ID Consult

[email protected]

Happy 2009! It's time for the annual look into the future of infectious diseases.

Two common themes were evident last year: increasing antibiotic resistance, and changing epidemiology and vaccine-preventable infections. Last year's predictions that were on the mark included the rise in pneumococcal serotype 19A, the drop in rotavirus cases, the lack of a national solution to vaccine reimbursement, the need for new strategies to raise vaccine coverage rates, and the rise in methicillin-resistant Staphylococcus aureus (MRSA) infections. This year, some similar themes prevail and some items may surprise you:

▸ MRSA will become a more prominent pathogen in your local neonatal intensive care unit (NICU). Practicing pediatricians are well aware of the emergence of MRSA. As evidence, most have probably drained more abscesses in the last year than in their entire career to date. Sporadic phone calls have alerted us to cases of MRSA infection in community hospital nurseries, and while we have not encountered a NICU outbreak of MRSA infection, they are well reported and may be difficult to halt. Active NICU surveillance (periodic nasal screening), screening of new admissions hospitalized elsewhere, and utilization of contact precautions (until results are available) may be necessary.

▸ Multidrug-resistant gram-negative infections will emerge throughout pediatric hospitals, and no new help is on the horizon for these bad bugs, which have been coined the ESKAPE bacteria. They include two gram-positive bugs—Enterococcus faecium, Staphylococcus aureus, and gram negatives including four species of Klebsiella, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—which together are responsible for two-thirds of all health care-associated infections. While a few new drugs are available or coming for MRSA, there are few that target gram-negative pathogens. For more information, check out the article by Dr. Helen Boucher of Tufts University (Clin. Infect. Dis. 2009;48:1-12).

▸ Parental declinations of certain vaccines will plateau. No question that pediatricians are spending an increasing amount of time addressing parental concerns regarding vaccines, but the majority of parents still trust their pediatrician to provide appropriate vaccine information. The key, though, is making sure you appropriately address their concerns and deliver a clear and positive message with high-quality information.

Check out Meg Fisher's article in the September 2008 Pediatric Infectious Disease Journal for a great discussion of vaccine safety (Pediatr. Infect. Dis J. 2008:27:827-30).

▸ Pertussis cases will hit an all time low overall but beware: Outbreaks will still occur, particularly among older children. Implementation of the adolescent/adult tetanus-diphtheria-reduced antigen acellular pertussis (Tdap) vaccine is ongoing, but we still have a large susceptible population of children aged 8-12 years, as well as adults. We recently cared for a 5-week-old infant with whooping cough who required ECMO (extracorporeal membrane oxygenation). I suspect we will continue to see such cases.

The role of postpartum Tdap is important, and pediatricians should encourage their obstetrics colleagues to use a standing order to give vaccine to mothers before hospital discharge (if they have not received a tetanus-containing vaccine in the past 2 years, or prior Tdap).

▸ The new improved pneumococcal conjugate vaccine may be closer than you think. The emergence of multidrug-resistant serotype 19A disease has challenged the management of pneumococcal infection from acute suppurative otitis media to more serious infections like pneumonia and meningitis. Last May, the Food and Drug Administration granted fast-track designation for the Wyeth 13-valent vaccine (which includes 19A) to speed the process.

▸ Cases of Clostridium difficile will increase. In 2005, the Centers for Disease Control and Prevention alerted us to the reports of an increase in incidence and severity of C. difficile-associated disease (CDAD), both community acquired and health care-facility acquired or associated. While most practitioners are aware that the major driving force in CDAD is antimicrobial use, this strain appears to be causing infection in otherwise healthy persons who haven't received antibiotics. One study confirmed that with respect to health care-associated CDAD, the availability of adequate infection control personnel was associated with lower rates.

▸ You might see Haemophilus influenzae type b (Hib) invasive infection in the coming year. A Nov. 21 CDC report detailed information regarding the continued vaccine shortage (MMWR 2008;57:1252-5). (See Policy &Practice item, p. 23.) Vaccine supplies currently are insufficient to supply the booster dose, and some studies suggest that this dose is particularly important for protection and herd immunity. In the United Kingdom, a booster dose was not initially recommended; after an initial decrease in disease, the rate of invasive infection rose again. There is concern that prolonged deferral of the Hib booster in the United States may produce similar results, so be on the look out.

