ID Consult

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Mononucleosis is no stranger to most clinicians, who know it is most often caused by Epstein-Barr virus. Still, it presents diagnostic and management difficulties.

Consider a 12-year-old with 4 days of fever, headache, severe sore throat, and fatigue. Your exam detects bilateral, mildly tender, swollen (greater than 1 cm) anterior cervical lymph nodes and white tonsillar exudate, but no splenomegaly, which you know is only present in about 50% of children with EBV. Other EBV signs, such as supraorbital edema or maculopapular rash are absent, although they are seen in about 15%–20% of cases. A negative rapid streptococcal antigen and throat culture point to a virus (although 5%–25% of patients with EBV can have concomitant group A streptococcus). Now, how do you go about confirming EBV?

▸ Pitfall 1. Laboratory confirmation is unlikely until at least the second week of EBV illness. It is tempting to order serology (monospot-like test or EBV-specific serology) plus a CBC when the patient feels lousy and parents want answers. But keep in mind that in the first week negative serology doesn't rule out EBV and complete blood count results are usually nonspecific.

Not until the second week (or maybe even later), after illness onset, does the picture become clearer. At this point, nonspecific viral illnesses will usually have resolved and EBV infection becomes more likely if fever, sore throat, and cervical adenopathy continue (although they may be diminished), while fatigue is increasing. Splenomegaly also may develop in the interim with more generalized symmetrically bilateral adenopathy (groin, axilla, or posterior cervical).

Now, a CBC could suggest EBV mono via lymphocytosis (greater than 50% lymphocytes), and more than 10% atypical lymphocytes. In the case above, this result would allow a correct clinical diagnosis of EBV even without serology 90% of the time. However, not all patients with EBV will have this CBC result.

▸ Pitfall 2. Monospot-like tests have limitations. When the CBC is not sufficiently consistent with EBV but the clinical picture still suggests EBV mono in the second week of illness or later, then it's time for a nonspecific but quick and inexpensive serology—a monospot-like test. Contrary to what its name suggests—and to what one might believe—it does not detect EBV-specific antibody. Rather, it detects heterophile antibody, a low-affinity, highly cross-reactive IgM produced when EBV infects uncommitted B cells. Some of this nonspecific antibody cross-reacts with membrane antigens on mammalian red blood cells. (“Heterophile” refers to the cross-species affinity).

Monospot-like tests may not turn positive for up to 4 weeks. Moreover, children younger than 8 years are less likely to ever produce heterophile antibody, so the test isn't useful in that age group. In addition, a positive monospot isn't always caused by currently active mononucleosis. A rare individual can have persistent heterophile antibody years after recovery.

Also, some individuals who had EBV mono in the past may have a positive monospot because of amnestic responses while ill with an alternative virus, such as rubella. Other causes of false-positive monospots include malaria, autoimmune hepatitis, systemic lupus erythematosus, leukemia, pancreatic cancer, or, rarely, primary HIV infection (Am. J. Med. 2001;111:192-4). Of course, primary HIV is far less common than EBV, but should be kept in mind.

Still, EBV mono is the most likely diagnosis in a patient with a positive monospot who has had the classic symptoms.

▸ Pitfall 3. Specific EBV serology panels can be confusing. An EBV-specific antibody panel is the next step in the persistently ill patient with a negative monospot test. It not only nails down the diagnosis but also can tell us where the patient is in the course of infection. Depending on the laboratory, either three or four antibodies are included in the EBV panel:

The first is IgM to viral capsid antigen (VCA). It is initially positive in the second or third week of infection. It usually wanes by 2–4 weeks and may not develop at all in young children.

Next is IgG to VCA. It is initially positive in second to fourth week of infection and detectable for life.

Third is an antibody to early antigen (EA). It is usually present during EBV replication. (This is the one that some labs omit.)

Fourth is an antibody to EBV nuclear antigen (EBNA). Its presence coincides with recovery and arises beyond 6 weeks.

A positive IgM to only VCA confirms that the patient is early in course of EBV mono. A positive IgG to VCA, with or without a positive IgM to VCA, is also diagnostic of currently active mono.

However, if EBNA antibody is present, EBV is NOT the likely cause of the current problem. I use an EBNA mnemonic, “EB Not Active.” Occasionally an anti-EBNA-positive patient is entering recovery even if they don't feel well quite yet. We can assure them that they will feel better soon.

If EBV serology indicates recovery from a past EBV infection (positive for both IgG to VCA and anti-EBNA) or it is completely negative, a different cause for current symptoms could be sought by testing for cytomegalovirus, adenovirus, or Toxoplasma gondii.

EBV-mono patients should expect to have symptoms for at least 4–6 weeks before recovery. Reactivation may occur, but is nearly always asymptomatic or involves short-lived nonspecific symptoms. Chronic mono is so rare as to not be considered in primary care.

▸ Pitfall 4. Avoid having the patient stay too long on bed rest. Patients infected with EBV should be on bed rest only for the highly febrile stage, usually less than a week. We no longer recommend that they stay home from school or away from routine activities while riding out mononucleosis. Once the fever goes away, encourage patients to return to as much activity as their energy level will allow. The important exception is to refrain from contact sports as long as the spleen is palpable (and perhaps a little longer) to minimize chance of splenic rupture. I tell athletes to hang up the current sports season.

Patients kept in bed too long have more difficulty readjusting to normal life routines. Some may even experience clinical depression. It's important to consider how a patient with mono is coping psychologically when fatigue remains the main complaint.

▸ Pitfall 5. Active treatment is not usually helpful. Unfortunately, antivirals such as acyclovir don't work. Current consensus is not to give patients corticosteroids during acute mononucleosis. Steroids were postulated to speed recovery, and subjective mood improvement is possible due to the “steroid high” effect. However, in controlled trials they do not improve recovery other than reducing pain in first 12 hours (Cochrane Database Syst. Rev. 2006;3:CD004 402).

Further, steroids kill off defensive T cells that hold EBV-driven expansion of potentially malignant B cells in check. Such an imbalance could lead to later lymphoma. Although I don't think this is a huge risk, transient symptom relief does not seem worth the risk to me and I don't believe it's something we should do routinely. However, there are a few exceptions: The risk/benefit ratio changes in favor of corticosteroids if tonsillar swelling compromises the airway, or if there are other life-threatening EBV complications such as severe thrombocytopenia, neutropenia, or encephalitis.

But for uncomplicated EBV-mono, our best tools are ibuprofen, supportive care, and the tincture of time.

[email protected]

Mononucleosis is no stranger to most clinicians, who know it is most often caused by Epstein-Barr virus. Still, it presents diagnostic and management difficulties.

Consider a 12-year-old with 4 days of fever, headache, severe sore throat, and fatigue. Your exam detects bilateral, mildly tender, swollen (greater than 1 cm) anterior cervical lymph nodes and white tonsillar exudate, but no splenomegaly, which you know is only present in about 50% of children with EBV. Other EBV signs, such as supraorbital edema or maculopapular rash are absent, although they are seen in about 15%–20% of cases. A negative rapid streptococcal antigen and throat culture point to a virus (although 5%–25% of patients with EBV can have concomitant group A streptococcus). Now, how do you go about confirming EBV?

▸ Pitfall 1. Laboratory confirmation is unlikely until at least the second week of EBV illness. It is tempting to order serology (monospot-like test or EBV-specific serology) plus a CBC when the patient feels lousy and parents want answers. But keep in mind that in the first week negative serology doesn't rule out EBV and complete blood count results are usually nonspecific.

Not until the second week (or maybe even later), after illness onset, does the picture become clearer. At this point, nonspecific viral illnesses will usually have resolved and EBV infection becomes more likely if fever, sore throat, and cervical adenopathy continue (although they may be diminished), while fatigue is increasing. Splenomegaly also may develop in the interim with more generalized symmetrically bilateral adenopathy (groin, axilla, or posterior cervical).

Now, a CBC could suggest EBV mono via lymphocytosis (greater than 50% lymphocytes), and more than 10% atypical lymphocytes. In the case above, this result would allow a correct clinical diagnosis of EBV even without serology 90% of the time. However, not all patients with EBV will have this CBC result.

▸ Pitfall 2. Monospot-like tests have limitations. When the CBC is not sufficiently consistent with EBV but the clinical picture still suggests EBV mono in the second week of illness or later, then it's time for a nonspecific but quick and inexpensive serology—a monospot-like test. Contrary to what its name suggests—and to what one might believe—it does not detect EBV-specific antibody. Rather, it detects heterophile antibody, a low-affinity, highly cross-reactive IgM produced when EBV infects uncommitted B cells. Some of this nonspecific antibody cross-reacts with membrane antigens on mammalian red blood cells. (“Heterophile” refers to the cross-species affinity).

Monospot-like tests may not turn positive for up to 4 weeks. Moreover, children younger than 8 years are less likely to ever produce heterophile antibody, so the test isn't useful in that age group. In addition, a positive monospot isn't always caused by currently active mononucleosis. A rare individual can have persistent heterophile antibody years after recovery.

Also, some individuals who had EBV mono in the past may have a positive monospot because of amnestic responses while ill with an alternative virus, such as rubella. Other causes of false-positive monospots include malaria, autoimmune hepatitis, systemic lupus erythematosus, leukemia, pancreatic cancer, or, rarely, primary HIV infection (Am. J. Med. 2001;111:192-4). Of course, primary HIV is far less common than EBV, but should be kept in mind.

Still, EBV mono is the most likely diagnosis in a patient with a positive monospot who has had the classic symptoms.

▸ Pitfall 3. Specific EBV serology panels can be confusing. An EBV-specific antibody panel is the next step in the persistently ill patient with a negative monospot test. It not only nails down the diagnosis but also can tell us where the patient is in the course of infection. Depending on the laboratory, either three or four antibodies are included in the EBV panel:

The first is IgM to viral capsid antigen (VCA). It is initially positive in the second or third week of infection. It usually wanes by 2–4 weeks and may not develop at all in young children.

Next is IgG to VCA. It is initially positive in second to fourth week of infection and detectable for life.

Third is an antibody to early antigen (EA). It is usually present during EBV replication. (This is the one that some labs omit.)

Fourth is an antibody to EBV nuclear antigen (EBNA). Its presence coincides with recovery and arises beyond 6 weeks.

A positive IgM to only VCA confirms that the patient is early in course of EBV mono. A positive IgG to VCA, with or without a positive IgM to VCA, is also diagnostic of currently active mono.

However, if EBNA antibody is present, EBV is NOT the likely cause of the current problem. I use an EBNA mnemonic, “EB Not Active.” Occasionally an anti-EBNA-positive patient is entering recovery even if they don't feel well quite yet. We can assure them that they will feel better soon.

If EBV serology indicates recovery from a past EBV infection (positive for both IgG to VCA and anti-EBNA) or it is completely negative, a different cause for current symptoms could be sought by testing for cytomegalovirus, adenovirus, or Toxoplasma gondii.

EBV-mono patients should expect to have symptoms for at least 4–6 weeks before recovery. Reactivation may occur, but is nearly always asymptomatic or involves short-lived nonspecific symptoms. Chronic mono is so rare as to not be considered in primary care.

▸ Pitfall 4. Avoid having the patient stay too long on bed rest. Patients infected with EBV should be on bed rest only for the highly febrile stage, usually less than a week. We no longer recommend that they stay home from school or away from routine activities while riding out mononucleosis. Once the fever goes away, encourage patients to return to as much activity as their energy level will allow. The important exception is to refrain from contact sports as long as the spleen is palpable (and perhaps a little longer) to minimize chance of splenic rupture. I tell athletes to hang up the current sports season.

Patients kept in bed too long have more difficulty readjusting to normal life routines. Some may even experience clinical depression. It's important to consider how a patient with mono is coping psychologically when fatigue remains the main complaint.

▸ Pitfall 5. Active treatment is not usually helpful. Unfortunately, antivirals such as acyclovir don't work. Current consensus is not to give patients corticosteroids during acute mononucleosis. Steroids were postulated to speed recovery, and subjective mood improvement is possible due to the “steroid high” effect. However, in controlled trials they do not improve recovery other than reducing pain in first 12 hours (Cochrane Database Syst. Rev. 2006;3:CD004 402).

Further, steroids kill off defensive T cells that hold EBV-driven expansion of potentially malignant B cells in check. Such an imbalance could lead to later lymphoma. Although I don't think this is a huge risk, transient symptom relief does not seem worth the risk to me and I don't believe it's something we should do routinely. However, there are a few exceptions: The risk/benefit ratio changes in favor of corticosteroids if tonsillar swelling compromises the airway, or if there are other life-threatening EBV complications such as severe thrombocytopenia, neutropenia, or encephalitis.

But for uncomplicated EBV-mono, our best tools are ibuprofen, supportive care, and the tincture of time.

[email protected]

Mononucleosis is no stranger to most clinicians, who know it is most often caused by Epstein-Barr virus. Still, it presents diagnostic and management difficulties.

Consider a 12-year-old with 4 days of fever, headache, severe sore throat, and fatigue. Your exam detects bilateral, mildly tender, swollen (greater than 1 cm) anterior cervical lymph nodes and white tonsillar exudate, but no splenomegaly, which you know is only present in about 50% of children with EBV. Other EBV signs, such as supraorbital edema or maculopapular rash are absent, although they are seen in about 15%–20% of cases. A negative rapid streptococcal antigen and throat culture point to a virus (although 5%–25% of patients with EBV can have concomitant group A streptococcus). Now, how do you go about confirming EBV?

▸ Pitfall 1. Laboratory confirmation is unlikely until at least the second week of EBV illness. It is tempting to order serology (monospot-like test or EBV-specific serology) plus a CBC when the patient feels lousy and parents want answers. But keep in mind that in the first week negative serology doesn't rule out EBV and complete blood count results are usually nonspecific.

Not until the second week (or maybe even later), after illness onset, does the picture become clearer. At this point, nonspecific viral illnesses will usually have resolved and EBV infection becomes more likely if fever, sore throat, and cervical adenopathy continue (although they may be diminished), while fatigue is increasing. Splenomegaly also may develop in the interim with more generalized symmetrically bilateral adenopathy (groin, axilla, or posterior cervical).

Now, a CBC could suggest EBV mono via lymphocytosis (greater than 50% lymphocytes), and more than 10% atypical lymphocytes. In the case above, this result would allow a correct clinical diagnosis of EBV even without serology 90% of the time. However, not all patients with EBV will have this CBC result.

▸ Pitfall 2. Monospot-like tests have limitations. When the CBC is not sufficiently consistent with EBV but the clinical picture still suggests EBV mono in the second week of illness or later, then it's time for a nonspecific but quick and inexpensive serology—a monospot-like test. Contrary to what its name suggests—and to what one might believe—it does not detect EBV-specific antibody. Rather, it detects heterophile antibody, a low-affinity, highly cross-reactive IgM produced when EBV infects uncommitted B cells. Some of this nonspecific antibody cross-reacts with membrane antigens on mammalian red blood cells. (“Heterophile” refers to the cross-species affinity).

Monospot-like tests may not turn positive for up to 4 weeks. Moreover, children younger than 8 years are less likely to ever produce heterophile antibody, so the test isn't useful in that age group. In addition, a positive monospot isn't always caused by currently active mononucleosis. A rare individual can have persistent heterophile antibody years after recovery.

Also, some individuals who had EBV mono in the past may have a positive monospot because of amnestic responses while ill with an alternative virus, such as rubella. Other causes of false-positive monospots include malaria, autoimmune hepatitis, systemic lupus erythematosus, leukemia, pancreatic cancer, or, rarely, primary HIV infection (Am. J. Med. 2001;111:192-4). Of course, primary HIV is far less common than EBV, but should be kept in mind.

