Christopher J. Harrison

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

Methicillin-resistant Staphylococcus aureus has become the new disease of the moment, with alarming headlines almost daily this autumn about the “killer” bacterium. While of course MRSA is a real concern, we physicians can help by reassuring people that we have tools to deal with this problem.

The media frenzy began early in October 2007, with reports of MRSA-related deaths of high school athletes in at least three states, and numerous other cases of MRSA infection in schools around the country.

Then on Oct. 17, the Centers for Disease Control and Prevention (CDC) reported on the 8,987 cases of invasive MRSA from July 2004 to December 2005 in nine sentinel sites associated with the Active Bacterial Core Surveillance system (JAMA 2007;298:1763-1804).

With headlines like CNN's “Experts: Drug-Resistant Staph Deaths May Surpass AIDS Toll,” it's not surprising that our phone lines became overheated. We received four times the usual number of calls after that item appeared, from both patients and physicians worried about MRSA.

One physician wanted to know how to advise a local high school about the industrial-strength fumigation performed by a hazmat-like team that had been shown on TV. One school proposed bleaching its football field because that's where players' injuries occurred. I suggested that neither procedure was warranted.

The fact is that humans have coexisted with S. aureus for a long time. More persistent MRSA strains appeared about 10 years ago. But both MRSA and methicillin-sensitive S. aureus (MSSA) are capable of causing serious invasive disease. In fact, I recently treated an adolescent with disseminated MSSA disease that included septic thrombophlebitis; abscesses in his lung, spleen and liver; septic arthritis; and sepsis.

On the flip side, the majority of MRSA cases still present as common skin and soft-tissue infections that do not progress to life-threatening illness.

We have long known that S. aureus causes more disease in the warmer months, that it seems to have a male predominance, and that it takes advantage of open wounds, whether surgical or traumatic.

What's new in the last 5-10 years is that more strains are resistant to traditional antistaphylococcal antibiotics, and some (both MRSA and MSSA) have virulence genes that make invasive infections more likely, often in otherwise healthy adolescents.

In our community, about 60% of local disease—furuncles, pyoderma, impetigo—are due to MRSA.

I follow an algorithm that involves incision and drainage as the first step, while obtaining a specimen for culture and stratifying the severity of systemic illness and vulnerability of the infected site(s) (AAP News 2004;25:105).

Antibiotics may not always be necessary with single site infection in a child who is afebrile and previously healthy, while those who are febrile should receive empiric clindamycin or trimethoprim/sulfamethoxazole in mild to moderate disease, or even vancomycin for severe life-threatening disease.

Usually we use clindamycin, which still covers 90% of MRSA strains in Kansas City.

However, if the child is critically ill, we start with vancomycin because we don't want to risk that 10%.

The data reported by the CDC tell us that the majority of cases continue to be health care associated, and the vast majority of cases occur in adults.

Among 5,287 cases from six of the sentinel sites, just 134 were aged 17 and younger.

That small a number makes it difficult to extrapolate meaningfully from the overall epidemiologic data.

An elderly person with underlying chronic illness who dies of MRSA bacteremia is not as striking a story on the evening news as a sudden death in a previously healthy 16-year-old athlete. Death in a healthy child is unexpected these days and raises concern because parents can feel that they have no control, leading to a sense of panic.

And the media don't help matters by using words like “Superbug.”

This term has been used at other recent times to refer to Clostridium difficile, Streptococcus pneumoniae, and a variety of other organisms that are either difficult to treat or that are associated with bad outcome. Will the real “Superbug” please stand up? On second thought, let's just stop using the word altogether.

Another overused phrase is “flesh-eating bacteria.” In fact, most S. aureus can “eat flesh,” using coagulase and other enzymes. That's what helps form boils or carbuncles in pockets within the subcutaneous tissues. Alarming “flesh-eating” strains which can be lethal in a day or 2 have been around for decades, although they are more frequent these days; they can be either MRSA or MSSA.

But in fact, Group A streptococcus was the original bug to be labeled “flesh eating bacteria”—another case of bacterial identity theft.

We physicians can be the voices of reason. We can reassure our patients about MRSA while giving them practical advice on how to avoid it and the danger signs if they do become infected. This includes such common-sense measures as frequent hand washing, which of course helps prevent influenza and other infectious diseases that kill far more people than MRSA does.

Physicians who work with athletes or athletic teams can help by offering players practical advice that includes wiping the last person's sweat off equipment with antiseptic solutions such as diluted Clorox before using it themselves, not sharing towels, giving prompt attention to skin wounds, and practicing general good hygiene. The CDC has an excellent MRSA site that you can recommend to patients: www.cdc.gov/features/mrsainschools

The newly reported CDC data provide us with important benchmark information about the prevalence of MRSA invasive disease in the United States, so that public health professionals can begin making recommendations about how best to minimize recurrent or serious disease using logical and practical tools.

Recognition of the early signs of systemic infection and prompt intervention are the keys.

We have multiple antibiotics that still effectively treat even the scariest strains.

Other simple strategies of infection control and hygiene can reduce risks, too. Rarely if ever will these strategies include fumigating or shutting down schools.

And let's keep in mind: Panic is not a practical tool.

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

[email protected]

Emerging evidence suggests that we shouldn't be prescribing prophylactic antibiotics for every child with recurrent urinary tract infection, even when vesicoureteral reflux is present.

Just as the pendulum has swung over the last decade away from universal use of antibiotics with acute otitis media toward selective use of “watchful waiting,” data on recurrent urinary tract infection (UTI) suggest that children with lower grades of reflux may not benefit from long-term prophylactic antibiotics. These children may in fact be disadvantaged by prophylaxis's selecting for increased antimicrobial resistance. Therefore, even when we decide to use antimicrobial prophylaxis in selected children with both recurrent UTI plus high-grade vesicoureteral reflux (VUR), we need to consider carefully whether the traditional prophylactic drugs are really the best choice.

The latest evidence comes from a large database study published by Dr. Patrick Conway of the University of Pennsylvania, Philadelphia, and his associates. They retrospectively analyzed the electronic health records of 74,974 children aged 6 years and younger in 27 primary care practices in Delaware, New Jersey, and Pennsylvania over a 5-year period, and identified 666 who had been diagnosed with a first UTI; 611 had at least 24 days of observation. There were 83 with recurrent UTIs, 51 (61%) of which were caused by a resistant pathogen (JAMA 2007;298:179-86).

Significant predictors of recurrence included age 3-4 years (not the toddler in diapers as we might have suspected), white race, and grades 4-5 VUR. Factors that did not affect the risk of recurrent infection included sex, grades 1-3 VUR, and antimicrobial exposure. Because children had different lengths of follow-up (mean 408 days), time to recurrence was used as the primary outcome measure. Use of antimicrobial prophylaxis had no significant overall effect on time between the initial UTI and the first recurrent UTI, even when the children were stratified by age, race, sex, or VUR grade.

Importantly, despite the lack of effect on time to recurrent UTI, prophylaxis was associated with a 7.5-fold increased likelihood of a resistant pathogen causing the recurrence. In the overall group of 611 children with UTI, trimethoprim-sulfamethoxazole was prescribed for 61%, amoxicillin for 29%, nitrofurantoin for 7%, and other antimicrobials including first-generation cephalosporins for the other 3%. Although the investigators didn't report which antibiotics were used in the 83 children with recurrent UTI, they did note that none of the 9 children who received nitrofurantoin had a recurrence.

This study follows last year's publication of a Cochrane review comprising data for 406 children from five randomized studies in which antibiotic prophylaxis was compared with placebo or no treatment (Cochrane Database Syst. Rev. 2006;3:CD001534).

The results were not conclusive. Antibiotics were found to reduce the risk of repeated positive urine culture (relative risk 0.44), but there was no information about rates of symptomatic recurrent infection or long-term renal sequelae. In one study, nitrofurantoin was more effective than trimethoprim in preventing recurrent UTI over a 6-month period (RR 0.48), but patients were more likely to discontinue nitrofurantoin because of side effects. In another study, cefixime was more effective than nitrofurantoin in preventing recurrent UTI during the first 6 months (RR 0.74), but adverse reactions were more common with cefixime than with nitrofurantoin (63% vs. 26%).

Historically, the use of antimicrobial prophylaxis in all children with UTIs–in the 1970s–was based on studies that included asymptomatic bacteriuria as well as the more important symptomatic UTIs. The '70s data suggested that prophylaxis prevented recurrent positive urine cultures, many of which were from asymptomatic children. There also were insufficient data to prove that prophylaxis prevented renal scarring or the need for kidney transplantation. People had presumed that asymptomatic bacteriuria was as important as symptomatic UTI in leading to long-term kidney issues, but there was no definitive evidence for this.

