediatrics (2013;132:245-52).

Dr. Knapp of Children’s Mercy Hospitals and Clinics, Kansas City, Mo., and her coauthors used national survey data on ED visits from a sample of nonfederal, general, and short-stay hospitals in the United States to compare the rates of x-ray use for three groups of children evaluated between 1995 and 2009: those with moderate to severe asthma, aged 2-18 years; children with bronchiolitis, aged 3 months to 1 year; and children with croup, aged 3 months to 6 years.

During this period, the use of x-rays did not change significantly for the groups with bronchiolitis and croup. But the use of x-rays for children with asthma increased every year, about 7% a year (OR, 1.07). Although this annual increase appears small, it added up to a 2.4-fold increase over the period of time studied, the authors said.

"...Reversing this trend could improve ED efficiency, decrease costs, and decrease radiation exposure."

In pediatric EDs specifically, the use of x-rays significantly decreased during the period studied for all three respiratory illnesses: asthma (OR, 0.44), bronchiolitis (OR, 0.37), and croup (OR, 0.34). A look at trends according to region showed that the use of x-rays in EDs for all three conditions increased significantly in the Midwest and South compared with the Northeast. In the West, use increased significantly for those with asthma and bronchiolitis only.

The increase in x-ray use among the children with asthma could not be explained by changes in the National Asthma Education and Prevention Program guidelines. The researchers speculated that some factors related to parents, patients, and physicians. They cited evidence that physicians are more likely to order antibiotics for a child or an x-ray for a respiratory illness or low back pain when parents or patients expect such measures. "Pressures on ED physicians to practice more aggressively could also be involved," they wrote.

Although the National Heart, Lung, and Blood Institute guidelines on the use of chest x-rays in children with asthma did not change during the study period, "we also believe that they do not provide the criteria that are sufficiently explicit to affect the discretionary use of x-rays," Dr Knapp and her associates said.

 “As we discussed in the article, we need to understand the reasons why more x-rays are being used over time in the ED care of the child with asthma rather than less. The reasons may be multifactorial, but just as we have worked to limit the overuse of antibiotics with guidelines, parental education, and individual and system performance evaluation, we need to find ways to limit the excess radiation and cost associated with the use of x-rays," Dr. Knapp said in an interview.

There are almost 1 million ED visits per year for pediatric asthma, bronchiolitis, and croup, they noted.

The study did not receive external funding and the authors had no disclosures.

[email protected]

This story was updated. 8/5/2013

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures. 

One of the most common conditions that complicate pregnancy is maternal asthma. Evidence continues to mount that adequate control of asthma, including appropriate use of medications, is the best approach to optimizing outcomes. Yet questions persist about the effect of asthma itself, as well as specific medications and the risk for major congenital malformations. As with any exposure during pregnancy, answering these questions is challenging because of the rarity of specific birth defects and the various and increasing number of medications that might be used to treat or prevent asthma symptoms.

Previously in this column ("Beta2-agonists for asthma, December 2011), we reviewed two studies that suggested short-acting beta-agonists used for the treatment of asthma were associated with an increased risk of oral clefts and that long-acting beta-agonists might be associated with an increased risk of cardiac anomalies (Hum. Reprod. 2011;26:3147-54; Birth Defects Res. A. Clin. Mol. Teratol. 2011;91:937-47).

What have we learned since then? Two studies published in 2013 add to the body of knowledge. The first, a database analysis using the United Kingdom’s General Practice Research Database, assessed pregnancy outcomes between 1991 and 2002 in 7,911 women exposed to asthma medications in the first trimester of pregnancy and 15,840 women who were not exposed (Pharmacotherapy 2013;33:363-8). Major anomalies were identified up to 1 year of age. Minor anomalies, chromosomal anomalies, and those associated with prematurity were excluded.

The overall risk for any exposure, compared with no exposure, for any congenital anomaly was 1.1 (95% confidence interval [CI], 1.0-1.3). No significant differences were found by class of asthma medication. Specific categories of defects also were evaluated, including musculoskeletal anomalies, oral clefts, cardiovascular defects, and multiple anomalies. Some estimates were elevated for specific medication classes.

For example, the relative risk (RR) of cleft lip or palate associated with exposure to long-acting beta-agonists was 2.4, but the confidence interval included 1 (0.3-21.8) based on 424 exposed pregnancies. The authors concluded that they found no significant increased risk of congenital anomalies associated with exposure to asthma, asthma medications, or any specific asthma medication classes in the first trimester. Limitations of the study included the inability to verify that exposure took place and insufficient data to adjust for confounding by vitamin supplementation, alcohol use, socioeconomic status, or markers of disease severity (other than number of medications prescribed).

The second study addressed the issue of maternal asthma itself and the risk for congenital anomalies (BJOG 2013;120:812-22). Using a meta-analysis approach, 21 cohort studies published between 1975 and 2012 met the criteria for inclusion. Combining major and minor congenital anomalies, the authors found a slight but statistically significant increased risk for any defect (RR, 1.11; 95% CI, 1.01-1.68), but when the analysis was restricted to major defects alone, the summary estimate was elevated but no longer significant (RR, 1.31; 95% CI, 0.57-3.02). When the specific defect grouping of oral clefts was examined, however, there was a significantly elevated overall relative risk of 1.30 (95% CI, 1.01-1.68). Limitations of this study include differing quality of studies and the appropriateness of combining data to derive a summary estimate.

Although both studies provide reassurance about the overall risk of major defects in the offspring of women with asthma, both suggest that more work needs to be done to follow up on the risk for oral clefts and whether this is linked to underlying disease severity and/or use of specific medications. Furthermore, safety of specific long-acting beta-agonist medications in pregnancy should be further examined.

The take-home message, however, continues to be that the risk for major defects in the offspring of pregnant women with asthma appears to be low, which supports the recommendation to follow guidelines for appropriate treatment of women with asthma both during and outside of pregnancy to control symptoms.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. She said that she had no relevant financial disclosures.