Still, EBV mono is the most likely diagnosis in a patient with a positive monospot who has had the classic symptoms.

▸ Pitfall 3. Specific EBV serology panels can be confusing. An EBV-specific antibody panel is the next step in the persistently ill patient with a negative monospot test. It not only nails down the diagnosis but also can tell us where the patient is in the course of infection. Depending on the laboratory, either three or four antibodies are included in the EBV panel:

The first is IgM to viral capsid antigen (VCA). It is initially positive in the second or third week of infection. It usually wanes by 2–4 weeks and may not develop at all in young children.

Next is IgG to VCA. It is initially positive in second to fourth week of infection and detectable for life.

Third is an antibody to early antigen (EA). It is usually present during EBV replication. (This is the one that some labs omit.)

Fourth is an antibody to EBV nuclear antigen (EBNA). Its presence coincides with recovery and arises beyond 6 weeks.

A positive IgM to only VCA confirms that the patient is early in course of EBV mono. A positive IgG to VCA, with or without a positive IgM to VCA, is also diagnostic of currently active mono.

However, if EBNA antibody is present, EBV is NOT the likely cause of the current problem. I use an EBNA mnemonic, “EB Not Active.” Occasionally an anti-EBNA-positive patient is entering recovery even if they don't feel well quite yet. We can assure them that they will feel better soon.

If EBV serology indicates recovery from a past EBV infection (positive for both IgG to VCA and anti-EBNA) or it is completely negative, a different cause for current symptoms could be sought by testing for cytomegalovirus, adenovirus, or Toxoplasma gondii.

EBV-mono patients should expect to have symptoms for at least 4–6 weeks before recovery. Reactivation may occur, but is nearly always asymptomatic or involves short-lived nonspecific symptoms. Chronic mono is so rare as to not be considered in primary care.

▸ Pitfall 4. Avoid having the patient stay too long on bed rest. Patients infected with EBV should be on bed rest only for the highly febrile stage, usually less than a week. We no longer recommend that they stay home from school or away from routine activities while riding out mononucleosis. Once the fever goes away, encourage patients to return to as much activity as their energy level will allow. The important exception is to refrain from contact sports as long as the spleen is palpable (and perhaps a little longer) to minimize chance of splenic rupture. I tell athletes to hang up the current sports season.

Patients kept in bed too long have more difficulty readjusting to normal life routines. Some may even experience clinical depression. It's important to consider how a patient with mono is coping psychologically when fatigue remains the main complaint.

▸ Pitfall 5. Active treatment is not usually helpful. Unfortunately, antivirals such as acyclovir don't work. Current consensus is not to give patients corticosteroids during acute mononucleosis. Steroids were postulated to speed recovery, and subjective mood improvement is possible due to the “steroid high” effect. However, in controlled trials they do not improve recovery other than reducing pain in first 12 hours (Cochrane Database Syst. Rev. 2006;3:CD004 402).

Further, steroids kill off defensive T cells that hold EBV-driven expansion of potentially malignant B cells in check. Such an imbalance could lead to later lymphoma. Although I don't think this is a huge risk, transient symptom relief does not seem worth the risk to me and I don't believe it's something we should do routinely. However, there are a few exceptions: The risk/benefit ratio changes in favor of corticosteroids if tonsillar swelling compromises the airway, or if there are other life-threatening EBV complications such as severe thrombocytopenia, neutropenia, or encephalitis.

But for uncomplicated EBV-mono, our best tools are ibuprofen, supportive care, and the tincture of time.

[email protected]

Since July 22nd, you have no doubt received phone calls from anxious parents who heard the news report about adverse events associated with the human papillomavirus vaccine, Gardasil. As usual, the media did a good job of creating anxiety both among parents and prescribing physicians. I've heard how much time clinicians now are spending discussing vaccine safety with their patients, and that some have begun administering the HPV vaccine separately from other recommended adolescent vaccines and others have just stopped giving it altogether.

I'd like to review what we know so that you can be prepared to answer questions and, I hope, alleviate fears about Gardasil and other recommended childhood and adolescent vaccines. A statement, issued jointly by the Centers for Disease Control and Prevention and the Food and Drug Administration, summarized all reports concerning Gardasil that were filed with the Vaccine Adverse Events Reporting System (VAERS) from the time the vaccine was licensed on June 8, 2006, through June 30, 2008.

A total of 9,749 adverse events were reported to VAERS in association with administration of Gardasil, of which 94% were classified as nonserious events, and 6% as serious events. It's important to keep in mind the denominator: At the time the statement was issued, Merck & Co. had distributed over 16 million doses of Gardasil in the United States.

Also remember that VAERS is a passive reporting system that receives unconfirmed reports of possible side effects following the use of all vaccines licensed in the United States.

Data from the system are reviewed on an ongoing basis to look for possible signals that require further investigation. Data from VAERS cannot and should not be viewed as implying causation.

The 9,164 nonserious reports included syncope, injection site pain, headache, nausea, and fever. Indeed, fainting after receipt of any vaccine is common among teenagers. Providers are reminded to keep patients seated for at least 15 minutes after vaccination to avoid injury from a possible fall.

The 585 serious adverse events included 20 deaths. There was no common pattern to these deaths that would suggest they were caused by the vaccine. Where autopsy results were available, the cause of death was unrelated to vaccine.

Other serious adverse event reports following receipt of Gardasil were attributable to Guillain-Barre Syndrome, a rare neurologic disorder for which the typical attack rate is highest during adolescence. Further investigation by FDA and CDC found no increase in GBS cases beyond the expected number among Gardasil recipients.

Thromboembolic disorders also were reported following vaccination with Gardasil, most of which occurred in individuals with risk factors for clotting, such as oral contraceptive use.

In addition to VAERS, there also is a safety monitoring system called the Vaccine Safety Datalink Project, a collaboration between CDC and eight managed care organizations that is set up to investigate any possible safety signals arising from VAERS. Gardasil and all other vaccines are monitored with these systems on an ongoing basis. In the meantime, the CDC has not made any changes to its recommendations for the use of Gardasil based on the available information, nor has the FDA revised its prescribing information.

Gardasil, the first HPV vaccine to be licensed, was approved for use in girls and women aged 9-26 years. It was recommended by the CDC's Advisory Committee on Immunization Practices (ACIP) as a three-dose series for routine vaccination of girls aged 11-12 years, and for catch-up in girls and women aged 13-26 years.

The vaccine is made from noninfectious particles, not live or attenuated virus. It contains no thimerosal. It protects against HPV strains 16 and 18, which cause 70% of all cervical cancers, and strains 6 and 11, responsible for 90% of all genital warts in the United States. Data show that the vaccine is most effective when given prior to onset of sexual activity.

When speaking with a worried parent, I think it's critical to explain that association does not imply causation. I also would review the rationale behind giving the HPV vaccine and reiterate that maximum benefit is achieved by immunization before sexual debut.

Every year, about 12,000 women in the United States are diagnosed with cervical cancer and almost 4,000 die from it. Worldwide, cervical cancer is the second most common cancer in women, causing an estimated 470,000 new cases and 233,000 deaths per year. I don't think you can put a price on the value of saving lives by administering a vaccine, although of course plenty of health economists have tried to do just that.

Going forward, I think it behooves physicians who administer vaccines to stay abreast of the news. When you see a headline about any vaccine, check out the Web sites of the CDC (www.cdc.govwww.aap.org

As we're seeing from the recent measles outbreaks across the country, the majority of cases are not the result of vaccine failure but of failure to vaccinate. Our role is to help parents make the right decision. We must be armed with data to prevent associations between daily events from being interpreted as causation.

I am a member of global advisory boards on vaccine for Novartis, Wyeth, and GlaxoSmithKline, for which I receive honoraria.

[email protected]

Since July 22nd, you have no doubt received phone calls from anxious parents who heard the news report about adverse events associated with the human papillomavirus vaccine, Gardasil. As usual, the media did a good job of creating anxiety both among parents and prescribing physicians. I've heard how much time clinicians now are spending discussing vaccine safety with their patients, and that some have begun administering the HPV vaccine separately from other recommended adolescent vaccines and others have just stopped giving it altogether.

I'd like to review what we know so that you can be prepared to answer questions and, I hope, alleviate fears about Gardasil and other recommended childhood and adolescent vaccines. A statement, issued jointly by the Centers for Disease Control and Prevention and the Food and Drug Administration, summarized all reports concerning Gardasil that were filed with the Vaccine Adverse Events Reporting System (VAERS) from the time the vaccine was licensed on June 8, 2006, through June 30, 2008.

A total of 9,749 adverse events were reported to VAERS in association with administration of Gardasil, of which 94% were classified as nonserious events, and 6% as serious events. It's important to keep in mind the denominator: At the time the statement was issued, Merck & Co. had distributed over 16 million doses of Gardasil in the United States.

Also remember that VAERS is a passive reporting system that receives unconfirmed reports of possible side effects following the use of all vaccines licensed in the United States.

Data from the system are reviewed on an ongoing basis to look for possible signals that require further investigation. Data from VAERS cannot and should not be viewed as implying causation.

The 9,164 nonserious reports included syncope, injection site pain, headache, nausea, and fever. Indeed, fainting after receipt of any vaccine is common among teenagers. Providers are reminded to keep patients seated for at least 15 minutes after vaccination to avoid injury from a possible fall.

The 585 serious adverse events included 20 deaths. There was no common pattern to these deaths that would suggest they were caused by the vaccine. Where autopsy results were available, the cause of death was unrelated to vaccine.

Other serious adverse event reports following receipt of Gardasil were attributable to Guillain-Barre Syndrome, a rare neurologic disorder for which the typical attack rate is highest during adolescence. Further investigation by FDA and CDC found no increase in GBS cases beyond the expected number among Gardasil recipients.

Thromboembolic disorders also were reported following vaccination with Gardasil, most of which occurred in individuals with risk factors for clotting, such as oral contraceptive use.

In addition to VAERS, there also is a safety monitoring system called the Vaccine Safety Datalink Project, a collaboration between CDC and eight managed care organizations that is set up to investigate any possible safety signals arising from VAERS. Gardasil and all other vaccines are monitored with these systems on an ongoing basis. In the meantime, the CDC has not made any changes to its recommendations for the use of Gardasil based on the available information, nor has the FDA revised its prescribing information.

Gardasil, the first HPV vaccine to be licensed, was approved for use in girls and women aged 9-26 years. It was recommended by the CDC's Advisory Committee on Immunization Practices (ACIP) as a three-dose series for routine vaccination of girls aged 11-12 years, and for catch-up in girls and women aged 13-26 years.

The vaccine is made from noninfectious particles, not live or attenuated virus. It contains no thimerosal. It protects against HPV strains 16 and 18, which cause 70% of all cervical cancers, and strains 6 and 11, responsible for 90% of all genital warts in the United States. Data show that the vaccine is most effective when given prior to onset of sexual activity.

When speaking with a worried parent, I think it's critical to explain that association does not imply causation. I also would review the rationale behind giving the HPV vaccine and reiterate that maximum benefit is achieved by immunization before sexual debut.

Every year, about 12,000 women in the United States are diagnosed with cervical cancer and almost 4,000 die from it. Worldwide, cervical cancer is the second most common cancer in women, causing an estimated 470,000 new cases and 233,000 deaths per year. I don't think you can put a price on the value of saving lives by administering a vaccine, although of course plenty of health economists have tried to do just that.

Going forward, I think it behooves physicians who administer vaccines to stay abreast of the news. When you see a headline about any vaccine, check out the Web sites of the CDC (www.cdc.govwww.aap.org

As we're seeing from the recent measles outbreaks across the country, the majority of cases are not the result of vaccine failure but of failure to vaccinate. Our role is to help parents make the right decision. We must be armed with data to prevent associations between daily events from being interpreted as causation.

I am a member of global advisory boards on vaccine for Novartis, Wyeth, and GlaxoSmithKline, for which I receive honoraria.

[email protected]

Since July 22nd, you have no doubt received phone calls from anxious parents who heard the news report about adverse events associated with the human papillomavirus vaccine, Gardasil. As usual, the media did a good job of creating anxiety both among parents and prescribing physicians. I've heard how much time clinicians now are spending discussing vaccine safety with their patients, and that some have begun administering the HPV vaccine separately from other recommended adolescent vaccines and others have just stopped giving it altogether.

I'd like to review what we know so that you can be prepared to answer questions and, I hope, alleviate fears about Gardasil and other recommended childhood and adolescent vaccines. A statement, issued jointly by the Centers for Disease Control and Prevention and the Food and Drug Administration, summarized all reports concerning Gardasil that were filed with the Vaccine Adverse Events Reporting System (VAERS) from the time the vaccine was licensed on June 8, 2006, through June 30, 2008.

A total of 9,749 adverse events were reported to VAERS in association with administration of Gardasil, of which 94% were classified as nonserious events, and 6% as serious events. It's important to keep in mind the denominator: At the time the statement was issued, Merck & Co. had distributed over 16 million doses of Gardasil in the United States.

Also remember that VAERS is a passive reporting system that receives unconfirmed reports of possible side effects following the use of all vaccines licensed in the United States.

Data from the system are reviewed on an ongoing basis to look for possible signals that require further investigation. Data from VAERS cannot and should not be viewed as implying causation.

The 9,164 nonserious reports included syncope, injection site pain, headache, nausea, and fever. Indeed, fainting after receipt of any vaccine is common among teenagers. Providers are reminded to keep patients seated for at least 15 minutes after vaccination to avoid injury from a possible fall.

The 585 serious adverse events included 20 deaths. There was no common pattern to these deaths that would suggest they were caused by the vaccine. Where autopsy results were available, the cause of death was unrelated to vaccine.

Other serious adverse event reports following receipt of Gardasil were attributable to Guillain-Barre Syndrome, a rare neurologic disorder for which the typical attack rate is highest during adolescence. Further investigation by FDA and CDC found no increase in GBS cases beyond the expected number among Gardasil recipients.

Thromboembolic disorders also were reported following vaccination with Gardasil, most of which occurred in individuals with risk factors for clotting, such as oral contraceptive use.

In addition to VAERS, there also is a safety monitoring system called the Vaccine Safety Datalink Project, a collaboration between CDC and eight managed care organizations that is set up to investigate any possible safety signals arising from VAERS. Gardasil and all other vaccines are monitored with these systems on an ongoing basis. In the meantime, the CDC has not made any changes to its recommendations for the use of Gardasil based on the available information, nor has the FDA revised its prescribing information.

Gardasil, the first HPV vaccine to be licensed, was approved for use in girls and women aged 9-26 years. It was recommended by the CDC's Advisory Committee on Immunization Practices (ACIP) as a three-dose series for routine vaccination of girls aged 11-12 years, and for catch-up in girls and women aged 13-26 years.

The vaccine is made from noninfectious particles, not live or attenuated virus. It contains no thimerosal. It protects against HPV strains 16 and 18, which cause 70% of all cervical cancers, and strains 6 and 11, responsible for 90% of all genital warts in the United States. Data show that the vaccine is most effective when given prior to onset of sexual activity.

When speaking with a worried parent, I think it's critical to explain that association does not imply causation. I also would review the rationale behind giving the HPV vaccine and reiterate that maximum benefit is achieved by immunization before sexual debut.

Every year, about 12,000 women in the United States are diagnosed with cervical cancer and almost 4,000 die from it. Worldwide, cervical cancer is the second most common cancer in women, causing an estimated 470,000 new cases and 233,000 deaths per year. I don't think you can put a price on the value of saving lives by administering a vaccine, although of course plenty of health economists have tried to do just that.