Later imaging results indicated that VUR was associated with more frequent UTI, although we still didn't have proof of their association with long-term renal damage. Recent data indicate that lower grades of reflux are not statistically associated with long-term kidney injury or renal scarring, and now we see that the first recurrent UTI occurs just as soon, whether children are on or off prophylaxis. At the same time, we are increasingly concerned about antimicrobial resistance. The drugs typically used for prophylaxis–amoxicillin, trimethoprim-sulfamethoxazole, and first-generation cephalosporins–have become less and less active in vitro against the most common UTI pathogen, Escherichia coli.

Until we get more definitive data, I think that we can be more selective in deciding which patients with a first UTI should receive antimicrobial prophylaxis without exposing these children to extra risks. My personal bias is to limit prophylaxis to those in whom imaging shows either grade 4 or 5 VUR or other obstructive anatomic abnormalities. For children with lower grades of reflux, I would simply observe them for a recurrence pattern, keeping in mind that some may show more frequent recurrences than expected. This subset might need urologic referral to look for more subtle problems that can benefit from intervention. Given what we know about the risk of antimicrobial resistance, my advice would be to avoid 365 days per year of antibiotic exposure (prophylaxis) with low-grade VUR unless there were more than three UTI recurrences per year.

For children with high degrees of reflux (4 and 5), in vitro resistance data and hints from recent studies suggest that nitrofurantoin may currently be our best bet for prophylaxis. The micronized formulation (Macrobid) appears to have the fewest gastrointestinal side effects, so I'd use it as a first choice.

If patients don't tolerate nitrofurantoin, we should look at local resistance patterns, or perhaps a first-generation cephalosporin might be the next best choice. It's possible that broader-spectrum antimicrobials may work well in certain patients, but we don't have enough data on the prevalence of mechanisms of resistance, and tendencies to induce resistance, to comfortably use them empirically.

And, of course, we need to remember that when we do decide to prescribe long-term daily antibiotics, we can't assume for a minute that adherence will be complete. As the old saying goes, “Two-thirds of patients take two-thirds of the antibiotic two-thirds of the days prescribed.” One thing for which we have definitive proof is that nobody takes a drug every single day.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

Two new studies may help identify the pathogen for cervical adenopathy in children, an often frustrating condition with numerous and divergent potential causes.

Most of us are comfortable treating certain presentations, such as tender, erythematous, anterior cervical lymphadenitis, for which the cause should be Staphylococcus aureus or Group A streptococci (GAS). We usually prescribe antibiotics and expect improvement within 10 days. A second presentation with a simple disposition is the nontender, unilateral, submandibular node with a purplish color and thinning of the skin over it. Usually, swelling has been present for weeks but has only recently developed the new color and thinning skin. This latter condition is usually nontuberculous mycobacterium (NTM) and is cause for referral to a surgical colleague.

But we have less certainty when predicting the cause of firm, unilateral, nontender adenopathy persisting after the usual 10-day course of antibiotics for initially tender adenitis, or when the child presents initially with nontender, unilateral, soft, mobile cervical adenopathy. Such nodes will often resolve spontaneously if we simply observe them for another 2–3 weeks. Those that don't are often the result of NTM. During the added observation, we often begin a diagnostic quest for such diverse causes as Epstein-Barr virus, Bartonella species, tuberculosis, NTM, Toxoplasma, or in some areas Histoplasma.

If our diagnostic quest is unrevealing and the node persists beyond 4–6 weeks, we usually refer for surgical excision to obtain histopathologic evaluation, plus cultures for mycobacteria, fungi, and conventional bacteria. Where available, fine-needle aspiration can fulfill the same objective. However, parents may become frustrated with the “tincture of time” approach and the slow pace before deciding on surgical referral. Two recent studies offer hope that we can make more rapid and accurate decisions.

A Dutch group reviewed the sensitivity and specificity of tuberculin skin testing (TST) in identifying NTM in Netherlands-born children (median age 48 months) with cervicofacial lymphadenopathy. Of these, 15 had immigrant parents, but none had traveled to TB-endemic areas (Clin. Infect. Dis. 2006;43:1547–51).

A total of 112 received a diagnosis of an NTM, confirmed by culture, polymerase chain reaction testing, or both. The infections were caused by Mycobacterium avium-intracellulare in 83 patients, by M. haemophilum in 21, and by other NTM species in eight. Nonmycobacterial lymphadenopathies were present in 46 of the children, including Bartonella henselae in 20, streptococcal infections in 14, staphylococcal infections in 11, and tuberculosis in one.

Using a cutoff of 5 mm of induration to define a “positive” NTM result, the TST's overall accuracy in detecting NTM was 0.84 (sensitivity, 70%; specificity, 98%; positive predictive value, 98%; and negative predictive value, 64%). Although 10-mm induration is the usual cutoff for M. tuberculosis, this study's data suggest that a 5–10-mm cutoff can predict NTM in previously healthy children with cervical lymphadenopathy, particularly where endemic TB is not common.

In my practice, I have used 5–10 mm of TST induration to strengthen my sense that NTM was the agent for nontender, unilateral cervical adenopathy of greater than 2 weeks' duration. This study increases my confidence with this approach.

In general, because community-acquired methicillin-resistant S. aureus has become more common, my algorithm is to first use 10 days of clindamycin, for antistaphylococcal and -GAS coverage. If the node persists but is asymptomatic and stable in size, I begin a work-up during a 2–4-week observation period before considering surgical referral. Unlike adults, in whom nonpainful neck masses are cancer until proven otherwise, prepubertal children rarely have this presentation for cancer, and so we can wait to see if slow resolution occurs.

My work-up includes serology, TST, and a chest x-ray (CXR). The CXR might show hilar adenopathy, histoplasmosis, or—rarely—tumor. Serology seems helpful only in the approximately 10% of these cases that turn out to be something other than NTM, such as Toxoplasma, Bartonella, or Histoplasma. Unfortunately, this work-up plus observation usually adds up to 6–8 weeks before surgical referral.

Clinical clues can sometimes hasten this process. If the node develops that rock-hard or adherent feel to palpation, I refer earlier to rule out the rare cancerous node. If the node breaks down to drain, or evolves into the purplish node noted above, prompt referral is warranted because of likely NTM.

Barring those or other new clues, can we more quickly feel confident in earlier surgical referral? The Dutch data suggest that we could postpone serologic evaluation until after a TST and perhaps a CXR. Here's how I would proceed, based on the size of the TST induration:

▸ Less than 5 mm and normal CXR. Proceed with serology and use standard observation before surgical referral.

▸ Less than 5 mm and hilar adenopathy. This can signify histoplasma, evolving NTM, or TB. If suspicion for TB is high because of social factors, obtain TST on family members. If family TSTs are negative and still no symptoms are present, then there are two options. First, one could do the serologies and, if they are negative, wait to reapply a TST in 4 weeks. Alternatively, referral for biopsy at this point could more rapidly identify the pathogen.

▸ 5–10 mm in size. Referral for surgical excision is appropriate if the child is not ill, lives where TB prevalence is low, and has no known TB exposure and no BCG vaccination. Excision not only is usually curative, but also provides tissue for microbiologic or histologic diagnosis, rendering serology unnecessary.

I don't agree with the editorial that accompanied this study, in which the author argued for multidrug antimicrobial treatment (Clin. Infect. Dis. 2006;43:1552–4). In my view, unless the position of the node places the facial nerve in jeopardy from excision, surgery is simpler than trying to keep a patient on 3–6 months of multiple, relatively expensive drugs that have potential adverse effects and that children don't like to take. At least one-third of these children either can't tolerate the regimen or don't respond to it, and end up having surgery anyway. The rate of recurrence after surgery is lower, about 5%–8%.

▸ Greater than 10 mm in size. This is generally presumed to be either latent or—if the CXR is positive—active TB. An appropriate TB regimen can be started. Some NTM infections can cause that degree of induration, but these cases are traditionally treated as TB is ruled out. This is possible with node biopsy. Whether to start TB medications before biopsy depends on risk factors.

For this situation, the second article, from Japan, offers future hope for an additional nonsurgical test to reduce the uncertainty about whether the child with a 10-mm or greater induration actually has NTM or TB. The authors evaluated a whole-blood interferon- and enzyme-linked immunosorbent assay (the Quantiferon TB-2G test, made by Cellestis Ltd.) in 50 healthy volunteers, 50 patients with active TB, and 100 patients with known NTM. They also skin-tested each individual (Clin. Infect. Dis. 2006;43:1540–6).

Among the healthy students, TSTs were negative in 64% and the Quantiferon test was negative in 94%. In confirmed TB cases, 64% had greater than 10-mm TST and only 4% had negative Quantiferon results. With pulmonary M. avium-intracellulare, 60% had greater than 10-mm TST and only 7% had positive Quantiferon results. The Quantiferon's mean sensitivity was 86% and specificity 94%. Although the Quantiferon does cross-react with a few NTM species, it does distinguish between TB and M. avium-intracellulare, which is the most common NTM.