▸ Most physicians are still unaware of the new guidelines for subacute bacterial prophylaxis. In 2007, the American Heart Association issued the first major revision of these guidelines and endorsed antimicrobial prophylaxis for only five circumstances: prosthetic heart valves, prior infective endocarditis, cardiac transplant with valvulopathy, unrepaired cyanotic congenital heart disease, and repaired congenital heart disease with either prosthetic patch or other device in the first 6 months after placement or beyond that if there is a residual defect at the site of patch or device. Read more about it at: www.americanheart.org/presenter.jhtml?identifier=3047051

▸ A rise in tuberculosis cases will occur in the United States. A recent study in Clinical Infectious Diseases showed a particular risk for undocumented immigrants with tuberculosis to be sicker longer than documented immigrants or U.S.-born patients. With this comes a potential for increased risk for transmission.

▸ Do you know about the CDC's Web site for students who are planning to Study Abroad (www.cdc.gov/Features/StudyAbroad

[email protected]

Happy 2009! It's time for the annual look into the future of infectious diseases.

Two common themes were evident last year: increasing antibiotic resistance, and changing epidemiology and vaccine-preventable infections. Last year's predictions that were on the mark included the rise in pneumococcal serotype 19A, the drop in rotavirus cases, the lack of a national solution to vaccine reimbursement, the need for new strategies to raise vaccine coverage rates, and the rise in methicillin-resistant Staphylococcus aureus (MRSA) infections. This year, some similar themes prevail and some items may surprise you:

▸ MRSA will become a more prominent pathogen in your local neonatal intensive care unit (NICU). Practicing pediatricians are well aware of the emergence of MRSA. As evidence, most have probably drained more abscesses in the last year than in their entire career to date. Sporadic phone calls have alerted us to cases of MRSA infection in community hospital nurseries, and while we have not encountered a NICU outbreak of MRSA infection, they are well reported and may be difficult to halt. Active NICU surveillance (periodic nasal screening), screening of new admissions hospitalized elsewhere, and utilization of contact precautions (until results are available) may be necessary.

▸ Multidrug-resistant gram-negative infections will emerge throughout pediatric hospitals, and no new help is on the horizon for these bad bugs, which have been coined the ESKAPE bacteria. They include two gram-positive bugs—Enterococcus faecium, Staphylococcus aureus, and gram negatives including four species of Klebsiella, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—which together are responsible for two-thirds of all health care-associated infections. While a few new drugs are available or coming for MRSA, there are few that target gram-negative pathogens. For more information, check out the article by Dr. Helen Boucher of Tufts University (Clin. Infect. Dis. 2009;48:1-12).

▸ Parental declinations of certain vaccines will plateau. No question that pediatricians are spending an increasing amount of time addressing parental concerns regarding vaccines, but the majority of parents still trust their pediatrician to provide appropriate vaccine information. The key, though, is making sure you appropriately address their concerns and deliver a clear and positive message with high-quality information.

Check out Meg Fisher's article in the September 2008 Pediatric Infectious Disease Journal for a great discussion of vaccine safety (Pediatr. Infect. Dis J. 2008:27:827-30).

▸ Pertussis cases will hit an all time low overall but beware: Outbreaks will still occur, particularly among older children. Implementation of the adolescent/adult tetanus-diphtheria-reduced antigen acellular pertussis (Tdap) vaccine is ongoing, but we still have a large susceptible population of children aged 8-12 years, as well as adults. We recently cared for a 5-week-old infant with whooping cough who required ECMO (extracorporeal membrane oxygenation). I suspect we will continue to see such cases.

The role of postpartum Tdap is important, and pediatricians should encourage their obstetrics colleagues to use a standing order to give vaccine to mothers before hospital discharge (if they have not received a tetanus-containing vaccine in the past 2 years, or prior Tdap).

▸ The new improved pneumococcal conjugate vaccine may be closer than you think. The emergence of multidrug-resistant serotype 19A disease has challenged the management of pneumococcal infection from acute suppurative otitis media to more serious infections like pneumonia and meningitis. Last May, the Food and Drug Administration granted fast-track designation for the Wyeth 13-valent vaccine (which includes 19A) to speed the process.