Going forward, I think it behooves physicians who administer vaccines to stay abreast of the news. When you see a headline about any vaccine, check out the Web sites of the CDC (www.cdc.govwww.aap.org

As we're seeing from the recent measles outbreaks across the country, the majority of cases are not the result of vaccine failure but of failure to vaccinate. Our role is to help parents make the right decision. We must be armed with data to prevent associations between daily events from being interpreted as causation.

I am a member of global advisory boards on vaccine for Novartis, Wyeth, and GlaxoSmithKline, for which I receive honoraria.

[email protected]

The data from three recent studies should prompt us to reexamine our approach to the management of upper respiratory infections in children.

Guidelines from the American Academy of Pediatrics recommend antimicrobial treatment for children with upper respiratory symptoms lasting longer than 10-14 days or for those with severe symptoms, including a high fever and toxicity (Pediatrics 2001;108:798-808). The Sinus and Allergy Health Partnership Guidelines—to which I contributed—also advised antimicrobial treatment for children with signs and symptoms of viral upper respiratory infection (URI) for more than 10 days or worsening symptoms after 5-7 days (Int. J. Pediatr. Otorhinolaryngol. 2002;63:1-13).

Now data suggest that we perhaps should consider antibiotic treatment only for children whose symptoms are worsening after 10 days.

The recommendation to treat rhinorrhea beyond 10 days with antibiotics as presumptive bacterial sinusitis requires a subjective judgment, and is based on small data sets.

This is problematic in an era in which we're trying to limit antimicrobial use to times when there is definite benefit. It's also been difficult to follow in practice, because parents often bring a child in who has had symptoms for fewer than 10 days. We're not supposed to treat at that point unless they have acute toxicity, but there can be a lot of real or perceived pressure to prescribe.

In fact, the 10-day rule appears to derive from a 40-year-old study on rhinovirus in adults (JAMA 1967;202;494-500). Surprisingly, it wasn't until earlier this year that good data became available regarding the symptom profile of colds in otherwise healthy school-aged children. In that study, which utilized nasopharyngeal aspirates and symptom diaries, 73% of 81 children with colds continued to be symptomatic 10 days after onset (Pediatr. Infect. Dis. J. 2008;27:8-11).

These new findings suggest we've probably been overtreating a proportion of school-aged children—for bacterial sinusitis—when they actually have had mild to moderate upper respiratory symptoms. Further, these data should provide reassurance that we're not putting such patients at risk for invasive complications if we don't treat before 10 days of illness, as long as they do not fit the acute severe criteria or the symptoms aren't getting rapidly worse.

Data from another recent study suggest that children with acute sinusitis who are destined to develop subperiosteal orbital abscess (SPA) typically do so well before 10 days of rhinorrhea. In this 10-year retrospective chart review from a tertiary pediatric center, 39 children required operative drainage for SPA, with only a mean of 1.6 days of antibiotics prediagnosis in just 10 (26%). Of the 28 children presenting with fever, the mean duration was 2.5 days. Only 28 had rhinorrhea/mucoid discharge, and that for a mean duration of 3.9 days (Int. J. Pediatr. Otorhinolaryngol. 2007;71:1003-6). Thus, complications arose in the first days of symptoms, even among those children on antibiotics.

Since it's not feasible—or wise—to give antibiotics to every child with cold symptoms in order to prevent SPA, the authors concluded that “SPA may not be a preventable complication of acute sinusitis in children” using standard oral antibiotics. Indeed, this paper suggests that children destined to develop complications are by and large not the ones who appear in your office with mild symptoms at days 4 to 7.

If the child has high fever and facial pain or swelling, there's little question you're going to treat. But for those without clear signs of toxicity or rapidly progressing disease, complications seem unlikely after 4 days.

A third study, of pneumococcal mastoiditis complicating acute otitis media (AOM), suggests that severe complications of URIs in children are becoming more difficult to treat with our usual oral drugs because of the emergence of multidrug-resistant pneumococcal serotype 19A, a strain that is not included in the 7-valent pneumococcal conjugate vaccine (PCV7).

Among 41 children with pneumococcal mastoiditis (mean age 23 months, range 3 months-12 years) who were seen at Texas Children's Hospital, Houston, between January 2005 and June 2007, 19 cases were caused by 19A. That strain was responsible for all cases of pneumococcal mastoiditis seen in 2006 and 2007, compared with just three of six seen between 2004 and 2005, and just one of two in 2003 (Pediatrics 2008;122:34-9).

Even more worrisome, all of the children with 19A mastoiditis had SPA, compared with only 2 of the 22 children with non-19A mastoiditis. Mastoidectomy was required in 17 of the 19A group (89%) compared with just 10 (45%) of those with non-19A strains. Thirteen of the 19A isolates (68%) were resistant to all antibiotics tested routinely.

These data correspond to what I've been seeing at my institution. We're seeing less otitis and sinusitis overall since the introduction of PCV7 in 2000. A concern in the last 2-3 years is that the incidence of difficult-to-treat pneumococcal mastoiditis—nearly all due to 19A—has risen among the difficult-to-treat AOM that does occur. In fact, I'm now seeing as much serious invasive pneumococcal disease as before PCV7 was licensed, nearly half due to 19A.

I believe there are two messages here. First, if you withhold antibiotics for 10 days in a nontoxic child with rhinorrhea, according to the guidelines, you probably aren't putting him or her at any greater risk for complicated sinus disease; even treating then is likely to overtreat a proportion of children. Second, we may need a new strategy for persistent or complicated AOM when 19A is the pathogen. These cases may not even respond to clindamycin or three doses of ceftriaxone and may require linezolid or a quinolone (JAMA 2007;298:1772-8) despite the new Food and Drug Administration black box warning on quinolones, usually along with a subspecialty consultation.

But there is hope on the horizon. Wyeth Pharmaceuticals, which partially funded the Texas mastoiditis study, announced at the end of May that the FDA has granted fast-track designation to the company's investigational 13-valent pneumococcal conjugate vaccine for infants and toddlers. That vaccine contains 19A as well as serotypes 1 and 3, the most common causes of empyema.

It's becoming obvious that we will need to stay ahead of the game from now on. Ongoing surveillance will be critical as we move forward.

I have no current disclosures for any products mentioned in this article.

[email protected]

The data from three recent studies should prompt us to reexamine our approach to the management of upper respiratory infections in children.

Guidelines from the American Academy of Pediatrics recommend antimicrobial treatment for children with upper respiratory symptoms lasting longer than 10-14 days or for those with severe symptoms, including a high fever and toxicity (Pediatrics 2001;108:798-808). The Sinus and Allergy Health Partnership Guidelines—to which I contributed—also advised antimicrobial treatment for children with signs and symptoms of viral upper respiratory infection (URI) for more than 10 days or worsening symptoms after 5-7 days (Int. J. Pediatr. Otorhinolaryngol. 2002;63:1-13).

Now data suggest that we perhaps should consider antibiotic treatment only for children whose symptoms are worsening after 10 days.

The recommendation to treat rhinorrhea beyond 10 days with antibiotics as presumptive bacterial sinusitis requires a subjective judgment, and is based on small data sets.

This is problematic in an era in which we're trying to limit antimicrobial use to times when there is definite benefit. It's also been difficult to follow in practice, because parents often bring a child in who has had symptoms for fewer than 10 days. We're not supposed to treat at that point unless they have acute toxicity, but there can be a lot of real or perceived pressure to prescribe.

In fact, the 10-day rule appears to derive from a 40-year-old study on rhinovirus in adults (JAMA 1967;202;494-500). Surprisingly, it wasn't until earlier this year that good data became available regarding the symptom profile of colds in otherwise healthy school-aged children. In that study, which utilized nasopharyngeal aspirates and symptom diaries, 73% of 81 children with colds continued to be symptomatic 10 days after onset (Pediatr. Infect. Dis. J. 2008;27:8-11).

These new findings suggest we've probably been overtreating a proportion of school-aged children—for bacterial sinusitis—when they actually have had mild to moderate upper respiratory symptoms. Further, these data should provide reassurance that we're not putting such patients at risk for invasive complications if we don't treat before 10 days of illness, as long as they do not fit the acute severe criteria or the symptoms aren't getting rapidly worse.

Data from another recent study suggest that children with acute sinusitis who are destined to develop subperiosteal orbital abscess (SPA) typically do so well before 10 days of rhinorrhea. In this 10-year retrospective chart review from a tertiary pediatric center, 39 children required operative drainage for SPA, with only a mean of 1.6 days of antibiotics prediagnosis in just 10 (26%). Of the 28 children presenting with fever, the mean duration was 2.5 days. Only 28 had rhinorrhea/mucoid discharge, and that for a mean duration of 3.9 days (Int. J. Pediatr. Otorhinolaryngol. 2007;71:1003-6). Thus, complications arose in the first days of symptoms, even among those children on antibiotics.

Since it's not feasible—or wise—to give antibiotics to every child with cold symptoms in order to prevent SPA, the authors concluded that “SPA may not be a preventable complication of acute sinusitis in children” using standard oral antibiotics. Indeed, this paper suggests that children destined to develop complications are by and large not the ones who appear in your office with mild symptoms at days 4 to 7.

If the child has high fever and facial pain or swelling, there's little question you're going to treat. But for those without clear signs of toxicity or rapidly progressing disease, complications seem unlikely after 4 days.

A third study, of pneumococcal mastoiditis complicating acute otitis media (AOM), suggests that severe complications of URIs in children are becoming more difficult to treat with our usual oral drugs because of the emergence of multidrug-resistant pneumococcal serotype 19A, a strain that is not included in the 7-valent pneumococcal conjugate vaccine (PCV7).

Among 41 children with pneumococcal mastoiditis (mean age 23 months, range 3 months-12 years) who were seen at Texas Children's Hospital, Houston, between January 2005 and June 2007, 19 cases were caused by 19A. That strain was responsible for all cases of pneumococcal mastoiditis seen in 2006 and 2007, compared with just three of six seen between 2004 and 2005, and just one of two in 2003 (Pediatrics 2008;122:34-9).

Even more worrisome, all of the children with 19A mastoiditis had SPA, compared with only 2 of the 22 children with non-19A mastoiditis. Mastoidectomy was required in 17 of the 19A group (89%) compared with just 10 (45%) of those with non-19A strains. Thirteen of the 19A isolates (68%) were resistant to all antibiotics tested routinely.

These data correspond to what I've been seeing at my institution. We're seeing less otitis and sinusitis overall since the introduction of PCV7 in 2000. A concern in the last 2-3 years is that the incidence of difficult-to-treat pneumococcal mastoiditis—nearly all due to 19A—has risen among the difficult-to-treat AOM that does occur. In fact, I'm now seeing as much serious invasive pneumococcal disease as before PCV7 was licensed, nearly half due to 19A.

I believe there are two messages here. First, if you withhold antibiotics for 10 days in a nontoxic child with rhinorrhea, according to the guidelines, you probably aren't putting him or her at any greater risk for complicated sinus disease; even treating then is likely to overtreat a proportion of children. Second, we may need a new strategy for persistent or complicated AOM when 19A is the pathogen. These cases may not even respond to clindamycin or three doses of ceftriaxone and may require linezolid or a quinolone (JAMA 2007;298:1772-8) despite the new Food and Drug Administration black box warning on quinolones, usually along with a subspecialty consultation.

But there is hope on the horizon. Wyeth Pharmaceuticals, which partially funded the Texas mastoiditis study, announced at the end of May that the FDA has granted fast-track designation to the company's investigational 13-valent pneumococcal conjugate vaccine for infants and toddlers. That vaccine contains 19A as well as serotypes 1 and 3, the most common causes of empyema.

It's becoming obvious that we will need to stay ahead of the game from now on. Ongoing surveillance will be critical as we move forward.

I have no current disclosures for any products mentioned in this article.

[email protected]

The data from three recent studies should prompt us to reexamine our approach to the management of upper respiratory infections in children.

Guidelines from the American Academy of Pediatrics recommend antimicrobial treatment for children with upper respiratory symptoms lasting longer than 10-14 days or for those with severe symptoms, including a high fever and toxicity (Pediatrics 2001;108:798-808). The Sinus and Allergy Health Partnership Guidelines—to which I contributed—also advised antimicrobial treatment for children with signs and symptoms of viral upper respiratory infection (URI) for more than 10 days or worsening symptoms after 5-7 days (Int. J. Pediatr. Otorhinolaryngol. 2002;63:1-13).

Now data suggest that we perhaps should consider antibiotic treatment only for children whose symptoms are worsening after 10 days.

The recommendation to treat rhinorrhea beyond 10 days with antibiotics as presumptive bacterial sinusitis requires a subjective judgment, and is based on small data sets.

This is problematic in an era in which we're trying to limit antimicrobial use to times when there is definite benefit. It's also been difficult to follow in practice, because parents often bring a child in who has had symptoms for fewer than 10 days. We're not supposed to treat at that point unless they have acute toxicity, but there can be a lot of real or perceived pressure to prescribe.

In fact, the 10-day rule appears to derive from a 40-year-old study on rhinovirus in adults (JAMA 1967;202;494-500). Surprisingly, it wasn't until earlier this year that good data became available regarding the symptom profile of colds in otherwise healthy school-aged children. In that study, which utilized nasopharyngeal aspirates and symptom diaries, 73% of 81 children with colds continued to be symptomatic 10 days after onset (Pediatr. Infect. Dis. J. 2008;27:8-11).

These new findings suggest we've probably been overtreating a proportion of school-aged children—for bacterial sinusitis—when they actually have had mild to moderate upper respiratory symptoms. Further, these data should provide reassurance that we're not putting such patients at risk for invasive complications if we don't treat before 10 days of illness, as long as they do not fit the acute severe criteria or the symptoms aren't getting rapidly worse.

Data from another recent study suggest that children with acute sinusitis who are destined to develop subperiosteal orbital abscess (SPA) typically do so well before 10 days of rhinorrhea. In this 10-year retrospective chart review from a tertiary pediatric center, 39 children required operative drainage for SPA, with only a mean of 1.6 days of antibiotics prediagnosis in just 10 (26%). Of the 28 children presenting with fever, the mean duration was 2.5 days. Only 28 had rhinorrhea/mucoid discharge, and that for a mean duration of 3.9 days (Int. J. Pediatr. Otorhinolaryngol. 2007;71:1003-6). Thus, complications arose in the first days of symptoms, even among those children on antibiotics.

Since it's not feasible—or wise—to give antibiotics to every child with cold symptoms in order to prevent SPA, the authors concluded that “SPA may not be a preventable complication of acute sinusitis in children” using standard oral antibiotics. Indeed, this paper suggests that children destined to develop complications are by and large not the ones who appear in your office with mild symptoms at days 4 to 7.

If the child has high fever and facial pain or swelling, there's little question you're going to treat. But for those without clear signs of toxicity or rapidly progressing disease, complications seem unlikely after 4 days.

A third study, of pneumococcal mastoiditis complicating acute otitis media (AOM), suggests that severe complications of URIs in children are becoming more difficult to treat with our usual oral drugs because of the emergence of multidrug-resistant pneumococcal serotype 19A, a strain that is not included in the 7-valent pneumococcal conjugate vaccine (PCV7).

Among 41 children with pneumococcal mastoiditis (mean age 23 months, range 3 months-12 years) who were seen at Texas Children's Hospital, Houston, between January 2005 and June 2007, 19 cases were caused by 19A. That strain was responsible for all cases of pneumococcal mastoiditis seen in 2006 and 2007, compared with just three of six seen between 2004 and 2005, and just one of two in 2003 (Pediatrics 2008;122:34-9).