The Quantiferon is currently marketed only for adults, and I don't think we have the data to support its use in children just yet. But ongoing studies should produce pediatric data in the next few years. Hopefully, this targeted test will become the new generation TB skin test substitute.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

The evolving picture of Clostridium difficile-associated disease suggests that we may need to revise our traditional approach to the child with persistent diarrhea.

The increase in frequency and severity of health care-associated Clostridium difficile-associated disease (CDAD) in North America over the last several years is believed to be due in large part to a newer, more virulent strain first reported a little over a year ago (N. Engl. J. Med. 2005;353:2433–41, 2442–9)

At the same time, we've been seeing previously healthy patients without prior antimicrobial use, including children, become infected in the community. Of 23 community-acquired cases reported to the CDC from four states during May and June of 2005, 11 were in children less than 18 years of age (MMWR 2005;54:1201–5).

In a 3-year prospective study published in the fall of 2006, 7% of 1,626 stool samples from children who presented to an emergency department with diarrhea were positive for C. difficile toxin (Clin. Infect. Dis. 2006;43:807–13). It's not clear from the data whether this represents an increase, but we do know that it's a problem.

I think we need to consider the possibility of CDAD in any child—even those without prior antibiotic use—who has persistent diarrhea lasting more than 5 days, or very severe diarrhea of more than 8–10 stools a day. The data suggest that about 1 in 10 of these children will have stool assays positive for C. difficile toxin.

Some children with CDAD—perhaps 25%–35%—improve on their own within a week and may not need treatment. The ones whose condition does not resolve in a week are candidates for metronidazole therapy. About 15%–20% of those treated will fail. For them, the American Academy of Pediatrics advises a second course of metronidazole. For the 15%–20% who will fail or relapse a second time, oral vancomycin is recommended.

While you're waiting for the toxin assay to come back, I think it's a good idea to use probiotics such as Lactobacillus GG species or Saccharomyces boulardii as a preemptive strike, even before you know the pathogen. Data suggest that those “good bacteria” might be helpful in restoring balance in the flora and thus reduce symptoms due to a variety of diarrhea-causing organisms, including rotavirus and other viral agents as well as C. difficile (Am. J. Gastroenterol. 2006;101:812–22).

Because alcohol-based hand sanitizers aren't as effective at removing infectious C. difficile spores from contaminated hands, it's important to wash your hands with soap and water after examining children with prolonged diarrhea. However, until you know what the pathogen is, use of alcohol-based products also is recommended because they're better at eliminating other GI pathogens including the usual virus suspects. I will typically wash with soap and water first, dry my hands, then rub in the sanitizer as I'm walking away from the sink after seeing children with persistent diarrhea and an as-yet undefined pathogen.

The appearance of CDAD in previously healthy, community-dwelling individuals is a new and worrisome change. Until recently, antibiotic use was believed to be the nearly universal culprit that disrupted the natural gut flora and allowed C. difficile to flourish, leading to the presentations ranging from frequent diarrhea to the characteristic pseudomembranous colitis.

Now, however, it appears that in some children CDAD may be initially triggered by a common viral gastroenteritis—such as rotavirus, norovirus, or adenovirus—which lowers the colonic pH enough to prompt the normally-quiescent C. difficile to begin overproducing toxin.

This recent shift may be related to the newly described strain, which not only produces many times the usual amount of C. difficile toxins A and B, but also contains a mutation that leads to the production of an additional binary toxin that appears to be even more toxic to gut mucosa than are A and B. We don't fully understand the implications of this new strain. It is becoming clear, though, that it's not a temporary situation as we had hoped.

On the positive side, several ongoing trials offer some reason for optimism. A group at Baylor College of Medicine in Houston is now conducting National Institutes of Health-funded phase III trials of nitazoxanide in adults with CDAD. Nitazoxanide (Alinia, manufactured by Romark Laboratories L.C., Tampa, Fla.), which acts by interfering with anaerobic metabolic pathways, is already licensed for the treatment of parasitic diseases of the gastrointestinal tract, such as giardiasis, and has been used in millions of children worldwide. So far, the CDAD data look good.

A totally different approach to CDAD treatment is with a nonabsorbable polymer called tolevamer, manufactured by Genzyme Corp., Cambridge, Mass. It works by binding C. difficile toxins A and B. Because it's not an antibiotic, tolevamer would be expected to avoid the problems associated with antimicrobial treatment, including resistance. Phase II data suggested that it worked at least as well as vancomycin and was associated with less recurrence of diarrhea, although there was an increased risk for hyperkalemia (Clin. Infect. Dis. 2006;43:411–20). Genzyme expects to complete phase III trials this year. The agent has been given fast-track designation by the Food and Drug Administration, and the company anticipates commercial approval in 2008.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

Prebiotics and probiotics might offer a way to both prevent and treat disease by enhancing the body's natural immune defense mechanisms.

Recognition that certain naturally occurring bacteria in the gut might be beneficial to health dates back to the early 1900s, when Nobel laureate Dr. Eli Metchnikoff reported that peasants who consumed sour milk with live Lactobacillus bulgaricus lived longer than other people. Now, emerging data suggest that supplementation with health-associated bacteria, also known as “probiotics,” can prevent or reduce diarrhea caused by altered gut flora from antibiotics or rotavirus.

In addition, “prebiotics,” the nondigestible oligosaccharides that stimulate growth of existing probiotic bacteria, also have drawn interest. Prebiotic supplements that do not contain added probiotics could avoid some of the problems associated with probiotics, such as difficulty maintaining live organisms until administration and potential bacteremia in immunosuppressed individuals.

Present in breast milk, prebiotics enhance the growth of existing probiotic bacteria strains Bifidobacteria and Lactobacillus, which predominate in the guts of breast-fed infants. The gut flora of bottle-fed infants, in contrast, tend to comprise primarily Enterobacteriaceae and Clostridia.

Several studies—some supported by infant formula manufacturers—show that adding prebiotic galacto-oligosaccharides and fructo-oligosaccharides to cow's milk formula can result in intestinal flora in bottle-fed infants similar to that in breast-fed infants. This, in turn, results in a reduced intestinal load of more pathogenic bacteria in the infant.

Mucosal and systemic immunity also appear to be enhanced with prebiotic supplementation, possibly reducing subsequent immune-mediated disease such as asthma and allergies. In one prospective, placebo-controlled study, 102 infants at high risk for atopy were fed prebiotic-containing formula (galacto- and long-chain fructo-oligosaccharides) or formula with a placebo (maltodextrin). The atopic dermatitis rate was 9.8% for infants receiving prebiotics, compared with 23.1% for placebo (Arch. Dis. Child. 2006;91:814–9).

A growing data set suggests that pre- and probiotic supplementation in infancy can enhance IgA responses to antigenic challenge, and favorably influence T-helper cell balance, thus reducing inflammatory and/or allergic responses. One prebiotic, lactulose, is commercially available in liquid form under various brand names and is approved for treating constipation.

Whether to routinely prescribe lactulose or other prebiotics for non-breast-fed infants remains an unanswered question. Stay tuned for more data.

Meantime, I believe the data on probiotics are sufficient to support several clinical uses. I advise using a product called Lactinex, which contains both Lactobacillus acidophilus and Lactobacillus bulgaricus, as antidiarrheal prophylaxis during prolonged antimicrobial therapy, particularly with broad-spectrum agents. I also recommend it during shorter antibiotic courses if mom says that her child always develops diarrhea while on antibiotics.

Lactinex comes in tablet or packet form, with 1 million colony-forming units per tablet or 100 million per packet. The granules can be mixed with food or formula. I advise one packet per day for all ages. Older children can take two to three tablets, three to four times a day.

In the 1990s, my colleagues and I conducted a study in children on a broad-spectrum antibiotic where a 30% reduction in daily stool number and 50% fewer diarrhea days occurred with Lactinex, compared with placebo supplements. The study, funded by an antibiotic manufacturer, was not published because of higher-than-expected diarrhea rates in controls. But, it encouraged me about the potential benefit of probiotics.

Another option for acute diarrhea is Lactobacillus GG, a widely studied probiotic strain sold commercially under the brand name Culturelle. A 2001 literature review revealed that probiotics significantly lowered the risk (odds ratio 0.43) of diarrhea lasting more than 3 days, particularly with rotavirus. Of individual strains, only Lactobacillus GG showed consistent effect (J. Pediatr. Gastroenterol. Nutr. 2001;33[suppl. 2]:S17–25).

But other data suggest benefit for other probiotic organisms. A randomized study of 201 healthy, non-breast-fed day care infants aged 4–10 months compared Lactobacillus reuteri or Bifidobacterium lactis with placebo, revealing significantly fewer episodes of fever (11%, 27%, and 41%, respectively) and diarrhea (13%, 2%, 31%). Duration of diarrhea was also shorter with the probiotics (Pediatrics 2005;115:5–9).