▸ Cases of Clostridium difficile will increase. In 2005, the Centers for Disease Control and Prevention alerted us to the reports of an increase in incidence and severity of C. difficile-associated disease (CDAD), both community acquired and health care-facility acquired or associated. While most practitioners are aware that the major driving force in CDAD is antimicrobial use, this strain appears to be causing infection in otherwise healthy persons who haven't received antibiotics. One study confirmed that with respect to health care-associated CDAD, the availability of adequate infection control personnel was associated with lower rates.

▸ You might see Haemophilus influenzae type b (Hib) invasive infection in the coming year. A Nov. 21 CDC report detailed information regarding the continued vaccine shortage (MMWR 2008;57:1252-5). (See Policy &Practice item, p. 23.) Vaccine supplies currently are insufficient to supply the booster dose, and some studies suggest that this dose is particularly important for protection and herd immunity. In the United Kingdom, a booster dose was not initially recommended; after an initial decrease in disease, the rate of invasive infection rose again. There is concern that prolonged deferral of the Hib booster in the United States may produce similar results, so be on the look out.

▸ Most physicians are still unaware of the new guidelines for subacute bacterial prophylaxis. In 2007, the American Heart Association issued the first major revision of these guidelines and endorsed antimicrobial prophylaxis for only five circumstances: prosthetic heart valves, prior infective endocarditis, cardiac transplant with valvulopathy, unrepaired cyanotic congenital heart disease, and repaired congenital heart disease with either prosthetic patch or other device in the first 6 months after placement or beyond that if there is a residual defect at the site of patch or device. Read more about it at: www.americanheart.org/presenter.jhtml?identifier=3047051

▸ A rise in tuberculosis cases will occur in the United States. A recent study in Clinical Infectious Diseases showed a particular risk for undocumented immigrants with tuberculosis to be sicker longer than documented immigrants or U.S.-born patients. With this comes a potential for increased risk for transmission.

▸ Do you know about the CDC's Web site for students who are planning to Study Abroad (www.cdc.gov/Features/StudyAbroad

[email protected]

Happy 2009! It's time for the annual look into the future of infectious diseases.

Two common themes were evident last year: increasing antibiotic resistance, and changing epidemiology and vaccine-preventable infections. Last year's predictions that were on the mark included the rise in pneumococcal serotype 19A, the drop in rotavirus cases, the lack of a national solution to vaccine reimbursement, the need for new strategies to raise vaccine coverage rates, and the rise in methicillin-resistant Staphylococcus aureus (MRSA) infections. This year, some similar themes prevail and some items may surprise you:

▸ MRSA will become a more prominent pathogen in your local neonatal intensive care unit (NICU). Practicing pediatricians are well aware of the emergence of MRSA. As evidence, most have probably drained more abscesses in the last year than in their entire career to date. Sporadic phone calls have alerted us to cases of MRSA infection in community hospital nurseries, and while we have not encountered a NICU outbreak of MRSA infection, they are well reported and may be difficult to halt. Active NICU surveillance (periodic nasal screening), screening of new admissions hospitalized elsewhere, and utilization of contact precautions (until results are available) may be necessary.

▸ Multidrug-resistant gram-negative infections will emerge throughout pediatric hospitals, and no new help is on the horizon for these bad bugs, which have been coined the ESKAPE bacteria. They include two gram-positive bugs—Enterococcus faecium, Staphylococcus aureus, and gram negatives including four species of Klebsiella, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—which together are responsible for two-thirds of all health care-associated infections. While a few new drugs are available or coming for MRSA, there are few that target gram-negative pathogens. For more information, check out the article by Dr. Helen Boucher of Tufts University (Clin. Infect. Dis. 2009;48:1-12).

▸ Parental declinations of certain vaccines will plateau. No question that pediatricians are spending an increasing amount of time addressing parental concerns regarding vaccines, but the majority of parents still trust their pediatrician to provide appropriate vaccine information. The key, though, is making sure you appropriately address their concerns and deliver a clear and positive message with high-quality information.

Check out Meg Fisher's article in the September 2008 Pediatric Infectious Disease Journal for a great discussion of vaccine safety (Pediatr. Infect. Dis J. 2008:27:827-30).

▸ Pertussis cases will hit an all time low overall but beware: Outbreaks will still occur, particularly among older children. Implementation of the adolescent/adult tetanus-diphtheria-reduced antigen acellular pertussis (Tdap) vaccine is ongoing, but we still have a large susceptible population of children aged 8-12 years, as well as adults. We recently cared for a 5-week-old infant with whooping cough who required ECMO (extracorporeal membrane oxygenation). I suspect we will continue to see such cases.