Even more worrisome, all of the children with 19A mastoiditis had SPA, compared with only 2 of the 22 children with non-19A mastoiditis. Mastoidectomy was required in 17 of the 19A group (89%) compared with just 10 (45%) of those with non-19A strains. Thirteen of the 19A isolates (68%) were resistant to all antibiotics tested routinely.

These data correspond to what I've been seeing at my institution. We're seeing less otitis and sinusitis overall since the introduction of PCV7 in 2000. A concern in the last 2-3 years is that the incidence of difficult-to-treat pneumococcal mastoiditis—nearly all due to 19A—has risen among the difficult-to-treat AOM that does occur. In fact, I'm now seeing as much serious invasive pneumococcal disease as before PCV7 was licensed, nearly half due to 19A.

I believe there are two messages here. First, if you withhold antibiotics for 10 days in a nontoxic child with rhinorrhea, according to the guidelines, you probably aren't putting him or her at any greater risk for complicated sinus disease; even treating then is likely to overtreat a proportion of children. Second, we may need a new strategy for persistent or complicated AOM when 19A is the pathogen. These cases may not even respond to clindamycin or three doses of ceftriaxone and may require linezolid or a quinolone (JAMA 2007;298:1772-8) despite the new Food and Drug Administration black box warning on quinolones, usually along with a subspecialty consultation.

But there is hope on the horizon. Wyeth Pharmaceuticals, which partially funded the Texas mastoiditis study, announced at the end of May that the FDA has granted fast-track designation to the company's investigational 13-valent pneumococcal conjugate vaccine for infants and toddlers. That vaccine contains 19A as well as serotypes 1 and 3, the most common causes of empyema.

It's becoming obvious that we will need to stay ahead of the game from now on. Ongoing surveillance will be critical as we move forward.

I have no current disclosures for any products mentioned in this article.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.

[email protected]

Innovative vaccines in the pipeline offer needleless alternatives that will help alleviate the human pincushion problem as well as facilitate immunization in the developing world.

Transdermal patches, oral administration via food or drink, and new intranasal vaccines are three exciting technologies that I foresee becoming available within the next 2-5 years.

Such alternative vaccine delivery systems are particularly critical in the developing world, where shortages of needles, contamination problems, and lack of trained personnel often make injections risky or impossible.

And of course, injections are uncomfortable no matter where in the world you happen to be.

It's logical to assume that one would target an infection that enters the body through the respiratory tract by an intranasal vaccine, while gastrointestinal pathogens would be more amenable to vaccines delivered orally.

However, that's not necessarily the case. Intranasal vaccine administration could be used for gastrointestinal pathogens, and oral administration for respiratory ones, because the process proceeds in the same fashion once the antigen gains access to the antigen-presenting cells and is taken to the B cells and T cells in the lymph nodes and spleen. And of course, antigens delivered via patch can go anywhere once they are delivered to the regional lymph nodes draining the skin.

Typically, these new technologies are developed with venture capital by small firms and, if successful, get picked up by the larger vaccine manufacturers.

The latest buzz has come from a recent phase II randomized, double-blind, placebo-controlled field trial of a traveler's diarrhea vaccine skin patch that contains heat-labile enterotoxin (LT) from Escherichia coli.

Of 201 healthy adults who were planning trips to either Mexico or Guatemala, 67 were randomized to receive the LT patch and 134 assigned placebo. A total of 59 received a second LT patch and completed in-country surveillance, as did 111 who received a second placebo patch. Patches were worn for about 6 hours and then discarded, at 3 weeks and 1 week prior to travel. The average stay in Mexico or Guatemala was 12.4 days (Lancet 2008;371:2019-25).

The results were promising: The proportion of individuals with diarrhea of any cause–as recorded in diary cards–was 15% with the LT patch, compared with 22% with placebo. Severe diarrhea occurred in 2% vs. 11%. The proportions with diarrhea caused by enterotoxigenic Escherichia coli (ETEC) were 5% with the LT vaccine patch vs. 10% with placebo, for a protective efficacy of 49%. For severe diarrhea, those proportions were 5% vs. 2%, translating to 62% protective efficacy.

Moreover, those who did develop diarrhea with the LT patch had a milder course of disease, with a mean stool frequency of 3.7 per episode, compared with 10.5 with placebo. Duration of diarrhea was also much less, 0.5 vs. 2.1 days. For ETEC diarrhea, the frequencies were 4.3 vs. 10.5 per episode, and the duration 0.4 vs. 2.2 days.

As it turns out, patches are very attractive delivery systems for vaccines because they introduce the antigens just below the epidermis. This local epidermal delivery appears to produce a more robust immune response than does an intramuscular injection.

On the downside, patches do involve greater potential for local site irritation. In the ETEC patch trial, application of the patch–which involves scraping the skin with a mild abrasive prior to affixing the patch–caused local pruritus in 67% vs. 4% with placebo, rash in 61% vs. 1%, respectively, and pigmentation changes in 7% vs. 0. However, there were no significant differences in systemic events such as fever, malaise, or headache. In my view, the local irritation is minor, compared with the benefits of needleless technology.

Patch technology also is being studied for the prevention of disease caused by a variety of other pathogens, including tetanus and Helicobacter pylori.

I'm also excited about the use of transgenic plants such as potatoes and corn as another alternative vaccine delivery method. Thus far in early human trials of diarrheal diseases, transgenic plant-derived vaccines appear to be safe and immunogenic without the need for a buffer or vehicle other than the plant cell.

Among these are transgenic potatoes and corn that express the B subunit of the ETEC toxin, another transgenic potato that expresses the hepatitis B surface antigen, and a third, the capsid protein of norovirus (NV).

In a study of the last, 24 healthy adult volunteers were randomly assigned to one of three regimens: Three doses of transgenic potato expressing NV capsid protein on days 0, 7, and 21, two doses of the transgenic potato on days 0 and 21 plus a dose of wild-type potato on day 7, or three doses of wild-type potato on days 0, 7, and 21. The potatoes were peeled and diced and ingested raw on the day of vaccination.

The volunteers in all three studies completed a diary each day for 7 days after ingesting each dose to record the occurrence of nausea, vomiting, cramps, diarrhea, or other symptoms. Blood was collected before and at 7, 14, 21, 28, and 60 days after the first dose of transgenic plant for measurement of serum antibodies to LT or NV capsid protein. Whole blood was collected for antibody-secreting cell assays on days 0, 7, 14, 21, and 28 (J. Infect. Dis. 2000;182:302-5).

Nineteen of the 20 subjects who ingested transgenic potatoes developed significant increases in the numbers of specific IgA antibody-secreting cells, 4 developed specific serum IgG, and 6 developed specific stool IgA.

Overall, 19 of 20 subjects developed an immune response of some kind, although the level of serum antibody increases was modest.

As for the intranasal route, my lab under National Institutes of Health-funded grants is working on anthrax, botulism, and tularemia in the bioterrorism arena.

Others are investigating intranasal vaccines against respiratory syncytial virus.

I doubt that companies will attempt to transition already-existing injectable vaccines to other modes of delivery, with a few exceptions like those for tetanus and hepatitis B. Rather, I think that much of this work will apply to the prevention of diseases that we currently are unable to prevent, both here and in the developing world.

I have no financial relationships with any of the companies developing these alternative vaccines.

We're starting to see the first evidence that rotavirus disease rates are going down, perhaps even more than we expected, thanks to the vaccine.

Although rates of both respiratory syncytial virus and influenza were up this past winter, compared with the previous couple of years, it's been very gratifying for the infectious disease community to see, for the first time, a paucity of rotavirus cases.

As every practitioner who treats children knows, rotavirus is the most common cause of severe wintertime gastroenteritis among children younger than 5 years. The numbers have stayed consistent: Every year, approximately 3 million children get rotavirus disease, about 700,000 seek health care for it, 250,000 present to the emergency department, 50,000 are admitted, and a small number (20–60) die. A recent analysis from the Centers for Disease Control and Prevention (CDC) showed that the total annual cost to society from rotavirus in the United States (in 2004 dollars) was $893 million, $319 million of which was to the health care system (Pediatrics 2007;119:684–97).

A previous oral rotavirus vaccine—the tetravalent rhesus vaccine, RotaShield—was removed from the market in 1999 because of a detected increase in intussusception after about a half-million children had received one or more doses. In February 2006, Rotateq—a new live, oral pentavalent human-bovine reassortment rotavirus vaccine (Merck & Co.)—was licensed and recommended. I'm excited about preliminary numbers, which suggest that rotavirus immunization may be more successful than predicted.

Here at Children's Mercy Hospital in Kansas City (317 beds/14,000 annual admissions), we test only the sickest children for rotavirus. During the 2006 rotavirus season, we tested 1,009 and got 514 positives (51%). In 2007, we had 686 positives out of 1,271 tested (54%)—not much different. We wouldn't have expected an impact that soon after the vaccine was licensed.

This year, however, we saw a dramatic change. Only 495 children presented with gastroenteritis who were sick enough to prompt testing, and of those, just 93 (19%) were positive. Even more amazing, only 38 children were admitted to the hospital, which represented a 10-fold decrease, compared with previous years. What happened to all our rotavirus cases?

This finding is even more remarkable when you look at how consistent our rotavirus disease rates have been over time. Last year, we combined our rotavirus data for the years 2000–2005 with those from Children's Hospital of Philadelphia (CHOP) from 2004–2006 and reported that approximately half of children admitted with severe diarrhea were tested for rotavirus (47% of 2,552 children at Mercy and 56% of 779 at CHOP). Of those, 71% of our 1,197 and 55% of CHOP's 438 were positive (Pediatr. Infect. Dis. J. 2007;26:914–9).

We haven't changed anything about our testing or admitting practices since those data were collected, which strongly suggests that our new numbers represent a real drop.

Moreover, if you look at the CDC's rotavirus surveillance data (www.cdc.gov/rotavirus

If nationwide surveillance data continue to bear out what we've seen at my hospital, the vaccine's impact will have far exceeded expectations. In the CDC cost analysis I mentioned earlier, investigators estimated that if vaccine coverage were equivalent to current national estimates for other vaccines such as diphtheria-tetanus-acellular pertussis—which is probably a big overestimate—a routine rotavirus vaccination program would prevent 51% of all cases of rotavirus gastroenteritis and 64% of all serious cases, including rotavirus-related hospitalization and emergency department visits.

Our 86% decrease (93 cases this year vs. 686 in 2007) is far greater than predicted by the CDC's analysis. Although viral shedding of the rotavirus vaccine is nowhere near what we used to see with oral polio vaccine, there is evidence that it occurs. In one study, fecal shedding of vaccine-virus strains was found in 8.9% of 360 recipients after the first dose (Int. J. Infect. Dis. 2007;11[Suppl 2]:S36–42), which raises the question of possible herd immunity.

Now, with the recent approval of Rotarix (GlaxoSmithKline)—another oral rotavirus vaccine that is given in two doses, compared with Rotateq's three—I'm optimistic that there will be more good news in the battle against this common childhood infection. Can you imagine the day when a pediatric resident will not see a hospitalized child who has rotavirus infection during the winter months?

I have no financial relationships with either Merck or GSK.

We're starting to see the first evidence that rotavirus disease rates are going down, perhaps even more than we expected, thanks to the vaccine.

Although rates of both respiratory syncytial virus and influenza were up this past winter, compared with the previous couple of years, it's been very gratifying for the infectious disease community to see, for the first time, a paucity of rotavirus cases.

As every practitioner who treats children knows, rotavirus is the most common cause of severe wintertime gastroenteritis among children younger than 5 years. The numbers have stayed consistent: Every year, approximately 3 million children get rotavirus disease, about 700,000 seek health care for it, 250,000 present to the emergency department, 50,000 are admitted, and a small number (20–60) die. A recent analysis from the Centers for Disease Control and Prevention (CDC) showed that the total annual cost to society from rotavirus in the United States (in 2004 dollars) was $893 million, $319 million of which was to the health care system (Pediatrics 2007;119:684–97).

A previous oral rotavirus vaccine—the tetravalent rhesus vaccine, RotaShield—was removed from the market in 1999 because of a detected increase in intussusception after about a half-million children had received one or more doses. In February 2006, Rotateq—a new live, oral pentavalent human-bovine reassortment rotavirus vaccine (Merck & Co.)—was licensed and recommended. I'm excited about preliminary numbers, which suggest that rotavirus immunization may be more successful than predicted.

Here at Children's Mercy Hospital in Kansas City (317 beds/14,000 annual admissions), we test only the sickest children for rotavirus. During the 2006 rotavirus season, we tested 1,009 and got 514 positives (51%). In 2007, we had 686 positives out of 1,271 tested (54%)—not much different. We wouldn't have expected an impact that soon after the vaccine was licensed.

This year, however, we saw a dramatic change. Only 495 children presented with gastroenteritis who were sick enough to prompt testing, and of those, just 93 (19%) were positive. Even more amazing, only 38 children were admitted to the hospital, which represented a 10-fold decrease, compared with previous years. What happened to all our rotavirus cases?

This finding is even more remarkable when you look at how consistent our rotavirus disease rates have been over time. Last year, we combined our rotavirus data for the years 2000–2005 with those from Children's Hospital of Philadelphia (CHOP) from 2004–2006 and reported that approximately half of children admitted with severe diarrhea were tested for rotavirus (47% of 2,552 children at Mercy and 56% of 779 at CHOP). Of those, 71% of our 1,197 and 55% of CHOP's 438 were positive (Pediatr. Infect. Dis. J. 2007;26:914–9).

We haven't changed anything about our testing or admitting practices since those data were collected, which strongly suggests that our new numbers represent a real drop.

Moreover, if you look at the CDC's rotavirus surveillance data (www.cdc.gov/rotavirus

If nationwide surveillance data continue to bear out what we've seen at my hospital, the vaccine's impact will have far exceeded expectations. In the CDC cost analysis I mentioned earlier, investigators estimated that if vaccine coverage were equivalent to current national estimates for other vaccines such as diphtheria-tetanus-acellular pertussis—which is probably a big overestimate—a routine rotavirus vaccination program would prevent 51% of all cases of rotavirus gastroenteritis and 64% of all serious cases, including rotavirus-related hospitalization and emergency department visits.

Our 86% decrease (93 cases this year vs. 686 in 2007) is far greater than predicted by the CDC's analysis. Although viral shedding of the rotavirus vaccine is nowhere near what we used to see with oral polio vaccine, there is evidence that it occurs. In one study, fecal shedding of vaccine-virus strains was found in 8.9% of 360 recipients after the first dose (Int. J. Infect. Dis. 2007;11[Suppl 2]:S36–42), which raises the question of possible herd immunity.

Now, with the recent approval of Rotarix (GlaxoSmithKline)—another oral rotavirus vaccine that is given in two doses, compared with Rotateq's three—I'm optimistic that there will be more good news in the battle against this common childhood infection. Can you imagine the day when a pediatric resident will not see a hospitalized child who has rotavirus infection during the winter months?

I have no financial relationships with either Merck or GSK.

We're starting to see the first evidence that rotavirus disease rates are going down, perhaps even more than we expected, thanks to the vaccine.

Although rates of both respiratory syncytial virus and influenza were up this past winter, compared with the previous couple of years, it's been very gratifying for the infectious disease community to see, for the first time, a paucity of rotavirus cases.