Other exciting data include reductions in atopic disease among children whose mothers took prenatal Lactobacillus GG (Lancet 2001;357:1076–9), enhanced immune response to typhoid immunization in adults given Lactobacilli (FASEB J 1999;13:A872 [abstr]), and reduced incidence/severity of necrotizing enterocolitis in very-low-birth-weight newborns receiving Lactobacillus acidophilus plus Bifidobacterium infantis (Infloran) (Pediatrics 2005;115:1–4).

To be sure, not all pre- and probiotic studies have had positive outcomes. But, excluding immunosuppressed individuals, risk is minimal from these naturally occurring organisms, so why not use them? I predict that we'll be hearing more about this in the future.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

A debate in the vaccine community currently revolves around the wisdom of recommending universal influenza vaccine administration, rather than continuing the current strategy of focusing on high-risk individuals. I come down solidly on the side of universal immunization.

The influenza-related death toll—36,000 annually in the United States—is greater than that from all other vaccine-preventable diseases combined. Influenza also results in an average of 150,000 hospitalizations and millions of physician visits each year. Among children aged less than 5 years, hospitalization rates are nearly 500/100,000 in children with high-risk medical conditions, but still are robust at 100/100,000 even in children without high-risk conditions (MMWR 2006;55[early release]:1–41).

Given those numbers, it seems to me that we're tying one hand behind our backs when trying to defend against influenza by not immunizing all our patients.

Even the current guidelines from the Centers for Disease Control and Prevention say that “physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.” To me, that makes everyone a potential candidate. The real sticking points at present in implementing universal influenza immunization are the limitations of our infrastructure for producing, distributing, and administering the vaccine.

I practiced primary care for 8 years in the 1970s and ′80s before specializing in infectious disease. Even then, I recommended influenza vaccine to everyone who came to the office in the time leading up to influenza season. It seemed illogical to protect only a select few of my patients.

The piecemeal approach we follow now is confusing and a headache for practitioners—things are never the same from year to year. For example, this year for the first time we'll need to order enough vaccine for 24- to 59-month-olds as well as 6- to 23-month-olds, plus our older patients with high-risk medical conditions and all of their household contacts. Wouldn't it be a lot simpler just to count how many children are in our practices and order that number?

If vaccine manufacturers could be assured that we would order a certain number of doses each year, they would gear up and make them. So far, they haven't been willing to do this because it's too much of a gamble—during some seasons, as much as two-thirds of their doses have gone unused. If there were a universal recommendation with consistent year-to-year utilization, it should remove their reticence.

Manufacturers also would be aided a great deal if there were a way to make influenza vaccine without having to grow the virus in thousands of fertilized chicken eggs. In June of this year, a Canadian company called Hepalife Technologies Inc. licensed technology from researchers at Michigan State University in East Lansing for the development of new cell culture-based influenza vaccines, including one for the potential pandemic-causing strain H5N1. If the cell line is able to grow influenza virus reliably—preliminary data indicate that it is—it would greatly facilitate the manufacturing process by enabling influenza vaccine to be grown more efficiently and less expensively. It also would eliminate the egg allergy problem. I don't own stock in the company, but I am excited about this product's potential.

Of course, immunizing all of our patients within a 6-week period during October and November would be a huge challenge. It wouldn't be practical for the primary care office to be the only avenue for distribution. Grocery and drugstore chains have become major influenza vaccine vendors for adults, but generally not for children because of liability concerns. I think the effort will need to utilize public health departments to extend the infrastructure, and perhaps coordinate with schools for the older children.

There has been precedent for this. During the influenza season 2 years ago that killed several children in Colorado and in this year's Midwest mumps outbreak, county health departments moved their mobile units to schools and managed to immunize large numbers of children. Documentation may be a bit of a problem, but this can be worked out. We just need the go-ahead of a universal recommendation to get the ball rolling.

A universal immunization recommendation for routine influenza seasons would also prepare us for a pandemic situation. We currently have incomplete logistical support for potential intervention involving the entire U.S. population. This would be excellent training for our health care system, and would provide templates upon which to build. If we had 2 or 3 years of practice in immunizing everyone prior to a pandemic, we'd all be much more expert when a pandemic arrived.

Obviously, a universal recommendation doesn't mean that everyone will be immunized. But, we would be far more likely to achieve herd immunity than with what we do now. We should see fewer hospitalizations in the very old and the very young, the two groups that utilize the greatest amount of health care resources.

We know that the severe complications of influenza—invasive bacterial infections such as empyemas, bacteremias, and meningococcemia—tend to peak during and just after each influenza season because bacterial pathogens more readily invade the mucosa of influenza-damaged respiratory tracts, which are still healing for weeks after the patient's influenza infection has resolved. In a bad influenza season, emergency departments are bombarded with influenza cases and patients with sequelae during January-April. Reducing that enormous utilization of medical resources should be worth every bit of effort we'd put into getting everyone immunized in the fall.

We now have one—and will probably soon have a second—new and improved rotavirus vaccine, with which we will be able to prevent much of the winter-spring infant gastroenteritis misery. Further, a lower economic burden will result from fewer lost parental workdays. And there's another bonus: Reactogenicity is lower with the new vaccines, compared with the old RotaShield, which was withdrawn from the market in 1999.

The design of the trials that were submitted for Food and Drug Administration approval of the new vaccines included a very large sample size—with over 60,000 children each for both Merck & Co.'s bovine-derived RotaTeq and GlaxoSmithKline's human-derived Rotarix—and close follow-up. Both vaccines have been highly effective against rotavirus disease in the first year of life, including the most severe forms of illness and hospitalizations, with lower rates of vaccine-associated fever, irritability, and loose stools.

Importantly, neither vaccine appears to increase the risk for intussusception, the adverse event that caused the removal of the previous rhesus-derived RotaShield vaccine from the market. Of course, we can't be absolutely certain until the new vaccines are in widespread use—that's when the problem with RotaShield was detected. However, it's likely that the problem would have revealed itself sooner if the recalled vaccine had been tested in 60,000 subjects prior to approval.

Moreover, it makes clinical sense that if a vaccine causes less systemic response (fever, irritability, and loose stools), it also might lead to lesser reactions in the gut-associated lymphoid tissue, a proposed mechanism for the vaccine-provoked intussusceptions.

About 400,000 rotavirus-associated deaths occur each year in the developing world, but rotavirus disease usually isn't lethal for children in the United States (20–60 deaths per year). In this country, cost effectiveness is the prime issue, particularly with regard to reducing the 50,000 annual rotavirus-associated hospitalizations.

According to one estimate, rotavirus costs the United States more than $1 billion a year, including direct medical costs and parental lost workdays. Compare that with the $770 million a year to immunize the estimated 4.1 million infants in an annual birth cohort with Rotateq, which Merck has just announced will cost $62.50/dose when purchased in 10 single-dose packs. Overall, this looks like we can still come out ahead.

The benefits of a protective rotavirus vaccine also may extend beyond simply preventing gastroenteritis. This winter, an 11-month-old ill-appearing child was transferred to our facility with a sepsis picture. He had a high fever, lethargy, vomiting, and a tense fontanelle. However, he had no diarrhea and had CSF pleocytosis (WBC count of 28, half neutrophils). The next day, he developed green, mucus-laden diarrhea, which tested positive for rotavirus antigen. This was a case of aseptic meningitis due to rotavirus infection.

Such nondiarrheal initial presentations of rotavirus infection during the winter and early spring are not all that rare. Indeed, in active surveillance of 763 children aged 15 days through 4 years and admitted to the hospital between November 1997 and June 1998 with eventual rotavirus diagnosis, 9% presented initially without diarrhea (Pediatr. Infect. Dis. J. 2002;21:221–7). Rotavirus as a cause of aseptic meningitis also has been confirmed using polymerase chain reaction detection of rotavirus RNA in the cerebrospinal fluid of children who present with seizures (J. Clin. Microbiol. 2002;40:4797–9).

Although most children with a nondiarrheal initial presentation develop the classic rotavirus stools within 48 hours, the initial sepsislike picture occurs most often in infants under 1 year of age. If the rotavirus antigen assay comes back positive in such patients, you can sometimes avoid adding to the diarrhea with unnecessary antibiotics.

The caveat, however, is that young infants may have positive stool rotavirus antigen tests in the absence of rotavirus-producing disease (false positive). This is thought to represent a “colonization” that occurs in most younger infants, becomes less common after 6 months, and is present in fewer than 10% of children as they reach 1 year of age. For this reason, some laboratories are reluctant to perform rotavirus antigen assays on children less than 6 months of age. So, even with a positive rotavirus assay in a young infant, antibiotics may need to be continued until bacterial cultures are confirmed negative.

Other studies have shown disseminated rotavirus outside the gastrointestinal tract.

One study found rotavirus antigen in 22 of 33 serum samples of children with rotavirus diarrhea, suggesting that the virus can “escape” the GI tract in children, resulting in viremia (Lancet 2003;362:1445–9). The virus itself has also been found in the liver and kidney in immunodeficient children (J. Pediatr. 1992;120:912–7).