The role of postpartum Tdap is important, and pediatricians should encourage their obstetrics colleagues to use a standing order to give vaccine to mothers before hospital discharge (if they have not received a tetanus-containing vaccine in the past 2 years, or prior Tdap).

▸ The new improved pneumococcal conjugate vaccine may be closer than you think. The emergence of multidrug-resistant serotype 19A disease has challenged the management of pneumococcal infection from acute suppurative otitis media to more serious infections like pneumonia and meningitis. Last May, the Food and Drug Administration granted fast-track designation for the Wyeth 13-valent vaccine (which includes 19A) to speed the process.

▸ Cases of Clostridium difficile will increase. In 2005, the Centers for Disease Control and Prevention alerted us to the reports of an increase in incidence and severity of C. difficile-associated disease (CDAD), both community acquired and health care-facility acquired or associated. While most practitioners are aware that the major driving force in CDAD is antimicrobial use, this strain appears to be causing infection in otherwise healthy persons who haven't received antibiotics. One study confirmed that with respect to health care-associated CDAD, the availability of adequate infection control personnel was associated with lower rates.

▸ You might see Haemophilus influenzae type b (Hib) invasive infection in the coming year. A Nov. 21 CDC report detailed information regarding the continued vaccine shortage (MMWR 2008;57:1252-5). (See Policy &Practice item, p. 23.) Vaccine supplies currently are insufficient to supply the booster dose, and some studies suggest that this dose is particularly important for protection and herd immunity. In the United Kingdom, a booster dose was not initially recommended; after an initial decrease in disease, the rate of invasive infection rose again. There is concern that prolonged deferral of the Hib booster in the United States may produce similar results, so be on the look out.

▸ Most physicians are still unaware of the new guidelines for subacute bacterial prophylaxis. In 2007, the American Heart Association issued the first major revision of these guidelines and endorsed antimicrobial prophylaxis for only five circumstances: prosthetic heart valves, prior infective endocarditis, cardiac transplant with valvulopathy, unrepaired cyanotic congenital heart disease, and repaired congenital heart disease with either prosthetic patch or other device in the first 6 months after placement or beyond that if there is a residual defect at the site of patch or device. Read more about it at: www.americanheart.org/presenter.jhtml?identifier=3047051

▸ A rise in tuberculosis cases will occur in the United States. A recent study in Clinical Infectious Diseases showed a particular risk for undocumented immigrants with tuberculosis to be sicker longer than documented immigrants or U.S.-born patients. With this comes a potential for increased risk for transmission.

▸ Do you know about the CDC's Web site for students who are planning to Study Abroad (www.cdc.gov/Features/StudyAbroad

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

www.pediatricnews.com

I'd like to clear up some of the controversy regarding short-course antibiotic therapy for streptococcal tonsillopharyngitis versus longer-term therapy.

A meta-analysis published this summer from a group in Athens is the latest to call into question the wisdom of using antibiotics for less than 10 days in the treatment of group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis. They examined 11 randomized controlled trials (including one of mine) comparing short-course (7 days or less) versus long-course (at least 2 days longer than short course) treatment.

The investigators concluded that short-course therapy produced inferior bacteriologic cure rates, even though the results were only statistically significant among the studies that compared short vs. long courses of penicillin (Mayo Clin. Proc. 2008;83:880–9).

In fact, in the study from my group that they included, 5 days of twice-daily treatment with cefpodoxime was as efficacious in bacteriologic eradication and clinical response (defined as cure plus improvement) as 10 days of cefpodoxime therapy, and both regimens produced superior bacteriologic efficacy, compared with a 10-day regimen of penicillin V three times daily in the treatment of GABHS tonsillopharyngitis in children (Arch. Pediatr. Adolesc. Med. 1994;148:1053–60).

Indeed, the Food and Drug Administration has approved three oral antibiotics for 5-day strep throat treatment in both children and adults: cefdinir (Omnicef), cefpodoxime (Vantin), and azithromycin (Zithromax). With the FDA approval, use of these three agents is considered a standard of care and therefore medicolegally safe. Nonetheless, the American Academy of Pediatrics continues to recommend 10 days of penicillin as the treatment of choice, and many practitioners are reluctant to embrace the short-course concept.