As every practitioner who treats children knows, rotavirus is the most common cause of severe wintertime gastroenteritis among children younger than 5 years. The numbers have stayed consistent: Every year, approximately 3 million children get rotavirus disease, about 700,000 seek health care for it, 250,000 present to the emergency department, 50,000 are admitted, and a small number (20–60) die. A recent analysis from the Centers for Disease Control and Prevention (CDC) showed that the total annual cost to society from rotavirus in the United States (in 2004 dollars) was $893 million, $319 million of which was to the health care system (Pediatrics 2007;119:684–97).

A previous oral rotavirus vaccine—the tetravalent rhesus vaccine, RotaShield—was removed from the market in 1999 because of a detected increase in intussusception after about a half-million children had received one or more doses. In February 2006, Rotateq—a new live, oral pentavalent human-bovine reassortment rotavirus vaccine (Merck & Co.)—was licensed and recommended. I'm excited about preliminary numbers, which suggest that rotavirus immunization may be more successful than predicted.

Here at Children's Mercy Hospital in Kansas City (317 beds/14,000 annual admissions), we test only the sickest children for rotavirus. During the 2006 rotavirus season, we tested 1,009 and got 514 positives (51%). In 2007, we had 686 positives out of 1,271 tested (54%)—not much different. We wouldn't have expected an impact that soon after the vaccine was licensed.

This year, however, we saw a dramatic change. Only 495 children presented with gastroenteritis who were sick enough to prompt testing, and of those, just 93 (19%) were positive. Even more amazing, only 38 children were admitted to the hospital, which represented a 10-fold decrease, compared with previous years. What happened to all our rotavirus cases?

This finding is even more remarkable when you look at how consistent our rotavirus disease rates have been over time. Last year, we combined our rotavirus data for the years 2000–2005 with those from Children's Hospital of Philadelphia (CHOP) from 2004–2006 and reported that approximately half of children admitted with severe diarrhea were tested for rotavirus (47% of 2,552 children at Mercy and 56% of 779 at CHOP). Of those, 71% of our 1,197 and 55% of CHOP's 438 were positive (Pediatr. Infect. Dis. J. 2007;26:914–9).

We haven't changed anything about our testing or admitting practices since those data were collected, which strongly suggests that our new numbers represent a real drop.

Moreover, if you look at the CDC's rotavirus surveillance data (www.cdc.gov/rotavirus

If nationwide surveillance data continue to bear out what we've seen at my hospital, the vaccine's impact will have far exceeded expectations. In the CDC cost analysis I mentioned earlier, investigators estimated that if vaccine coverage were equivalent to current national estimates for other vaccines such as diphtheria-tetanus-acellular pertussis—which is probably a big overestimate—a routine rotavirus vaccination program would prevent 51% of all cases of rotavirus gastroenteritis and 64% of all serious cases, including rotavirus-related hospitalization and emergency department visits.

Our 86% decrease (93 cases this year vs. 686 in 2007) is far greater than predicted by the CDC's analysis. Although viral shedding of the rotavirus vaccine is nowhere near what we used to see with oral polio vaccine, there is evidence that it occurs. In one study, fecal shedding of vaccine-virus strains was found in 8.9% of 360 recipients after the first dose (Int. J. Infect. Dis. 2007;11[Suppl 2]:S36–42), which raises the question of possible herd immunity.

Now, with the recent approval of Rotarix (GlaxoSmithKline)—another oral rotavirus vaccine that is given in two doses, compared with Rotateq's three—I'm optimistic that there will be more good news in the battle against this common childhood infection. Can you imagine the day when a pediatric resident will not see a hospitalized child who has rotavirus infection during the winter months?

I have no financial relationships with either Merck or GSK.

[email protected]

The pediatric and family medicine communities need to do a better job of assessing sexual activity in adolescent patients, screening sexually active teens for sexually transmitted diseases, and counseling them about how to avoid becoming infected in the future.

Recently, a report of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) revealed that one in four American teenagers had at least one prior sexually transmitted disease (STD). This should provide strong support for clinicians to incorporate guidelines from the Centers for Disease Control and Prevention and the American Academy of Pediatrics into their practices.

The survey found that 26% of a nationally representative sample of 838 adolescent girls aged 14–19 years were infected with at least one STD, while 15% had more than one. For the entire U.S. population, this translates to more than 3.2 million adolescent girls with human papillomavirus, chlamydia, herpes simplex virus, and/or trichomonas infections. The analysis excluded the prevalence of gonorrhea, syphilis, and HIV infections, although of course our adolescent population can contract those as well.

The data confirm that although the rate of teen pregnancy has recently declined, adolescent sexual behavior remains prevalent. While I'm not aware of data regarding the reasons for the drop in pregnancies among teens, I suspect that it's due at least in part to increased use of birth control, as well as abortion, rather than a large shift away from sexual behavior.

Indeed, teenagers—and even some preteens—are having sex. Clinicians need to ask adolescent patients if they are engaging in sexual behavior, and if so, to test them annually for STDs, screen for HIV (“Screen Sexually Active Teens for HIV,” PEDIATRIC NEWS, February 2007, p. 20) and counsel those who choose sexual activity about how to approach it safely and responsibly. And we need to start early. The CDC found that these infections, especially HPV, occur quickly after sexual debut. In fact, the STD prevalence was already 20% among those who reported just 1 year of sexual activity.

While there were racial differences—48% of black teens had at least one STD, compared with 20% of white teens—we should never assume that any early sexual activity is limited to specific racial or socioeconomic groups. This is an issue for every clinician, whether you practice in an urban, suburban, small-town, or rural setting. Yes, some of your patients are at greater risk than others—but you can't be sure which ones without asking about sexual activity.

Screening should take place annually at routine visits as well as at acute care visits whenever possible. Particularly in the adolescent age group, I think we need to take advantage of every opportunity. Specifically, teens should be asked if they're sexually active, and if so, what kind of activity they engage in, whether it is with members of their own or the opposite gender, and whether they use barrier protection (condoms).

All sexually active teens should be counseled about the importance of condoms and their proper use. For a variety of reasons, condom use is currently quite low among adolescents. Teen boys often don't want to use them because they decrease sensitivity or simply aren't seen as “manly.” An excellent resource for how to talk to teens about condoms is available at www.hws.wsu.edu/healthycoug/Men/condoms.html

Sexually active females should be screened yearly for Neisseria gonorrhoeae and Chlamydia trachomatis using a cervical or urine GC/CT nucleic acid amplification test, with urine being the preferred method today.

For males who have had sex with other males in the past year, an annual RPR (rapid plasma reagin) test for syphilis is recommended, along with annual pharyngeal gonorrhea cultures for those who have engaged in oral sex and rectal GC/CT swabs for those engaging in receptive anal intercourse. Although there are no specific recommendations for heterosexual males, we have learned that STDs can be asymptomatic. Personally I think screening is appropriate because it can be done easily with a urine specimen.

Recent CDC guidelines recommend that all sexually active individuals be screened annually for HIV, beginning at age 13. I endorse that recommendation, although many states have maintained the requirement for written informed consent for HIV testing, which places a barrier to proceeding. At least now all 50 states allow adolescents to sign their own consent forms without the need for a parental signature.

Although screening for HPV is not recommended, we can now offer the HPV vaccine to all of our female patients prior to sexual debut. Potentially, we will soon be able to offer it to our male patients as well.

Finally, I think we also should make an effort to encourage abstinence among our adolescent patients who have not yet embarked on sexual activity. I recently read an article about a female Harvard student who said she felt isolated because she had chosen to abstain from casual sex and decided to form a support group for like-minded young people. Contrary to popular belief, not every adolescent or young adult who chooses to abstain from casual sex or sex in general is of a strict religious or right-wing persuasion. Some have simply weighed the risks and benefits for themselves, and decided it's not right for them at this early stage in their lives.

[email protected]

The pediatric and family medicine communities need to do a better job of assessing sexual activity in adolescent patients, screening sexually active teens for sexually transmitted diseases, and counseling them about how to avoid becoming infected in the future.

Recently, a report of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) revealed that one in four American teenagers had at least one prior sexually transmitted disease (STD). This should provide strong support for clinicians to incorporate guidelines from the Centers for Disease Control and Prevention and the American Academy of Pediatrics into their practices.

The survey found that 26% of a nationally representative sample of 838 adolescent girls aged 14–19 years were infected with at least one STD, while 15% had more than one. For the entire U.S. population, this translates to more than 3.2 million adolescent girls with human papillomavirus, chlamydia, herpes simplex virus, and/or trichomonas infections. The analysis excluded the prevalence of gonorrhea, syphilis, and HIV infections, although of course our adolescent population can contract those as well.

The data confirm that although the rate of teen pregnancy has recently declined, adolescent sexual behavior remains prevalent. While I'm not aware of data regarding the reasons for the drop in pregnancies among teens, I suspect that it's due at least in part to increased use of birth control, as well as abortion, rather than a large shift away from sexual behavior.

Indeed, teenagers—and even some preteens—are having sex. Clinicians need to ask adolescent patients if they are engaging in sexual behavior, and if so, to test them annually for STDs, screen for HIV (“Screen Sexually Active Teens for HIV,” PEDIATRIC NEWS, February 2007, p. 20) and counsel those who choose sexual activity about how to approach it safely and responsibly. And we need to start early. The CDC found that these infections, especially HPV, occur quickly after sexual debut. In fact, the STD prevalence was already 20% among those who reported just 1 year of sexual activity.

While there were racial differences—48% of black teens had at least one STD, compared with 20% of white teens—we should never assume that any early sexual activity is limited to specific racial or socioeconomic groups. This is an issue for every clinician, whether you practice in an urban, suburban, small-town, or rural setting. Yes, some of your patients are at greater risk than others—but you can't be sure which ones without asking about sexual activity.

Screening should take place annually at routine visits as well as at acute care visits whenever possible. Particularly in the adolescent age group, I think we need to take advantage of every opportunity. Specifically, teens should be asked if they're sexually active, and if so, what kind of activity they engage in, whether it is with members of their own or the opposite gender, and whether they use barrier protection (condoms).

All sexually active teens should be counseled about the importance of condoms and their proper use. For a variety of reasons, condom use is currently quite low among adolescents. Teen boys often don't want to use them because they decrease sensitivity or simply aren't seen as “manly.” An excellent resource for how to talk to teens about condoms is available at www.hws.wsu.edu/healthycoug/Men/condoms.html

Sexually active females should be screened yearly for Neisseria gonorrhoeae and Chlamydia trachomatis using a cervical or urine GC/CT nucleic acid amplification test, with urine being the preferred method today.

For males who have had sex with other males in the past year, an annual RPR (rapid plasma reagin) test for syphilis is recommended, along with annual pharyngeal gonorrhea cultures for those who have engaged in oral sex and rectal GC/CT swabs for those engaging in receptive anal intercourse. Although there are no specific recommendations for heterosexual males, we have learned that STDs can be asymptomatic. Personally I think screening is appropriate because it can be done easily with a urine specimen.

Recent CDC guidelines recommend that all sexually active individuals be screened annually for HIV, beginning at age 13. I endorse that recommendation, although many states have maintained the requirement for written informed consent for HIV testing, which places a barrier to proceeding. At least now all 50 states allow adolescents to sign their own consent forms without the need for a parental signature.

Although screening for HPV is not recommended, we can now offer the HPV vaccine to all of our female patients prior to sexual debut. Potentially, we will soon be able to offer it to our male patients as well.

Finally, I think we also should make an effort to encourage abstinence among our adolescent patients who have not yet embarked on sexual activity. I recently read an article about a female Harvard student who said she felt isolated because she had chosen to abstain from casual sex and decided to form a support group for like-minded young people. Contrary to popular belief, not every adolescent or young adult who chooses to abstain from casual sex or sex in general is of a strict religious or right-wing persuasion. Some have simply weighed the risks and benefits for themselves, and decided it's not right for them at this early stage in their lives.

[email protected]

The pediatric and family medicine communities need to do a better job of assessing sexual activity in adolescent patients, screening sexually active teens for sexually transmitted diseases, and counseling them about how to avoid becoming infected in the future.

Recently, a report of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) revealed that one in four American teenagers had at least one prior sexually transmitted disease (STD). This should provide strong support for clinicians to incorporate guidelines from the Centers for Disease Control and Prevention and the American Academy of Pediatrics into their practices.

The survey found that 26% of a nationally representative sample of 838 adolescent girls aged 14–19 years were infected with at least one STD, while 15% had more than one. For the entire U.S. population, this translates to more than 3.2 million adolescent girls with human papillomavirus, chlamydia, herpes simplex virus, and/or trichomonas infections. The analysis excluded the prevalence of gonorrhea, syphilis, and HIV infections, although of course our adolescent population can contract those as well.

The data confirm that although the rate of teen pregnancy has recently declined, adolescent sexual behavior remains prevalent. While I'm not aware of data regarding the reasons for the drop in pregnancies among teens, I suspect that it's due at least in part to increased use of birth control, as well as abortion, rather than a large shift away from sexual behavior.

Indeed, teenagers—and even some preteens—are having sex. Clinicians need to ask adolescent patients if they are engaging in sexual behavior, and if so, to test them annually for STDs, screen for HIV (“Screen Sexually Active Teens for HIV,” PEDIATRIC NEWS, February 2007, p. 20) and counsel those who choose sexual activity about how to approach it safely and responsibly. And we need to start early. The CDC found that these infections, especially HPV, occur quickly after sexual debut. In fact, the STD prevalence was already 20% among those who reported just 1 year of sexual activity.

While there were racial differences—48% of black teens had at least one STD, compared with 20% of white teens—we should never assume that any early sexual activity is limited to specific racial or socioeconomic groups. This is an issue for every clinician, whether you practice in an urban, suburban, small-town, or rural setting. Yes, some of your patients are at greater risk than others—but you can't be sure which ones without asking about sexual activity.

Screening should take place annually at routine visits as well as at acute care visits whenever possible. Particularly in the adolescent age group, I think we need to take advantage of every opportunity. Specifically, teens should be asked if they're sexually active, and if so, what kind of activity they engage in, whether it is with members of their own or the opposite gender, and whether they use barrier protection (condoms).

All sexually active teens should be counseled about the importance of condoms and their proper use. For a variety of reasons, condom use is currently quite low among adolescents. Teen boys often don't want to use them because they decrease sensitivity or simply aren't seen as “manly.” An excellent resource for how to talk to teens about condoms is available at www.hws.wsu.edu/healthycoug/Men/condoms.html

Sexually active females should be screened yearly for Neisseria gonorrhoeae and Chlamydia trachomatis using a cervical or urine GC/CT nucleic acid amplification test, with urine being the preferred method today.

For males who have had sex with other males in the past year, an annual RPR (rapid plasma reagin) test for syphilis is recommended, along with annual pharyngeal gonorrhea cultures for those who have engaged in oral sex and rectal GC/CT swabs for those engaging in receptive anal intercourse. Although there are no specific recommendations for heterosexual males, we have learned that STDs can be asymptomatic. Personally I think screening is appropriate because it can be done easily with a urine specimen.

Recent CDC guidelines recommend that all sexually active individuals be screened annually for HIV, beginning at age 13. I endorse that recommendation, although many states have maintained the requirement for written informed consent for HIV testing, which places a barrier to proceeding. At least now all 50 states allow adolescents to sign their own consent forms without the need for a parental signature.

Although screening for HPV is not recommended, we can now offer the HPV vaccine to all of our female patients prior to sexual debut. Potentially, we will soon be able to offer it to our male patients as well.