Another presentation that can throw you off the rotavirus track is when the presenting symptoms are heavily respiratory in the first 36 hours. Rotavirus has been found in nasopharyngeal secretions of such patients (Diagn. Microbiol. Infect. Dis. 1986;4:87–8), and it makes sense that the upper respiratory tract could be part of the initial portal of infection.

So, beyond a notable reduction in winter diarrhea in infants, the new rotavirus vaccines may also have the added benefit of preventing some febrile seizures and even an occasional case of aseptic meningitis.

I currently have no financial connections with either the Merck or the GSK rotavirus vaccines, although I participated in early studies involving the Merck product more than 5 years ago.

We now have one—and will probably soon have a second—new and improved rotavirus vaccine, with which we will be able to prevent much of the winter-spring infant gastroenteritis misery. Further, a lower economic burden will result from fewer lost parental workdays. And there's another bonus: Reactogenicity is lower with the new vaccines, compared with the old RotaShield, which was withdrawn from the market in 1999.

The design of the trials that were submitted for Food and Drug Administration approval of the new vaccines included a very large sample size—with over 60,000 children each for both Merck & Co.'s bovine-derived RotaTeq and GlaxoSmithKline's human-derived Rotarix—and close follow-up. Both vaccines have been highly effective against rotavirus disease in the first year of life, including the most severe forms of illness and hospitalizations, with lower rates of vaccine-associated fever, irritability, and loose stools.

Importantly, neither vaccine appears to increase the risk for intussusception, the adverse event that caused the removal of the previous rhesus-derived RotaShield vaccine from the market. Of course, we can't be absolutely certain until the new vaccines are in widespread use—that's when the problem with RotaShield was detected. However, it's likely that the problem would have revealed itself sooner if the recalled vaccine had been tested in 60,000 subjects prior to approval.

Moreover, it makes clinical sense that if a vaccine causes less systemic response (fever, irritability, and loose stools), it also might lead to lesser reactions in the gut-associated lymphoid tissue, a proposed mechanism for the vaccine-provoked intussusceptions.

About 400,000 rotavirus-associated deaths occur each year in the developing world, but rotavirus disease usually isn't lethal for children in the United States (20–60 deaths per year). In this country, cost effectiveness is the prime issue, particularly with regard to reducing the 50,000 annual rotavirus-associated hospitalizations.

According to one estimate, rotavirus costs the United States more than $1 billion a year, including direct medical costs and parental lost workdays. Compare that with the $770 million a year to immunize the estimated 4.1 million infants in an annual birth cohort with Rotateq, which Merck has just announced will cost $62.50/dose when purchased in 10 single-dose packs. Overall, this looks like we can still come out ahead.

The benefits of a protective rotavirus vaccine also may extend beyond simply preventing gastroenteritis. This winter, an 11-month-old ill-appearing child was transferred to our facility with a sepsis picture. He had a high fever, lethargy, vomiting, and a tense fontanelle. However, he had no diarrhea and had CSF pleocytosis (WBC count of 28, half neutrophils). The next day, he developed green, mucus-laden diarrhea, which tested positive for rotavirus antigen. This was a case of aseptic meningitis due to rotavirus infection.

Such nondiarrheal initial presentations of rotavirus infection during the winter and early spring are not all that rare. Indeed, in active surveillance of 763 children aged 15 days through 4 years and admitted to the hospital between November 1997 and June 1998 with eventual rotavirus diagnosis, 9% presented initially without diarrhea (Pediatr. Infect. Dis. J. 2002;21:221–7). Rotavirus as a cause of aseptic meningitis also has been confirmed using polymerase chain reaction detection of rotavirus RNA in the cerebrospinal fluid of children who present with seizures (J. Clin. Microbiol. 2002;40:4797–9).

Although most children with a nondiarrheal initial presentation develop the classic rotavirus stools within 48 hours, the initial sepsislike picture occurs most often in infants under 1 year of age. If the rotavirus antigen assay comes back positive in such patients, you can sometimes avoid adding to the diarrhea with unnecessary antibiotics.

The caveat, however, is that young infants may have positive stool rotavirus antigen tests in the absence of rotavirus-producing disease (false positive). This is thought to represent a “colonization” that occurs in most younger infants, becomes less common after 6 months, and is present in fewer than 10% of children as they reach 1 year of age. For this reason, some laboratories are reluctant to perform rotavirus antigen assays on children less than 6 months of age. So, even with a positive rotavirus assay in a young infant, antibiotics may need to be continued until bacterial cultures are confirmed negative.

Other studies have shown disseminated rotavirus outside the gastrointestinal tract.

One study found rotavirus antigen in 22 of 33 serum samples of children with rotavirus diarrhea, suggesting that the virus can “escape” the GI tract in children, resulting in viremia (Lancet 2003;362:1445–9). The virus itself has also been found in the liver and kidney in immunodeficient children (J. Pediatr. 1992;120:912–7).

Another presentation that can throw you off the rotavirus track is when the presenting symptoms are heavily respiratory in the first 36 hours. Rotavirus has been found in nasopharyngeal secretions of such patients (Diagn. Microbiol. Infect. Dis. 1986;4:87–8), and it makes sense that the upper respiratory tract could be part of the initial portal of infection.

So, beyond a notable reduction in winter diarrhea in infants, the new rotavirus vaccines may also have the added benefit of preventing some febrile seizures and even an occasional case of aseptic meningitis.

I currently have no financial connections with either the Merck or the GSK rotavirus vaccines, although I participated in early studies involving the Merck product more than 5 years ago.

We now have one—and will probably soon have a second—new and improved rotavirus vaccine, with which we will be able to prevent much of the winter-spring infant gastroenteritis misery. Further, a lower economic burden will result from fewer lost parental workdays. And there's another bonus: Reactogenicity is lower with the new vaccines, compared with the old RotaShield, which was withdrawn from the market in 1999.

The design of the trials that were submitted for Food and Drug Administration approval of the new vaccines included a very large sample size—with over 60,000 children each for both Merck & Co.'s bovine-derived RotaTeq and GlaxoSmithKline's human-derived Rotarix—and close follow-up. Both vaccines have been highly effective against rotavirus disease in the first year of life, including the most severe forms of illness and hospitalizations, with lower rates of vaccine-associated fever, irritability, and loose stools.

Importantly, neither vaccine appears to increase the risk for intussusception, the adverse event that caused the removal of the previous rhesus-derived RotaShield vaccine from the market. Of course, we can't be absolutely certain until the new vaccines are in widespread use—that's when the problem with RotaShield was detected. However, it's likely that the problem would have revealed itself sooner if the recalled vaccine had been tested in 60,000 subjects prior to approval.

Moreover, it makes clinical sense that if a vaccine causes less systemic response (fever, irritability, and loose stools), it also might lead to lesser reactions in the gut-associated lymphoid tissue, a proposed mechanism for the vaccine-provoked intussusceptions.

About 400,000 rotavirus-associated deaths occur each year in the developing world, but rotavirus disease usually isn't lethal for children in the United States (20–60 deaths per year). In this country, cost effectiveness is the prime issue, particularly with regard to reducing the 50,000 annual rotavirus-associated hospitalizations.

According to one estimate, rotavirus costs the United States more than $1 billion a year, including direct medical costs and parental lost workdays. Compare that with the $770 million a year to immunize the estimated 4.1 million infants in an annual birth cohort with Rotateq, which Merck has just announced will cost $62.50/dose when purchased in 10 single-dose packs. Overall, this looks like we can still come out ahead.

The benefits of a protective rotavirus vaccine also may extend beyond simply preventing gastroenteritis. This winter, an 11-month-old ill-appearing child was transferred to our facility with a sepsis picture. He had a high fever, lethargy, vomiting, and a tense fontanelle. However, he had no diarrhea and had CSF pleocytosis (WBC count of 28, half neutrophils). The next day, he developed green, mucus-laden diarrhea, which tested positive for rotavirus antigen. This was a case of aseptic meningitis due to rotavirus infection.

Such nondiarrheal initial presentations of rotavirus infection during the winter and early spring are not all that rare. Indeed, in active surveillance of 763 children aged 15 days through 4 years and admitted to the hospital between November 1997 and June 1998 with eventual rotavirus diagnosis, 9% presented initially without diarrhea (Pediatr. Infect. Dis. J. 2002;21:221–7). Rotavirus as a cause of aseptic meningitis also has been confirmed using polymerase chain reaction detection of rotavirus RNA in the cerebrospinal fluid of children who present with seizures (J. Clin. Microbiol. 2002;40:4797–9).

Although most children with a nondiarrheal initial presentation develop the classic rotavirus stools within 48 hours, the initial sepsislike picture occurs most often in infants under 1 year of age. If the rotavirus antigen assay comes back positive in such patients, you can sometimes avoid adding to the diarrhea with unnecessary antibiotics.