When I advocate in favor of short-course therapy, I'm speaking only of those that have the FDA labeling to back it up. I wouldn't use first-generation cephalosporins such as cephalexin (Keflex) or cefadroxil (Duricef) in short course, for example, even though those generics are nearly as cheap as penicillin and might be more effective than 10 days of penicillin or as effective as 5 days of one of the approved agents (although they probably aren't). Without the FDA indication for 5-day use, the medicolegal risk is too great.

But with cefdinir, cefpodoxime, and azithromycin, the literature clearly supports 5-day efficacy—defined by the FDA as 85% or better bacterial eradication at the end of treatment—in treating strep throat. Cefdinir and cefpodoxime have recently become available as generics and thus are less costly than they were before, although they are still more expensive than the first-generation cephalosporins.

In a meta-analysis Dr. Janet Casey and I conducted of 22 trials involving a total of 7,470 patients, short-course second- and third-generation cephalosporins produced a bacterial cure rate superior to 10 days of penicillin, with an odds ratio of 1.47 and cure rates of 90% vs. 70%. On the other hand, we found that 5 days of penicillin is inferior to 10 days of penicillin, just as the Mayo group did (Pediatr. Infect. Dis. J. 2005;24:909–17).

The Athens group lumped together studies using different types of comparisons in making their overall conclusion, which I don't think is a helpful way of reporting meta-analysis data. Moreover, as Dr. Casey and I pointed out in our article, in the real world few children complete 10 days of treatment anyway. When you factor that in, the 5-day option looks even better.

Another important issue affecting the results of these studies is whether strep carriers were excluded. Penicillin does not do a good job of eradicating carrier status, whereas cephalosporins do. In addition, a strep carrier who has symptoms caused by a virus would be mistakenly recorded as a clinical failure.

We separately analyzed the nine studies that excluded strep carriers in our 2005 meta-analysis, as well as in another meta-analysis that we published in 2004 in which we showed that the likelihood of bacteriologic and clinical failure of GABHS tonsillopharyngitis in children is significantly less with 10 days of treatment with an oral cephalosporin than with oral penicillin for 10 days (Pediatrics 2004;113:866–82). In both analyses, the cephalosporins still came out ahead.

Finally, cure rates for azithromycin should not be lumped into the same category as rates for the cephalosporins, because azithromycin has a half-life of about 96 hours, compared with 2–4 hours with the cephalosporins. Thus, when you give azithromycin for 5 days, it stays in the body as long as 10 days of another antibiotic.

The issue here is in the dosing, which often causes confusion among practitioners. For strep throat, the 5-day dose of azithromycin for children is a single 10- to 12-mg/kg per day dose for each of the 5 days. This is different from the dosage given for otitis media or sinusitis, which is 10–12 mg/kg per day for just the first day, followed by 5 mg/kg per day for the next 4 days. It's easy to forget that, because we write far more prescriptions for ear and sinus infections.

Dr. Casey and I have shown that the otitis media dose of azithromycin is inferior for the treatment of strep throat (Clin. Infect. Dis. 2005;40:1748–55). If you accidentally prescribe the lower dose for strep throat and the child develops rheumatic fever, you may have a lawsuit on your hands.

In adolescents and adults with strep throat, this means that you need two of the standard “Z-PAKs” in order to give a high enough dose for eradication. The Z-PAKs label doesn't say this because our data showing inferiority weren't published until after the product was approved for treating strep throat. Thus, in this case you won't get sued if you just prescribe one pack, … but there's a better chance the patient will be cured if you prescribe two.

I hope I've convinced you that 5-day treatment is a viable option for strep throat, because the guidelines from AAP and other organizations aren't likely to change any time soon. Guidelines should be based on data, but the current guideline writers prefer to harken back to penicillin studies done in the 1940s and 1950s, when rheumatic fever was still prevalent. However, a recommendation for 10 days of cephalosporin or amoxicillin for treating strep throat is currently under discussion. It stands to reason: The only way to prevent rheumatic fever is to eradicate strep, and these drugs do that better than penicillin!

Keep in mind too that at the time those old studies were done, penicillin cured 95% of strep bacteria. Today that number is just 65%, because of the bombardment of antimicrobials we've been using for the last several decades. The newer literature suggests it's time for change.

I have performed clinical trials, received honoraria, and/or served as a consultant for Abbott Laboratories and Pfizer Inc.

[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]

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.