Finally, I think we also should make an effort to encourage abstinence among our adolescent patients who have not yet embarked on sexual activity. I recently read an article about a female Harvard student who said she felt isolated because she had chosen to abstain from casual sex and decided to form a support group for like-minded young people. Contrary to popular belief, not every adolescent or young adult who chooses to abstain from casual sex or sex in general is of a strict religious or right-wing persuasion. Some have simply weighed the risks and benefits for themselves, and decided it's not right for them at this early stage in their lives.

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

I would like to clear up some of the confusion surrounding a recent federal government ruling that vaccines might have contributed to autismlike symptoms in a child with underlying mitochondrial disorder. The media have portrayed this as an acknowledgment of a link between vaccines and autism, and that simply isn't the case.

The story broke on the Internet blog of journalist David Kirby, the author of a book promoting the theory that the thimerosal preservative in vaccines is linked with autism. He obtained a copy of the ruling from an unnamed source and posted it on the Internet. The family of the child then spoke publicly about the case at a press briefing sponsored by an autism advocacy group.

The document was evidently issued last November by an official in the Department of Justice who wrote that medical personnel at the Department of Health and Human Services' Division of Vaccine Injury Compensation (DVIC) had reviewed the case and “concluded that compensation is appropriate.”

The case involves a 9-year-old girl who, at 18 months of age, received five different vaccines on the same day and in the following months began exhibiting abnormal symptoms deemed to be “regressive encephalopathy with features consistent with an autism spectrum disorder.” Subsequent evaluation led to the diagnosis of a previously unrecognized underlying mitochondrial disorder.

At this writing, the federal Health Resources and Services Administration (HRSA), which administers the Vaccine Injury Compensation Program through which this case was reportedly filed, could not confirm any of the information reported because the agency had not yet received written consent from the family to do so.

However, HRSA said in a statement that “HRSA has maintained and continues to maintain the position that vaccines do not cause autism, and has never concluded in any case that autism was caused by vaccination.”

But that hasn't stopped the media reports, which have caused a great deal of concern and confusion among the public and the medical community. According to the document, “DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [the child] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.”

First of all, note that this report is not talking about the disorder “autism.” Indeed, children with mitochondrial disorders, which produce severe deficits in cellular energy metabolism, often develop regressive encephalopathy and features of autism spectrum disorder such as loss of language skills and impaired motor coordination.

Such manifestations are more likely to occur in those with mitochondrial disorders when there is a physiological stressor such as a viral or bacterial illness. Therefore, it is plausible that receiving five vaccines in 1 day also could provoke the same outcome.

Is that stress equivalent to influenza or a cold? We don't know, but anything that perturbs the balance of energy metabolism in these children is likely to have an adverse impact. Therefore, we could argue that these children should be vaccinated to prevent more severe illness.

Note, too, that the ruling does not mention thimerosal, the vaccine ingredient—now removed from nearly all childhood vaccines—that many activists have claimed causes autism.

In February, my colleagues and I published a study in which we showed that the measurement of blood levels of methylmercury from fish used to make nearly all recommendations pertaining to safe levels of mercury exposure were completely inaccurate for risk assessments of children who received vaccines containing thimerosal.

The recommendations in 1999 by the American Academy of Pediatrics and others were based on toxicology data in adults regarding the oral consumption of methylmercury, as would occur from eating fish. Compared with the blood half-life of about 45 days associated with methylmercury from fish consumption, the half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter, at a mean of 3.7 days with a return to baseline by 30 days post vaccination (Pediatrics 2008;121:e208–14).

Unfortunately, the antivaccine claims are unlikely to abate until more is known about what really does cause autism. Several reports in the literature have documented an association between mitochondrial disorders and similarities to autism spectrum disorders, but none have shown a direct connection.

On the other hand, there is increasing evidence that autism is an inherited disorder. In one interesting example, new data from 751 families with autism participating in the Autism Genetic Resource Exchange point to a novel, recurrent gene microdeletion and a reciprocal microduplication that are associated with substantial susceptibility to autism, and appear to account for approximately 1% of cases (N. Engl. J. Med. 2008;358:667–75).

I suspect we will see more evidence of genetic markers for autism in the future.

In the meantime, I hope that clinicians will view the situation of this particular child as a sad but isolated case. Mitochondrial disorders are extremely rare—I have never seen one in my 20-plus years of practicing general pediatrics. And even among these patients, the benefits of vaccination still likely outweigh the risks.

Thimerosal has now been removed from all childhood vaccines except for multidose influenza vaccines, but the rates of autism have not abated, thus providing very strong epidemiologic evidence that thimerosal did not cause the upswing in autism spectrum disorder diagnoses that began in the 1990s and still continues. The antivaccine folks have begun switching their argument to say that it is multiple vaccines that cause autism and other neurodevelopmental problems by “overwhelming” the immune system.

In an effort to quantitate that, current research is looking at the effect on the immune system when a healthy child becomes colonized with common bacteria such as Streptococcus pneumoniae. Thus far, we know that the immune “stress” associated with asymptomatic nasal colonization is quite a bit greater than that of the purified vaccines given to children today.

Infectious diseases are “stressful” to the immune system. Vaccines are not risk free, but they induce far less “stress.” We need to inform our patients and their families that while everything has some risk, the real question is risk versus benefit. From that perspective, vaccines are the clear winners.

[email protected]

Acute respiratory disease associated with emerging adenovirus serotype 14 that caused nine deaths last fall in the United States is a development worth noting, but there seems little reason to fear this strain will lead to larger ongoing outbreaks of “killer colds.”

In fact, it is probably part of a natural life cycle that has been going on for millennia. We're only learning of these mutations in recent years because of active surveillance that the Centers for Disease Control and Prevention now routinely conducts at sentinel sites around the country. When the system detects something noteworthy, the findings are published in the Morbidity and Mortality Weekly Report (MMWR). Media are mining the MMWR for stories, we're seeing frequent infectious disease stories with alarmist headlines. We should be prepared to explain them to worried parents of patients.

As we know, adenovirus typically isn't a life-threatening problem. In 99% of cases it's a self-limited infection that causes conjunctivitis, rhinorrhea, exudative pharyngitis, and/or fever for 3–8 days.

Adenovirus serotype 14 (Ad14) does appear to be a bit different, though: In May 2006, a 12-day-old infant in New York died of respiratory illness caused by “Ad14.” From March to June 2007, a total of 140 additional cases of confirmed Ad14 respiratory illness were identified in clusters of patients in Oregon, Washington, and Texas. Of those, 38% were hospitalized and 5% died (MMWR 2007;56:1181–4). Deaths were due to progressive pneumonias, not colds.

It's possible that Ad14 produces less frequent disease in young children than in the elderly, considering the relative ages of Ad14 patients. Among 12 cases with available medical information in Oregon, 11 (92%) of non-type-14 adenovirus patients were younger than 5 years, compared with only 5 (17%) out of 30 cases of Ad14. There was, however, one death in a 1-month-old in the Ad14 group.

But Ad14 is not new. It was initially described in 1955, and was associated with epidemic of acute respiratory disease in military recruits in Europe in 1969. According to the CDC, in 2001–2002 it was reported to be associated with approximately 8% of all respiratory adenoviral infections in the pediatric ward of a Taiwan Hospital.

However, because Ad14 hasn't been circulating in a while—it's just one of at least 42 different adenovirus strains—the current population isn't likely to be immune. While most healthy individuals are still able to mount an immune response to it, certain susceptible people will become more ill, including the very old, the very young, and those with compromised immune systems; perhaps some healthy people will have a genetic predisposition that makes them more vulnerable.

Indeed, a single nucleotide polymorphism (SNP)—one change in the DNA of a key gene—can have a dramatic effect on how a person responds to environmental or infectious triggers. Consider as an example the case of a disease that we are more familiar with than Ad14, respiratory syncytial virus (RSV) in children. Hospitalization and more severe symptoms have been demonstrated with one SNP (Pediatr. Infect. Dis. J. 2007;26:1094–8), and it's likely that similar mechanisms explain some of the variation in disease severity with other viruses as well. We're just beginning to learn about these mechanisms within the innate immune system.

In the meantime, we might want to consider obtaining viral cultures—commercially available testing systems do include adenovirus—in hospitalized pneumonia patients who do not have positive RSV or influenza rapid tests and who do not improve quickly despite appropriate supportive and perhaps empiric antibiotic therapy.

Even though we don't have a commonly used effective antiviral for adenovirus, such as oseltamivir for influenza, it can be important to be aware of cases of severe adenovirus occurring outside of the surveillance network. While Ad14 is a recent culprit, other serotypes also have been implicated in sporadic outbreaks. Also, if you have a firm viral diagnosis, you don't need to keep escalating broad-spectrum antibiotics. Adenovirus can initially mimic the high fever, leukocytosis, and ill-appearing presentation of bacterial pneumonia, particularly in young children. The x-ray findings usually are bilateral and patchy initially, but the infiltrates can become dense and appear more “bacterial” as time goes on.

Another reason to culture for adenovirus is its potential to mimic Kawasaki disease, with the nonpurulent conjunctivitis, red throat, mucositis, high fever, and swollen lymph nodes. If you can confirm that the child actually has adenovirus during the Kawasaki work-up, you can save thousands of dollars that would otherwise be spent on intravenous immune globulin (IVIG) therapy. Of course, to be really useful, you'll need to get the viral cultures early, because current culture techniques—shell vial or standard—require anywhere from 48 hours to 7 days for results to develop. Because the window of effective use of IVIG in Kawasaki disease is within 10 days of the onset of fever, getting viral cultures more than 5 days into the fever may not give you time to make the diagnosis before you will need to empirically use IVIG.

New multiplex polymerase chain reaction (PCR) technology should improve on that situation in the near future. Already in use at some teaching institutions, multiplex PCR improves the diagnostic capacity of traditional PCR by amplifying target sequences of multiple viruses all at once. The technology allows you to order a panel of 17–20 different viral tests in one batch and get the results back in a day (J. Clin. Microbiol. 2007;45:2965–70), at a cost of not much more than the $150-$200 for the current viral panel of just 6 or 7.

Another new technology on the horizon—flocked nasal swabs—will make it easier to obtain the sample from the child. Currently approved for use in adults, the swabs are made with perpendicular nylon fibers that allow you to collect epithelial cells and surrounding pathogens with a few simple twirls in the nares, a technique far more comfortable for the patient than a nasal wash. Data from the company's abstracts suggest that the sample you get from the swab is equivalent to that from the nasal wash (information available at www.copanusa.com

These new modalities together should make viral testing as simple as taking a throat culture for the group A streptococcus bacterium, and allow us to obtain timely information that is more pertinent while the child is still sick. But at the same time we need to remind our patients—and ourselves—that in the vast majority of cases we're not talking about a “killer” disease, even with adenovirus.

[email protected]

Acute respiratory disease associated with emerging adenovirus serotype 14 that caused nine deaths last fall in the United States is a development worth noting, but there seems little reason to fear this strain will lead to larger ongoing outbreaks of “killer colds.”

In fact, it is probably part of a natural life cycle that has been going on for millennia. We're only learning of these mutations in recent years because of active surveillance that the Centers for Disease Control and Prevention now routinely conducts at sentinel sites around the country. When the system detects something noteworthy, the findings are published in the Morbidity and Mortality Weekly Report (MMWR). Media are mining the MMWR for stories, we're seeing frequent infectious disease stories with alarmist headlines. We should be prepared to explain them to worried parents of patients.

As we know, adenovirus typically isn't a life-threatening problem. In 99% of cases it's a self-limited infection that causes conjunctivitis, rhinorrhea, exudative pharyngitis, and/or fever for 3–8 days.

Adenovirus serotype 14 (Ad14) does appear to be a bit different, though: In May 2006, a 12-day-old infant in New York died of respiratory illness caused by “Ad14.” From March to June 2007, a total of 140 additional cases of confirmed Ad14 respiratory illness were identified in clusters of patients in Oregon, Washington, and Texas. Of those, 38% were hospitalized and 5% died (MMWR 2007;56:1181–4). Deaths were due to progressive pneumonias, not colds.

It's possible that Ad14 produces less frequent disease in young children than in the elderly, considering the relative ages of Ad14 patients. Among 12 cases with available medical information in Oregon, 11 (92%) of non-type-14 adenovirus patients were younger than 5 years, compared with only 5 (17%) out of 30 cases of Ad14. There was, however, one death in a 1-month-old in the Ad14 group.

But Ad14 is not new. It was initially described in 1955, and was associated with epidemic of acute respiratory disease in military recruits in Europe in 1969. According to the CDC, in 2001–2002 it was reported to be associated with approximately 8% of all respiratory adenoviral infections in the pediatric ward of a Taiwan Hospital.

However, because Ad14 hasn't been circulating in a while—it's just one of at least 42 different adenovirus strains—the current population isn't likely to be immune. While most healthy individuals are still able to mount an immune response to it, certain susceptible people will become more ill, including the very old, the very young, and those with compromised immune systems; perhaps some healthy people will have a genetic predisposition that makes them more vulnerable.

Indeed, a single nucleotide polymorphism (SNP)—one change in the DNA of a key gene—can have a dramatic effect on how a person responds to environmental or infectious triggers. Consider as an example the case of a disease that we are more familiar with than Ad14, respiratory syncytial virus (RSV) in children. Hospitalization and more severe symptoms have been demonstrated with one SNP (Pediatr. Infect. Dis. J. 2007;26:1094–8), and it's likely that similar mechanisms explain some of the variation in disease severity with other viruses as well. We're just beginning to learn about these mechanisms within the innate immune system.

In the meantime, we might want to consider obtaining viral cultures—commercially available testing systems do include adenovirus—in hospitalized pneumonia patients who do not have positive RSV or influenza rapid tests and who do not improve quickly despite appropriate supportive and perhaps empiric antibiotic therapy.

Even though we don't have a commonly used effective antiviral for adenovirus, such as oseltamivir for influenza, it can be important to be aware of cases of severe adenovirus occurring outside of the surveillance network. While Ad14 is a recent culprit, other serotypes also have been implicated in sporadic outbreaks. Also, if you have a firm viral diagnosis, you don't need to keep escalating broad-spectrum antibiotics. Adenovirus can initially mimic the high fever, leukocytosis, and ill-appearing presentation of bacterial pneumonia, particularly in young children. The x-ray findings usually are bilateral and patchy initially, but the infiltrates can become dense and appear more “bacterial” as time goes on.

Another reason to culture for adenovirus is its potential to mimic Kawasaki disease, with the nonpurulent conjunctivitis, red throat, mucositis, high fever, and swollen lymph nodes. If you can confirm that the child actually has adenovirus during the Kawasaki work-up, you can save thousands of dollars that would otherwise be spent on intravenous immune globulin (IVIG) therapy. Of course, to be really useful, you'll need to get the viral cultures early, because current culture techniques—shell vial or standard—require anywhere from 48 hours to 7 days for results to develop. Because the window of effective use of IVIG in Kawasaki disease is within 10 days of the onset of fever, getting viral cultures more than 5 days into the fever may not give you time to make the diagnosis before you will need to empirically use IVIG.

New multiplex polymerase chain reaction (PCR) technology should improve on that situation in the near future. Already in use at some teaching institutions, multiplex PCR improves the diagnostic capacity of traditional PCR by amplifying target sequences of multiple viruses all at once. The technology allows you to order a panel of 17–20 different viral tests in one batch and get the results back in a day (J. Clin. Microbiol. 2007;45:2965–70), at a cost of not much more than the $150-$200 for the current viral panel of just 6 or 7.