The caveat, however, is that young infants may have positive stool rotavirus antigen tests in the absence of rotavirus-producing disease (false positive). This is thought to represent a “colonization” that occurs in most younger infants, becomes less common after 6 months, and is present in fewer than 10% of children as they reach 1 year of age. For this reason, some laboratories are reluctant to perform rotavirus antigen assays on children less than 6 months of age. So, even with a positive rotavirus assay in a young infant, antibiotics may need to be continued until bacterial cultures are confirmed negative.

Other studies have shown disseminated rotavirus outside the gastrointestinal tract.

One study found rotavirus antigen in 22 of 33 serum samples of children with rotavirus diarrhea, suggesting that the virus can “escape” the GI tract in children, resulting in viremia (Lancet 2003;362:1445–9). The virus itself has also been found in the liver and kidney in immunodeficient children (J. Pediatr. 1992;120:912–7).

Another presentation that can throw you off the rotavirus track is when the presenting symptoms are heavily respiratory in the first 36 hours. Rotavirus has been found in nasopharyngeal secretions of such patients (Diagn. Microbiol. Infect. Dis. 1986;4:87–8), and it makes sense that the upper respiratory tract could be part of the initial portal of infection.

So, beyond a notable reduction in winter diarrhea in infants, the new rotavirus vaccines may also have the added benefit of preventing some febrile seizures and even an occasional case of aseptic meningitis.

I currently have no financial connections with either the Merck or the GSK rotavirus vaccines, although I participated in early studies involving the Merck product more than 5 years ago.

We should be concerned but not panicked about avian influenza. As clinicians, we need to reassure families about the small but perhaps increasing potential for pandemic flu and answer their questions, but at the same time focus our immediate efforts on prevention and management of the nonpandemic annual influenza season that is just around the corner.

There appears to be confusion out there—even among some physicians—about the details concerning what avian influenza is and what would need to happen for it to become a pandemic. In fact, avian influenza isn't new—periodic outbreaks have occurred and been reasonably controlled in animals worldwide, including in the United States, for decades.

At least one strain of avian influenza, an H5N1 strain, is now endemic in much of Asia and has recently spread to Europe, killing poultry and other birds in several countries. The H5N1 strain was first recognized in 1997, when it infected 18 people and killed 6 in Hong Kong. Since 2003, it has been diagnosed in more than 100 humans in several countries in Southeast Asia with greater than a 50% mortality.

But this avian H5N1 strain in humans has not become pandemic. A true pandemic requires sustained human-to-human transmission. To date, nearly all of the infected individuals have been in direct contact with infected poultry. For a pandemic to occur, a human influenza strain and an avian influenza strain need to simultaneously infect an intermediate host (usually a pig but perhaps even a cat). Then the strains would need to exchange genes via reassortment, and a reassortment mutant would then need to reemerge and reinfect humans.

This hasn't happened yet, and if we're lucky it never will. Indeed, H5N1 has been circulating among birds in the Far East since 1997 without this reassortment occurring. But humans packed densely into small geographic areas together with avian species and intermediate mammalian hosts—the current situation in parts of Asia—do increase the chance that reassortment might happen.

This theoretical possibility is why many officials are concerned. The U.S. Department of Health and Human Services has now developed a $7.1 billion national strategy to address pandemic influenza (www.pandemicflu.gov

1. Intensifying surveillance and collaborating on containment.

2. Stockpiling antivirals and vaccines.

3. Creating a network of federal, state, and local preparedness agencies.

4. Increasing public education and communication.

Although not perfect or complete, this plan is evolving rapidly.

For this reason, I have recently changed my view about personal stockpiling of antivirals. A few months ago, when there were apparently ample supplies, I believed that families and first responders should keep a neuraminidase inhibitor on hand, anticipating influenza season. I no longer support this practice because demand has risen, and there simply isn't enough antiviral medication to go around.

Now I think it makes more sense to keep these drugs in central locations to be distributed to outbreak sites for pandemic influenza—instead of scattered among individuals around the country.

Of course, if you have a patient with confirmed influenza for less than 48 hours, it still makes sense to treat with oseltamivir or zanamivir if these drugs are available. When the local type is an influenza A, you could also use rimantadine or amantadine, depending on their availability and on the patient's age, if no other contraindications to these two drugs are present.

But for now I strongly believe that our top priority should be immunizing our patients against the nonpandemic annual influenza that we know is coming soon. And I mean all children, not just those aged 6–23 months or those with high-risk medical conditions. Indeed, I support the emerging viewpoint that immunizing school-aged children is also critical to preventing transmission within a community.

Among the many lines of emerging evidence for this approach is a recent report from Japan saying that although both oral oseltamivir and inhaled zanamivir reduce the duration of influenza symptoms in children, they do not significantly shorten the period of viral shedding (Pediatr. Infect. Dis. J. 2005;24:931–2). Another recent study determined that children aged 3–4 years are the first to become infected with influenza each season, and therefore serve as vectors for the rest of the community (Am. J. Epidemiol. 2005;162:686–93).

These findings are of concern because children typically go back to school or day care once their symptoms diminish. I agree with Ram Yogev, M.D., who recently called for the policy-making organizations to consider issuing an evidence-based recommendation for routine vaccination of all healthy children (Pediatrics 2005;116:1214–5). Of course, there are logistics to overcome with such a large undertaking, but I feel the benefits can be huge, too.

The Centers for Disease Control and Prevention advises, “In addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected (the vaccine can be administered to children [older than] 6 months), depending on vaccine availability” (MMWR 2005;54[RR08]:1–40).

In my mind, that's what we should be doing. Not only will this protect our patients and their contacts, but it will also reduce the chance that garden-variety influenza will be mistaken for H5N1. In fact, the human H5N1 cases seen in Asia have involved more gastrointestinal symptoms in children than does the typical annual flu; the human H5N1 cases have also had leukopenia, thrombocytopenia, and elevated liver enzyme levels, which are not normally seen with the regular flu. Be especially alert for those symptoms, particularly in a child who has traveled overseas where H5N1 has been found.

We should be concerned but not panicked about avian influenza. As clinicians, we need to reassure families about the small but perhaps increasing potential for pandemic flu and answer their questions, but at the same time focus our immediate efforts on prevention and management of the nonpandemic annual influenza season that is just around the corner.

There appears to be confusion out there—even among some physicians—about the details concerning what avian influenza is and what would need to happen for it to become a pandemic. In fact, avian influenza isn't new—periodic outbreaks have occurred and been reasonably controlled in animals worldwide, including in the United States, for decades.

At least one strain of avian influenza, an H5N1 strain, is now endemic in much of Asia and has recently spread to Europe, killing poultry and other birds in several countries. The H5N1 strain was first recognized in 1997, when it infected 18 people and killed 6 in Hong Kong. Since 2003, it has been diagnosed in more than 100 humans in several countries in Southeast Asia with greater than a 50% mortality.

But this avian H5N1 strain in humans has not become pandemic. A true pandemic requires sustained human-to-human transmission. To date, nearly all of the infected individuals have been in direct contact with infected poultry. For a pandemic to occur, a human influenza strain and an avian influenza strain need to simultaneously infect an intermediate host (usually a pig but perhaps even a cat). Then the strains would need to exchange genes via reassortment, and a reassortment mutant would then need to reemerge and reinfect humans.

This hasn't happened yet, and if we're lucky it never will. Indeed, H5N1 has been circulating among birds in the Far East since 1997 without this reassortment occurring. But humans packed densely into small geographic areas together with avian species and intermediate mammalian hosts—the current situation in parts of Asia—do increase the chance that reassortment might happen.

This theoretical possibility is why many officials are concerned. The U.S. Department of Health and Human Services has now developed a $7.1 billion national strategy to address pandemic influenza (www.pandemicflu.gov

1. Intensifying surveillance and collaborating on containment.

2. Stockpiling antivirals and vaccines.

3. Creating a network of federal, state, and local preparedness agencies.

4. Increasing public education and communication.

Although not perfect or complete, this plan is evolving rapidly.

For this reason, I have recently changed my view about personal stockpiling of antivirals. A few months ago, when there were apparently ample supplies, I believed that families and first responders should keep a neuraminidase inhibitor on hand, anticipating influenza season. I no longer support this practice because demand has risen, and there simply isn't enough antiviral medication to go around.

Now I think it makes more sense to keep these drugs in central locations to be distributed to outbreak sites for pandemic influenza—instead of scattered among individuals around the country.

Of course, if you have a patient with confirmed influenza for less than 48 hours, it still makes sense to treat with oseltamivir or zanamivir if these drugs are available. When the local type is an influenza A, you could also use rimantadine or amantadine, depending on their availability and on the patient's age, if no other contraindications to these two drugs are present.

But for now I strongly believe that our top priority should be immunizing our patients against the nonpandemic annual influenza that we know is coming soon. And I mean all children, not just those aged 6–23 months or those with high-risk medical conditions. Indeed, I support the emerging viewpoint that immunizing school-aged children is also critical to preventing transmission within a community.

Among the many lines of emerging evidence for this approach is a recent report from Japan saying that although both oral oseltamivir and inhaled zanamivir reduce the duration of influenza symptoms in children, they do not significantly shorten the period of viral shedding (Pediatr. Infect. Dis. J. 2005;24:931–2). Another recent study determined that children aged 3–4 years are the first to become infected with influenza each season, and therefore serve as vectors for the rest of the community (Am. J. Epidemiol. 2005;162:686–93).

These findings are of concern because children typically go back to school or day care once their symptoms diminish. I agree with Ram Yogev, M.D., who recently called for the policy-making organizations to consider issuing an evidence-based recommendation for routine vaccination of all healthy children (Pediatrics 2005;116:1214–5). Of course, there are logistics to overcome with such a large undertaking, but I feel the benefits can be huge, too.

The Centers for Disease Control and Prevention advises, “In addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected (the vaccine can be administered to children [older than] 6 months), depending on vaccine availability” (MMWR 2005;54[RR08]:1–40).

In my mind, that's what we should be doing. Not only will this protect our patients and their contacts, but it will also reduce the chance that garden-variety influenza will be mistaken for H5N1. In fact, the human H5N1 cases seen in Asia have involved more gastrointestinal symptoms in children than does the typical annual flu; the human H5N1 cases have also had leukopenia, thrombocytopenia, and elevated liver enzyme levels, which are not normally seen with the regular flu. Be especially alert for those symptoms, particularly in a child who has traveled overseas where H5N1 has been found.

We should be concerned but not panicked about avian influenza. As clinicians, we need to reassure families about the small but perhaps increasing potential for pandemic flu and answer their questions, but at the same time focus our immediate efforts on prevention and management of the nonpandemic annual influenza season that is just around the corner.

There appears to be confusion out there—even among some physicians—about the details concerning what avian influenza is and what would need to happen for it to become a pandemic. In fact, avian influenza isn't new—periodic outbreaks have occurred and been reasonably controlled in animals worldwide, including in the United States, for decades.

At least one strain of avian influenza, an H5N1 strain, is now endemic in much of Asia and has recently spread to Europe, killing poultry and other birds in several countries. The H5N1 strain was first recognized in 1997, when it infected 18 people and killed 6 in Hong Kong. Since 2003, it has been diagnosed in more than 100 humans in several countries in Southeast Asia with greater than a 50% mortality.

But this avian H5N1 strain in humans has not become pandemic. A true pandemic requires sustained human-to-human transmission. To date, nearly all of the infected individuals have been in direct contact with infected poultry. For a pandemic to occur, a human influenza strain and an avian influenza strain need to simultaneously infect an intermediate host (usually a pig but perhaps even a cat). Then the strains would need to exchange genes via reassortment, and a reassortment mutant would then need to reemerge and reinfect humans.

This hasn't happened yet, and if we're lucky it never will. Indeed, H5N1 has been circulating among birds in the Far East since 1997 without this reassortment occurring. But humans packed densely into small geographic areas together with avian species and intermediate mammalian hosts—the current situation in parts of Asia—do increase the chance that reassortment might happen.

This theoretical possibility is why many officials are concerned. The U.S. Department of Health and Human Services has now developed a $7.1 billion national strategy to address pandemic influenza (www.pandemicflu.gov

1. Intensifying surveillance and collaborating on containment.

2. Stockpiling antivirals and vaccines.

3. Creating a network of federal, state, and local preparedness agencies.

4. Increasing public education and communication.

Although not perfect or complete, this plan is evolving rapidly.

For this reason, I have recently changed my view about personal stockpiling of antivirals. A few months ago, when there were apparently ample supplies, I believed that families and first responders should keep a neuraminidase inhibitor on hand, anticipating influenza season. I no longer support this practice because demand has risen, and there simply isn't enough antiviral medication to go around.

Now I think it makes more sense to keep these drugs in central locations to be distributed to outbreak sites for pandemic influenza—instead of scattered among individuals around the country.

Of course, if you have a patient with confirmed influenza for less than 48 hours, it still makes sense to treat with oseltamivir or zanamivir if these drugs are available. When the local type is an influenza A, you could also use rimantadine or amantadine, depending on their availability and on the patient's age, if no other contraindications to these two drugs are present.

But for now I strongly believe that our top priority should be immunizing our patients against the nonpandemic annual influenza that we know is coming soon. And I mean all children, not just those aged 6–23 months or those with high-risk medical conditions. Indeed, I support the emerging viewpoint that immunizing school-aged children is also critical to preventing transmission within a community.

Among the many lines of emerging evidence for this approach is a recent report from Japan saying that although both oral oseltamivir and inhaled zanamivir reduce the duration of influenza symptoms in children, they do not significantly shorten the period of viral shedding (Pediatr. Infect. Dis. J. 2005;24:931–2). Another recent study determined that children aged 3–4 years are the first to become infected with influenza each season, and therefore serve as vectors for the rest of the community (Am. J. Epidemiol. 2005;162:686–93).

These findings are of concern because children typically go back to school or day care once their symptoms diminish. I agree with Ram Yogev, M.D., who recently called for the policy-making organizations to consider issuing an evidence-based recommendation for routine vaccination of all healthy children (Pediatrics 2005;116:1214–5). Of course, there are logistics to overcome with such a large undertaking, but I feel the benefits can be huge, too.

The Centers for Disease Control and Prevention advises, “In addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected (the vaccine can be administered to children [older than] 6 months), depending on vaccine availability” (MMWR 2005;54[RR08]:1–40).

In my mind, that's what we should be doing. Not only will this protect our patients and their contacts, but it will also reduce the chance that garden-variety influenza will be mistaken for H5N1. In fact, the human H5N1 cases seen in Asia have involved more gastrointestinal symptoms in children than does the typical annual flu; the human H5N1 cases have also had leukopenia, thrombocytopenia, and elevated liver enzyme levels, which are not normally seen with the regular flu. Be especially alert for those symptoms, particularly in a child who has traveled overseas where H5N1 has been found.

Just in time for summer, I thought I'd offer some pointers on parasites.

Of course, parasites exist year round. But as the weather gets warmer and our patients head outside to play in the dirt or splash around in the toddler pool, the possibility that they'll pick up one of the following five organisms increases.

Here they are in approximate order of the frequency that we see them in central Kentucky:

▸ Pinworms. By far the most common parasite seen in preschool children, the diagnosis is usually made by a parent who finds a little wriggling rice-sized creature in the child's diaper, underwear, or bedding. Treatment—liquid mebendazole or chewable pyrantel pamoate—is given once, then repeated about 10–14 days later.

Families should be advised to wash all bed linens in hot water to get rid of any residual eggs and to prevent reinfestation.

If the problem recurs, retreat the child and consider treating the whole family and the child's playmates. If the parent reports a third sighting after two rounds of treatment, I will ask that they actually bring the worm in.

Some parents become so excessively concerned that they misinterpret many things as pinworms. It's been quite interesting—I've seen husks of corn, pea shells, and little bits of mucus that aren't even organisms.

Once, we got back a housefly larvae from a child's stool. I'm not sure how it got there.

We've also seen the proglottid of a tapeworm—these often fold up on themselves, and can almost look like a pinworm. That child had been treated several times for pinworms before referral.

Another pinworm-related problem is that the child may continue to experience perianal or vulvar itching and continue to scratch even after the pinworms are eradicated. Sitz baths may be helpful in easing the irritation. If itching continues, applying 1% hydrocortisone cream to the area for no more than 1 week can often break the itch-scratch cycle.

Pinworms are often an emotional issue for families. It's important to convince parents that it's not because they or their child is dirty, but, rather, that they picked up pinworms from their friends. To diffuse the worry, I often tell parents that the upside of pinworms is that their child likely has good social skills.

▸ Giardia. Toddler pools are a frequent yet underrecognized source of giardia, which are more familiarly associated with food-borne outbreaks or with transmission via fresh water, such as mountain springs.

But “kiddy pools” in the backyard or even at professionally maintained pool complexes are a particularly likely source of giardia transmission. Because they're shallow, sunlight can degrade the chlorine to below the giardia-inhibiting levels, which are higher than needed for coliforms.

If you see more than one giardia patient from the same swim club or backyard pool, advise the swim club pool staff or pool owners to make sure the chlorine level is being monitored more often. We had a giardia outbreak in an upscale country club's pool, and the parents were mortified. Acquisition of giardia in the pool is likely due to other toddlers using the pool in diapers.

Giardia typically presents with diarrhea, cramps, an extreme amount of flatulence, and stools with a characteristic green bubbly appearance. Once you've seen a giardia stool, you will know it again. The diagnosis is made with a routine laboratory ova and parasite screen.

Furazolidone is the treatment of choice, but metronidazole also works. Of course, these are two of the worst-tasting medicines around. You might advise parents to try chasing it with a spoonful of Hershey's syrup. In older kids, a Hershey's Kiss works. No, I receive no funding from Hershey's.