Another new technology on the horizon—flocked nasal swabs—will make it easier to obtain the sample from the child. Currently approved for use in adults, the swabs are made with perpendicular nylon fibers that allow you to collect epithelial cells and surrounding pathogens with a few simple twirls in the nares, a technique far more comfortable for the patient than a nasal wash. Data from the company's abstracts suggest that the sample you get from the swab is equivalent to that from the nasal wash (information available at www.copanusa.com

These new modalities together should make viral testing as simple as taking a throat culture for the group A streptococcus bacterium, and allow us to obtain timely information that is more pertinent while the child is still sick. But at the same time we need to remind our patients—and ourselves—that in the vast majority of cases we're not talking about a “killer” disease, even with adenovirus.

[email protected]

Acute respiratory disease associated with emerging adenovirus serotype 14 that caused nine deaths last fall in the United States is a development worth noting, but there seems little reason to fear this strain will lead to larger ongoing outbreaks of “killer colds.”

In fact, it is probably part of a natural life cycle that has been going on for millennia. We're only learning of these mutations in recent years because of active surveillance that the Centers for Disease Control and Prevention now routinely conducts at sentinel sites around the country. When the system detects something noteworthy, the findings are published in the Morbidity and Mortality Weekly Report (MMWR). Media are mining the MMWR for stories, we're seeing frequent infectious disease stories with alarmist headlines. We should be prepared to explain them to worried parents of patients.

As we know, adenovirus typically isn't a life-threatening problem. In 99% of cases it's a self-limited infection that causes conjunctivitis, rhinorrhea, exudative pharyngitis, and/or fever for 3–8 days.

Adenovirus serotype 14 (Ad14) does appear to be a bit different, though: In May 2006, a 12-day-old infant in New York died of respiratory illness caused by “Ad14.” From March to June 2007, a total of 140 additional cases of confirmed Ad14 respiratory illness were identified in clusters of patients in Oregon, Washington, and Texas. Of those, 38% were hospitalized and 5% died (MMWR 2007;56:1181–4). Deaths were due to progressive pneumonias, not colds.

It's possible that Ad14 produces less frequent disease in young children than in the elderly, considering the relative ages of Ad14 patients. Among 12 cases with available medical information in Oregon, 11 (92%) of non-type-14 adenovirus patients were younger than 5 years, compared with only 5 (17%) out of 30 cases of Ad14. There was, however, one death in a 1-month-old in the Ad14 group.

But Ad14 is not new. It was initially described in 1955, and was associated with epidemic of acute respiratory disease in military recruits in Europe in 1969. According to the CDC, in 2001–2002 it was reported to be associated with approximately 8% of all respiratory adenoviral infections in the pediatric ward of a Taiwan Hospital.

However, because Ad14 hasn't been circulating in a while—it's just one of at least 42 different adenovirus strains—the current population isn't likely to be immune. While most healthy individuals are still able to mount an immune response to it, certain susceptible people will become more ill, including the very old, the very young, and those with compromised immune systems; perhaps some healthy people will have a genetic predisposition that makes them more vulnerable.

Indeed, a single nucleotide polymorphism (SNP)—one change in the DNA of a key gene—can have a dramatic effect on how a person responds to environmental or infectious triggers. Consider as an example the case of a disease that we are more familiar with than Ad14, respiratory syncytial virus (RSV) in children. Hospitalization and more severe symptoms have been demonstrated with one SNP (Pediatr. Infect. Dis. J. 2007;26:1094–8), and it's likely that similar mechanisms explain some of the variation in disease severity with other viruses as well. We're just beginning to learn about these mechanisms within the innate immune system.

In the meantime, we might want to consider obtaining viral cultures—commercially available testing systems do include adenovirus—in hospitalized pneumonia patients who do not have positive RSV or influenza rapid tests and who do not improve quickly despite appropriate supportive and perhaps empiric antibiotic therapy.

Even though we don't have a commonly used effective antiviral for adenovirus, such as oseltamivir for influenza, it can be important to be aware of cases of severe adenovirus occurring outside of the surveillance network. While Ad14 is a recent culprit, other serotypes also have been implicated in sporadic outbreaks. Also, if you have a firm viral diagnosis, you don't need to keep escalating broad-spectrum antibiotics. Adenovirus can initially mimic the high fever, leukocytosis, and ill-appearing presentation of bacterial pneumonia, particularly in young children. The x-ray findings usually are bilateral and patchy initially, but the infiltrates can become dense and appear more “bacterial” as time goes on.

Another reason to culture for adenovirus is its potential to mimic Kawasaki disease, with the nonpurulent conjunctivitis, red throat, mucositis, high fever, and swollen lymph nodes. If you can confirm that the child actually has adenovirus during the Kawasaki work-up, you can save thousands of dollars that would otherwise be spent on intravenous immune globulin (IVIG) therapy. Of course, to be really useful, you'll need to get the viral cultures early, because current culture techniques—shell vial or standard—require anywhere from 48 hours to 7 days for results to develop. Because the window of effective use of IVIG in Kawasaki disease is within 10 days of the onset of fever, getting viral cultures more than 5 days into the fever may not give you time to make the diagnosis before you will need to empirically use IVIG.

New multiplex polymerase chain reaction (PCR) technology should improve on that situation in the near future. Already in use at some teaching institutions, multiplex PCR improves the diagnostic capacity of traditional PCR by amplifying target sequences of multiple viruses all at once. The technology allows you to order a panel of 17–20 different viral tests in one batch and get the results back in a day (J. Clin. Microbiol. 2007;45:2965–70), at a cost of not much more than the $150-$200 for the current viral panel of just 6 or 7.

Another new technology on the horizon—flocked nasal swabs—will make it easier to obtain the sample from the child. Currently approved for use in adults, the swabs are made with perpendicular nylon fibers that allow you to collect epithelial cells and surrounding pathogens with a few simple twirls in the nares, a technique far more comfortable for the patient than a nasal wash. Data from the company's abstracts suggest that the sample you get from the swab is equivalent to that from the nasal wash (information available at www.copanusa.com

These new modalities together should make viral testing as simple as taking a throat culture for the group A streptococcus bacterium, and allow us to obtain timely information that is more pertinent while the child is still sick. But at the same time we need to remind our patients—and ourselves—that in the vast majority of cases we're not talking about a “killer” disease, even with adenovirus.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Vaccine shortages have become all too common in the United States, with no end in sight. In my view, the best solution would be for the federal government to step in and provide incentives to vaccine manufacturers to bring more products to the U.S. market.

The current situation with Haemophilus influenzae type b (Hib) vaccine is just the latest in a string of vaccine production problems that has been causing major headaches for physicians and patients over the past several years.

As you know, on Dec. 13, 2007, Merck & Co. announced a voluntary recall of certain lots of both of its Hib conjugate vaccines, PedvaxHIB (monovalent) and Comvax (combined Hib/hepatitis B), because of concerns about contamination. Merck does not anticipate resumption of distribution until the fourth quarter of 2008. Sanofi Pasteur, the other company that makes Hib vaccines that are licensed for the U.S. market (ActHIB and TriHIBit), won't be able to produce enough to cover all the remaining children for whom the vaccine is recommended. We've also seen recent supply problems with measles-mumps-rubella-varicella (MMRV) and hepatitis A vaccines.

In 2004 there were major shortages of influenza vaccine and of pneumococcal conjugate vaccine because of various production problems. And any pediatrician who was practicing in 2001-2002 will remember the nightmare when five different vaccines that protect against eight different diseases–diphtheria, tetanus, pertussis, measles, mumps, rubella, pneumococcus, and varicella–all fell into short supply simultaneously. There was no single reason for those shortages; rather, they were due to a combination of factors: manufacturing and compliance problems; vaccine manufacturers' leaving the market for business reasons; supply and demand issues; and the removal of thimerosal from vaccines, which led to a lower yield.

Each time a shortage occurs, we're handed yet another set of interim guidelines for prioritization that means more paperwork; more hassles for us, our staffs, and our patients; plus the ongoing concern that at some point these shortages will result in true resurgence of disease. That hasn't happened yet, but I worry that it's right around the corner–herd immunity can take us only so far.

The Centers for Disease Control and Prevention maintains a stockpile of routine pediatric vaccines, which is a good safety net in case of a disease outbreak or a short-term production problem. However, not all pediatric vaccines are included in the stockpile, and it contains only a 6-month supply. Some of the recent shortages have lasted longer than that. Moreover, that stockpile competes for government dollars with vaccines devoted to bioterrorism and pandemic flu vaccines.

Some of my colleagues have talked about stockpiling their own vaccines. I don't think that is a viable solution, given the short shelf life of vaccines and the high cost that would be involved. In my practice, vaccines now are the second most expensive item on my balance sheet–second only to my staff payroll. My rent comes in third.

Of course, this is primarily because the newer vaccines–Prevnar, Menactra, Gardasil, etc.–are still patent protected and cost around $80-$120 per dose. For an average pediatrician, even a short-term supply would end up totaling around $40,000-$50,000. Multiply that by the number of partners in a group practice, and you'd easily be up to a quarter of a million dollars' worth of vaccine in your refrigerators and freezers. It's not a long-term solution to the shortage problem.

I believe the real answer is to ensure an adequate number of products from an adequate number of manufacturers. In 1967 there were 26 licensed vaccine manufacturers in the United States. By 2005, only six U.S. manufacturers with licensed products remained. What's worse, for several vaccines–including inactivated polio virus, MMR, and pneumococcal conjugate vaccines–there is only one manufacturer (Pediatrics 2006;6:2269-75).

This isn't good news. Just as they do after mergers in the airline industry, consumers end up with fewer choices and higher prices. The consolidation we've seen in the vaccine industry–brought on by increased regulatory demands for licensure; the high risk involved in developing a product, and competition with products like Lipitor, which patients take for a lifetime and generate billion-dollar profits–is really the core of the problem. Vaccine companies must be given incentives to compete.

How? The National Institute of Allergy and Infectious Diseases (NIAID) maintains nine Vaccine Treatment and Evaluation Units (VTEUs) around the country. Funded by the National Institutes of Health, these centers have stepped in at various times to conduct phase I and phase II testing on vaccines when there was critical need, such as the 2005 influenza vaccine shortage.

At that time, the NIAID worked closely with the Food and Drug Administration to conduct a clinical trial of GlaxoSmithKline's Fluarix–which was already available in Europe–to rapidly demonstrate sufficient safety and immunogenicity for the FDA to approve it in less than a year, in time for that year's influenza season. “The Fluarix study is an excellent example of what government and industry can accomplish in a short time frame, when faced with a serious public health need,” NIH Director Elias A. Zerhouni said at the time.

The VTEUs played a role in testing acellular pertussis vaccines in the late 1980s, when pressure from activist groups led to congressional demands for a safer alternative to whole-cell pertussis vaccines, and again in the 1990s, when the United States initiated the transition from oral to inactivated poliovirus vaccines. In each case, the FDA has been in the loop to ensure that adequate testing takes place. And importantly, the government also has promised to purchase a certain number of vaccine doses from the companies, thereby further ensuring economic feasibility.

Thus far the VTEUs have been brought into use on a case-by-case basis. I think their use should become a routine mechanism in shortage situations. For example, GlaxoSmithKline (GSK) currently has another Hib vaccine on the market in Europe called Hiberix. It's virtually identical to Sanofi Pasteur's ACTHib, yet it is not licensed in the United States. Why? My guess is that GSK has determined that the large investment it would take to satisfy FDA's stringent safety and immunogenicity requirements wouldn't be worthwhile simply to bring a third Hib vaccine to market.

In the interest of public health, I believe the FDA should ask the VTEUs to conduct those studies in order to bring Hiberix here to help alleviate our current Hib vaccine shortage. The same goes for an MMRV vaccine that GSK also makes for the European market. Both are “mature” vaccines that can't command the kind of prices that the newer vaccines like Prevnar and Menactra can. I believe these are cases where the government must step in and help. We should not have to rely on a single source for these products. It's unsafe for the public.

[email protected]

Happy New Year! It's time again for my annual prognosis of the top 10 infectious disease issues likely to have an impact on our practices in the next 12 months.

▸ 1. Local school-based immunization programs could become a reality. Nationally, it will take increased vaccine production and better organization of school-based infrastructure. Still, I foresee some local initiatives coming to fruition in 2008.

We have evidence that such programs work. In a recent study, Dr. James C. King Jr. and his associates at the University of Maryland, Baltimore, identified 11 demographically similar clusters of elementary schools (24 total) in four states. One school in each cluster served as the “intervention” school, and the others as controls. Healthy children aged 5 years and older in the intervention schools were offered free nasal influenza vaccine before the 2004–2005 influenza season (N. Engl. J. Med. 2006;355:2523–32).

The investigators identified the predicted peak weeks of influenza activity for each state, then evaluated rates of illness and school absence in the respective schools by a survey of parents immediately following the predicted week of peak influenza activity. Of the 5,840 children in the intervention schools, 47% (2,717) received the vaccine.

Compared with the children in the control schools, those in vaccinated schools were significantly less likely to experience any fever or flulike illness (40% vs. 52%) or to visit a clinic or physician's office for any type of care (7 vs. 11 per 100 patients). They also received fewer prescriptions, used fewer over-the-counter medicines, and were less likely to miss school.

While we're waiting for school programs, remember that it's still not too late to have an impact personally on influenza disease by targeting your high-risk patients and offering vaccine to any child in your practice.

▸ 2. Community pneumonia and otitis media may become harder to treat as pneumococcal disease rates plateau and new strains continue to appear. Serotype 19A will emerge as the nemesis and cause more disease associated with multidrug resistance. In the PROTEKT US study, coverage with the 7-valent conjugate pneumococcal vaccine (PCV7) and antimicrobial susceptibility among Streptococcus pneumoniae isolates collected from children aged 0–14 years were examined for the periods 2000–2001, 2002–2003, and 2003–2004. The most common serotypes in year 4 were the nonvaccine serotypes 19A (19% of all isolates), 6A (8%), 3 (8%), 15 (6%), and 35B (6%), along with 19F (13%), which is included in the vaccine (J. Clin. Microbiol. 2007;45:290–3).

Although the proportion of S. pneumoniae isolates from the U.S. pediatric population covered by PCV7 decreased substantially in the 4 years after the vaccine was introduced, there were significant increases in strains that were resistant to commonly used antibiotics, including beta-lactams and macrolides, as well as in multidrug resistant strains, particularly among respiratory tract isolates.

In a separate report, Dr. Michael E. Pichichero and Dr. Janet R. Casey identified serotype 19A pneumococcus as an otopathogen that is resistant to all antibiotics currently approved for the treatment of acute otitis media in children (JAMA 2007;298:1772–8). Will pediatricians need to be trained in tympanocentesis again? My crystal ball says maybe.

▸ 3. Travel-related issues will arise more often in your practice. The number of children traveling overseas continues to increase. While curbside consultations generally target malaria prophylaxis, pediatricians also should offer counseling regarding food- and waterborne disease, other vector-borne diseases, and airborne diseases.

Such counseling should take into account the patient's age, nutritional status, and any underlying illness. All routine immunizations should be updated. The country, accommodations, and length of trip will all dictate which travel vaccines the child will need. Other topics to cover include food and water precautions, planning for symptomatic treatment of traveler's diarrhea, protection against mosquito-borne pathogens and TB where it is endemic, and a plan for evaluation on return for those staying longer than a month. I particularly recommend an article entitled, “Germs on a plane—infectious issues and the pediatric international traveler: What pediatricians should know,” by two Canadian researchers (Pediatr. Ann. 2007;36:344–51).

▸ 4. A new blood test for tuberculosis may supplant intradermal skin testing. Interferon-γ release assays using whole blood may reliably determine if a child has been infected with TB. The tests require just one visit and the results are often available within 1 day. The tests provide greater specificity than tests using purified protein derivatives such as the TB antigen, with similar sensitivity.

▸ 5. The vaccine reimbursement issue will continue to dominate discussions among policy experts, but it's not likely we'll see a solution. In February 2007, the American Academy of Pediatrics and the American Medical Association held a joint congress at which major proposals included setting national standards for minimal reimbursement, standardizing vaccine administration fees, and having vaccine manufacturers work with pediatricians to offset the cost for inventory of new vaccines. It's a start. I hope that working through bureaucratic channels won't take as long as I anticipate.

▸ 6. Infections from exotic pets will continue to rise. Many families with young children continue to own reptiles and other unusual animals, despite AAP recommendations against it. Every well-child evaluation should include a question about pet ownership. There is cause for concern if the family has an animal other than a dog, cat, small rodent, or fish. Here is a question-based mnemonic borrowed from the Black Pine Animal Park, an exotic animal rescue organization in Indiana:

G: How much will this animal Grow?

O: How Old can this animal live to be?

O: Will this animal create Odors I won't like?

D: What kind of Diet does this animal require?

L: Can this animal be Lethal to me and others?

I: Is it Illegal for me to own this animal?

F: Just how much Fun will it really be to own this animal?

E: What are the Environmental requirements for this animal?

▸ 7. Rotavirus cases will decrease. There is high hope that the rotavirus vaccine will have an impact on hospitalization and emergency visit rates for rotavirus disease. Currently 1 in 17 children infected with rotavirus becomes ill enough to visit the emergency department, and 1 in 65 is hospitalized. If, as anticipated, the vaccine eliminates 98% of such severe cases, it will be easy to appreciate its impact.

▸ 8. Vaccination coverage will be high, but still not high enough. Although the 2004 numbers showed the highest rates ever recorded, about 20% of children younger than 2 years are still inadequately immunized. New strategies will be needed for 2008, but they must be designed carefully.

A court in Maryland recently ordered that parents be sent to jail if their children are not immunized. This did not go over well with the public and many physicians questioned the approach.

▸ 9. Methicillin-resistant Staphylococcus aureus cases will continue to rise. Unfortunately, clindamycin-resistance rates will increase in 2008, making empiric treatment of invasive diseases such as osteomyelitis increasingly difficult.

▸ 10. Active surveillance for MRSA will become a reality for the hospitalized patient, at least for children in high-risk settings such as the intensive care unit. Where and how often children will be cultured (nasal/axilla/rectal?weekly/while hospitalized?) will vary from institution to institution. However, all institutions will attempt to identify those patients already colonized with MRSA at the time of hospitalization and will utilize barrier precautions to prevent hospital spread.

[email protected]

Happy New Year! It's time again for my annual prognosis of the top 10 infectious disease issues likely to have an impact on our practices in the next 12 months.

▸ 1. Local school-based immunization programs could become a reality. Nationally, it will take increased vaccine production and better organization of school-based infrastructure. Still, I foresee some local initiatives coming to fruition in 2008.

We have evidence that such programs work. In a recent study, Dr. James C. King Jr. and his associates at the University of Maryland, Baltimore, identified 11 demographically similar clusters of elementary schools (24 total) in four states. One school in each cluster served as the “intervention” school, and the others as controls. Healthy children aged 5 years and older in the intervention schools were offered free nasal influenza vaccine before the 2004–2005 influenza season (N. Engl. J. Med. 2006;355:2523–32).

The investigators identified the predicted peak weeks of influenza activity for each state, then evaluated rates of illness and school absence in the respective schools by a survey of parents immediately following the predicted week of peak influenza activity. Of the 5,840 children in the intervention schools, 47% (2,717) received the vaccine.

Compared with the children in the control schools, those in vaccinated schools were significantly less likely to experience any fever or flulike illness (40% vs. 52%) or to visit a clinic or physician's office for any type of care (7 vs. 11 per 100 patients). They also received fewer prescriptions, used fewer over-the-counter medicines, and were less likely to miss school.

While we're waiting for school programs, remember that it's still not too late to have an impact personally on influenza disease by targeting your high-risk patients and offering vaccine to any child in your practice.

▸ 2. Community pneumonia and otitis media may become harder to treat as pneumococcal disease rates plateau and new strains continue to appear. Serotype 19A will emerge as the nemesis and cause more disease associated with multidrug resistance. In the PROTEKT US study, coverage with the 7-valent conjugate pneumococcal vaccine (PCV7) and antimicrobial susceptibility among Streptococcus pneumoniae isolates collected from children aged 0–14 years were examined for the periods 2000–2001, 2002–2003, and 2003–2004. The most common serotypes in year 4 were the nonvaccine serotypes 19A (19% of all isolates), 6A (8%), 3 (8%), 15 (6%), and 35B (6%), along with 19F (13%), which is included in the vaccine (J. Clin. Microbiol. 2007;45:290–3).

Although the proportion of S. pneumoniae isolates from the U.S. pediatric population covered by PCV7 decreased substantially in the 4 years after the vaccine was introduced, there were significant increases in strains that were resistant to commonly used antibiotics, including beta-lactams and macrolides, as well as in multidrug resistant strains, particularly among respiratory tract isolates.

In a separate report, Dr. Michael E. Pichichero and Dr. Janet R. Casey identified serotype 19A pneumococcus as an otopathogen that is resistant to all antibiotics currently approved for the treatment of acute otitis media in children (JAMA 2007;298:1772–8). Will pediatricians need to be trained in tympanocentesis again? My crystal ball says maybe.

▸ 3. Travel-related issues will arise more often in your practice. The number of children traveling overseas continues to increase. While curbside consultations generally target malaria prophylaxis, pediatricians also should offer counseling regarding food- and waterborne disease, other vector-borne diseases, and airborne diseases.

Such counseling should take into account the patient's age, nutritional status, and any underlying illness. All routine immunizations should be updated. The country, accommodations, and length of trip will all dictate which travel vaccines the child will need. Other topics to cover include food and water precautions, planning for symptomatic treatment of traveler's diarrhea, protection against mosquito-borne pathogens and TB where it is endemic, and a plan for evaluation on return for those staying longer than a month. I particularly recommend an article entitled, “Germs on a plane—infectious issues and the pediatric international traveler: What pediatricians should know,” by two Canadian researchers (Pediatr. Ann. 2007;36:344–51).

▸ 4. A new blood test for tuberculosis may supplant intradermal skin testing. Interferon-γ release assays using whole blood may reliably determine if a child has been infected with TB. The tests require just one visit and the results are often available within 1 day. The tests provide greater specificity than tests using purified protein derivatives such as the TB antigen, with similar sensitivity.

▸ 5. The vaccine reimbursement issue will continue to dominate discussions among policy experts, but it's not likely we'll see a solution. In February 2007, the American Academy of Pediatrics and the American Medical Association held a joint congress at which major proposals included setting national standards for minimal reimbursement, standardizing vaccine administration fees, and having vaccine manufacturers work with pediatricians to offset the cost for inventory of new vaccines. It's a start. I hope that working through bureaucratic channels won't take as long as I anticipate.

▸ 6. Infections from exotic pets will continue to rise. Many families with young children continue to own reptiles and other unusual animals, despite AAP recommendations against it. Every well-child evaluation should include a question about pet ownership. There is cause for concern if the family has an animal other than a dog, cat, small rodent, or fish. Here is a question-based mnemonic borrowed from the Black Pine Animal Park, an exotic animal rescue organization in Indiana:

G: How much will this animal Grow?

O: How Old can this animal live to be?

O: Will this animal create Odors I won't like?

D: What kind of Diet does this animal require?

L: Can this animal be Lethal to me and others?

I: Is it Illegal for me to own this animal?

F: Just how much Fun will it really be to own this animal?

E: What are the Environmental requirements for this animal?

▸ 7. Rotavirus cases will decrease. There is high hope that the rotavirus vaccine will have an impact on hospitalization and emergency visit rates for rotavirus disease. Currently 1 in 17 children infected with rotavirus becomes ill enough to visit the emergency department, and 1 in 65 is hospitalized. If, as anticipated, the vaccine eliminates 98% of such severe cases, it will be easy to appreciate its impact.

▸ 8. Vaccination coverage will be high, but still not high enough. Although the 2004 numbers showed the highest rates ever recorded, about 20% of children younger than 2 years are still inadequately immunized. New strategies will be needed for 2008, but they must be designed carefully.

A court in Maryland recently ordered that parents be sent to jail if their children are not immunized. This did not go over well with the public and many physicians questioned the approach.

▸ 9. Methicillin-resistant Staphylococcus aureus cases will continue to rise. Unfortunately, clindamycin-resistance rates will increase in 2008, making empiric treatment of invasive diseases such as osteomyelitis increasingly difficult.

▸ 10. Active surveillance for MRSA will become a reality for the hospitalized patient, at least for children in high-risk settings such as the intensive care unit. Where and how often children will be cultured (nasal/axilla/rectal?weekly/while hospitalized?) will vary from institution to institution. However, all institutions will attempt to identify those patients already colonized with MRSA at the time of hospitalization and will utilize barrier precautions to prevent hospital spread.

[email protected]

Happy New Year! It's time again for my annual prognosis of the top 10 infectious disease issues likely to have an impact on our practices in the next 12 months.

▸ 1. Local school-based immunization programs could become a reality. Nationally, it will take increased vaccine production and better organization of school-based infrastructure. Still, I foresee some local initiatives coming to fruition in 2008.

We have evidence that such programs work. In a recent study, Dr. James C. King Jr. and his associates at the University of Maryland, Baltimore, identified 11 demographically similar clusters of elementary schools (24 total) in four states. One school in each cluster served as the “intervention” school, and the others as controls. Healthy children aged 5 years and older in the intervention schools were offered free nasal influenza vaccine before the 2004–2005 influenza season (N. Engl. J. Med. 2006;355:2523–32).

The investigators identified the predicted peak weeks of influenza activity for each state, then evaluated rates of illness and school absence in the respective schools by a survey of parents immediately following the predicted week of peak influenza activity. Of the 5,840 children in the intervention schools, 47% (2,717) received the vaccine.

Compared with the children in the control schools, those in vaccinated schools were significantly less likely to experience any fever or flulike illness (40% vs. 52%) or to visit a clinic or physician's office for any type of care (7 vs. 11 per 100 patients). They also received fewer prescriptions, used fewer over-the-counter medicines, and were less likely to miss school.

While we're waiting for school programs, remember that it's still not too late to have an impact personally on influenza disease by targeting your high-risk patients and offering vaccine to any child in your practice.

▸ 2. Community pneumonia and otitis media may become harder to treat as pneumococcal disease rates plateau and new strains continue to appear. Serotype 19A will emerge as the nemesis and cause more disease associated with multidrug resistance. In the PROTEKT US study, coverage with the 7-valent conjugate pneumococcal vaccine (PCV7) and antimicrobial susceptibility among Streptococcus pneumoniae isolates collected from children aged 0–14 years were examined for the periods 2000–2001, 2002–2003, and 2003–2004. The most common serotypes in year 4 were the nonvaccine serotypes 19A (19% of all isolates), 6A (8%), 3 (8%), 15 (6%), and 35B (6%), along with 19F (13%), which is included in the vaccine (J. Clin. Microbiol. 2007;45:290–3).

Although the proportion of S. pneumoniae isolates from the U.S. pediatric population covered by PCV7 decreased substantially in the 4 years after the vaccine was introduced, there were significant increases in strains that were resistant to commonly used antibiotics, including beta-lactams and macrolides, as well as in multidrug resistant strains, particularly among respiratory tract isolates.

In a separate report, Dr. Michael E. Pichichero and Dr. Janet R. Casey identified serotype 19A pneumococcus as an otopathogen that is resistant to all antibiotics currently approved for the treatment of acute otitis media in children (JAMA 2007;298:1772–8). Will pediatricians need to be trained in tympanocentesis again? My crystal ball says maybe.

▸ 3. Travel-related issues will arise more often in your practice. The number of children traveling overseas continues to increase. While curbside consultations generally target malaria prophylaxis, pediatricians also should offer counseling regarding food- and waterborne disease, other vector-borne diseases, and airborne diseases.

Such counseling should take into account the patient's age, nutritional status, and any underlying illness. All routine immunizations should be updated. The country, accommodations, and length of trip will all dictate which travel vaccines the child will need. Other topics to cover include food and water precautions, planning for symptomatic treatment of traveler's diarrhea, protection against mosquito-borne pathogens and TB where it is endemic, and a plan for evaluation on return for those staying longer than a month. I particularly recommend an article entitled, “Germs on a plane—infectious issues and the pediatric international traveler: What pediatricians should know,” by two Canadian researchers (Pediatr. Ann. 2007;36:344–51).

▸ 4. A new blood test for tuberculosis may supplant intradermal skin testing. Interferon-γ release assays using whole blood may reliably determine if a child has been infected with TB. The tests require just one visit and the results are often available within 1 day. The tests provide greater specificity than tests using purified protein derivatives such as the TB antigen, with similar sensitivity.

▸ 5. The vaccine reimbursement issue will continue to dominate discussions among policy experts, but it's not likely we'll see a solution. In February 2007, the American Academy of Pediatrics and the American Medical Association held a joint congress at which major proposals included setting national standards for minimal reimbursement, standardizing vaccine administration fees, and having vaccine manufacturers work with pediatricians to offset the cost for inventory of new vaccines. It's a start. I hope that working through bureaucratic channels won't take as long as I anticipate.

▸ 6. Infections from exotic pets will continue to rise. Many families with young children continue to own reptiles and other unusual animals, despite AAP recommendations against it. Every well-child evaluation should include a question about pet ownership. There is cause for concern if the family has an animal other than a dog, cat, small rodent, or fish. Here is a question-based mnemonic borrowed from the Black Pine Animal Park, an exotic animal rescue organization in Indiana:

G: How much will this animal Grow?

O: How Old can this animal live to be?

O: Will this animal create Odors I won't like?

D: What kind of Diet does this animal require?

L: Can this animal be Lethal to me and others?

I: Is it Illegal for me to own this animal?

F: Just how much Fun will it really be to own this animal?

E: What are the Environmental requirements for this animal?

▸ 7. Rotavirus cases will decrease. There is high hope that the rotavirus vaccine will have an impact on hospitalization and emergency visit rates for rotavirus disease. Currently 1 in 17 children infected with rotavirus becomes ill enough to visit the emergency department, and 1 in 65 is hospitalized. If, as anticipated, the vaccine eliminates 98% of such severe cases, it will be easy to appreciate its impact.

▸ 8. Vaccination coverage will be high, but still not high enough. Although the 2004 numbers showed the highest rates ever recorded, about 20% of children younger than 2 years are still inadequately immunized. New strategies will be needed for 2008, but they must be designed carefully.

A court in Maryland recently ordered that parents be sent to jail if their children are not immunized. This did not go over well with the public and many physicians questioned the approach.

▸ 9. Methicillin-resistant Staphylococcus aureus cases will continue to rise. Unfortunately, clindamycin-resistance rates will increase in 2008, making empiric treatment of invasive diseases such as osteomyelitis increasingly difficult.

▸ 10. Active surveillance for MRSA will become a reality for the hospitalized patient, at least for children in high-risk settings such as the intensive care unit. Where and how often children will be cultured (nasal/axilla/rectal?weekly/while hospitalized?) will vary from institution to institution. However, all institutions will attempt to identify those patients already colonized with MRSA at the time of hospitalization and will utilize barrier precautions to prevent hospital spread.