▸ Ascaris. In a typical scenario with ascaris, the parent reports finding a 2- to 4-inch long “fishing worm” in the child's diaper. This is the easy diagnosis.

However, we had a case last year of a 4-year-old who had been diagnosed with asthma and who continued wheezing over an 8-month period despite all the usual asthma medications including a couple rounds of steroids. He had eosinophilia, which had been attributed to allergies.

As it turned out, this child did not have asthma at all, but rather a classic case of Loeffler's pneumonia, in which the ascaris larvae had migrated to his lungs, triggering eosinophilia and an asthma-like picture. We treated the child with mebendazole twice a day for 3 days, and both the wheezing and the eosinophilia disappeared. The child didn't wheeze thereafter.

Ascaris was far more common in years past. These days we've become such a clean society we just don't see it as much as we used to and it's dropped off the radar screen. Yet, in addition to the pulmonary case, we've actually had two more classical ascaris cases just in the last month—one was spotted by the mother in the child's diaper, the other in the toilet.

Ascaris can produce abdominal pain and discomfort, and may lead to malabsorption syndrome, weight loss, or vitamin deficiency. Very large infestations can sometimes lead to intestinal obstruction—I saw a case of this a few years ago, when I was working in Omaha, Neb. The parasite also can migrate to the bile duct and obstruct the liver.

With lower-level infestations, however, the nonspecific epigastric and diffuse abdominal discomfort may be indistinguishable from functional abdominal pain.

However, if the problem persists—or if the child has wheezing or pneumonia symptoms, get a complete blood count. If you see eosinophilia, order an ova and parasite stool exam.

▸ Dientamoeba fragilis. If you trained prior to the 1990s, you probably were taught that D. fragilis is merely a harmless commensal and doesn't need to be treated. However, it has become apparent in the last decade or so that this parasite can cause symptoms, including chronic loose stools, cramps, and flatulence. The child usually doesn't look especially ill but complains of abdominal upset and may have up to three to four loose, mucus-containing stools per day.

And D. fragilis hangs on—after the second week or so, you can be fairly certain it's not rotavirus or another acute gastrointestinal virus. Along with giardia, also think of D. fragilis.

Interestingly, D. fragilis will often piggyback with pinworms, literally sticking itself to the pinworm eggs. Therefore, if you've already treated the child for pinworms and the GI symptoms continue, you might want to order another ova and parasite stool exam. This time, however, special procedures are required. Because this organism is so fragile—hence the name—it deteriorates rapidly at room temperature. Parents should be instructed to collect a fresh stool sample and immediately place it in a preservative-containing pack (we use ParaPak). For the greatest sensitivity, three samples must be collected on separate days. Sensitivity of the test is about 85%–90% for three samples taken on consecutive days, and up to 95% if collected on alternate days.

The order to the lab should request a microscopic exam, not just an antigen screen. Microscopy will pick up not only D. fragilis, but other less common parasitic creatures that you don't want to miss, such as Entamoeba histolytica. Parents must also be told to stop any over-the-counter antidiarrheals such as Kaopectate or Pepto-Bismol 24–48 hours prior to the first stool collection, as these agents will make it difficult to visualize the parasites.

If D. fragilis is identified, treatment is metronidazole three times a day for 10 days. Because of fecal-oral transmission, consider asking the parents if they're experiencing loose stools as well. Symptoms tend not to be as dramatic in adults as in kids, but if they've got D. fragilis and you treat them, they often feel better.

▸ Blastocystis hominis. Although similar to D. fragilis in structure, B. hominis is still considered a commensal and not pathogenic. However, if present in high enough quantities, it can still cause nonspecific abdominal symptoms, loose stools, flatulence, and mucus in the stool. If you do a work-up and find no other explanation for the symptoms, it's not unreasonable to treat using the 10-day metronidazole regimen. Here, too, a microscopic exam is necessary to visualize the cysts in the stool.

Although not known to produce any toxins or direct irritants to the colon, it's possible that B. hominis just has not been investigated closely enough to prove its pathogenicity. New data suggest this may be the case.

We've been seeing more lab reports of both D. fragilis and B. hominis in the last few years. It's not clear whether that's because of increased use of preservative packs or actual increased prevalence.

But we definitely seem to get more calls from parents and physicians about parasites as the weather gets warmer.

Just in time for summer, I thought I'd offer some pointers on parasites.

Of course, parasites exist year round. But as the weather gets warmer and our patients head outside to play in the dirt or splash around in the toddler pool, the possibility that they'll pick up one of the following five organisms increases.

Here they are in approximate order of the frequency that we see them in central Kentucky:

▸ Pinworms. By far the most common parasite seen in preschool children, the diagnosis is usually made by a parent who finds a little wriggling rice-sized creature in the child's diaper, underwear, or bedding. Treatment—liquid mebendazole or chewable pyrantel pamoate—is given once, then repeated about 10–14 days later.

Families should be advised to wash all bed linens in hot water to get rid of any residual eggs and to prevent reinfestation.

If the problem recurs, retreat the child and consider treating the whole family and the child's playmates. If the parent reports a third sighting after two rounds of treatment, I will ask that they actually bring the worm in.

Some parents become so excessively concerned that they misinterpret many things as pinworms. It's been quite interesting—I've seen husks of corn, pea shells, and little bits of mucus that aren't even organisms.

Once, we got back a housefly larvae from a child's stool. I'm not sure how it got there.

We've also seen the proglottid of a tapeworm—these often fold up on themselves, and can almost look like a pinworm. That child had been treated several times for pinworms before referral.

Another pinworm-related problem is that the child may continue to experience perianal or vulvar itching and continue to scratch even after the pinworms are eradicated. Sitz baths may be helpful in easing the irritation. If itching continues, applying 1% hydrocortisone cream to the area for no more than 1 week can often break the itch-scratch cycle.

Pinworms are often an emotional issue for families. It's important to convince parents that it's not because they or their child is dirty, but, rather, that they picked up pinworms from their friends. To diffuse the worry, I often tell parents that the upside of pinworms is that their child likely has good social skills.

▸ Giardia. Toddler pools are a frequent yet underrecognized source of giardia, which are more familiarly associated with food-borne outbreaks or with transmission via fresh water, such as mountain springs.

But “kiddy pools” in the backyard or even at professionally maintained pool complexes are a particularly likely source of giardia transmission. Because they're shallow, sunlight can degrade the chlorine to below the giardia-inhibiting levels, which are higher than needed for coliforms.

If you see more than one giardia patient from the same swim club or backyard pool, advise the swim club pool staff or pool owners to make sure the chlorine level is being monitored more often. We had a giardia outbreak in an upscale country club's pool, and the parents were mortified. Acquisition of giardia in the pool is likely due to other toddlers using the pool in diapers.

Giardia typically presents with diarrhea, cramps, an extreme amount of flatulence, and stools with a characteristic green bubbly appearance. Once you've seen a giardia stool, you will know it again. The diagnosis is made with a routine laboratory ova and parasite screen.

Furazolidone is the treatment of choice, but metronidazole also works. Of course, these are two of the worst-tasting medicines around. You might advise parents to try chasing it with a spoonful of Hershey's syrup. In older kids, a Hershey's Kiss works. No, I receive no funding from Hershey's.

▸ Ascaris. In a typical scenario with ascaris, the parent reports finding a 2- to 4-inch long “fishing worm” in the child's diaper. This is the easy diagnosis.

However, we had a case last year of a 4-year-old who had been diagnosed with asthma and who continued wheezing over an 8-month period despite all the usual asthma medications including a couple rounds of steroids. He had eosinophilia, which had been attributed to allergies.

As it turned out, this child did not have asthma at all, but rather a classic case of Loeffler's pneumonia, in which the ascaris larvae had migrated to his lungs, triggering eosinophilia and an asthma-like picture. We treated the child with mebendazole twice a day for 3 days, and both the wheezing and the eosinophilia disappeared. The child didn't wheeze thereafter.

Ascaris was far more common in years past. These days we've become such a clean society we just don't see it as much as we used to and it's dropped off the radar screen. Yet, in addition to the pulmonary case, we've actually had two more classical ascaris cases just in the last month—one was spotted by the mother in the child's diaper, the other in the toilet.

Ascaris can produce abdominal pain and discomfort, and may lead to malabsorption syndrome, weight loss, or vitamin deficiency. Very large infestations can sometimes lead to intestinal obstruction—I saw a case of this a few years ago, when I was working in Omaha, Neb. The parasite also can migrate to the bile duct and obstruct the liver.

With lower-level infestations, however, the nonspecific epigastric and diffuse abdominal discomfort may be indistinguishable from functional abdominal pain.

However, if the problem persists—or if the child has wheezing or pneumonia symptoms, get a complete blood count. If you see eosinophilia, order an ova and parasite stool exam.

▸ Dientamoeba fragilis. If you trained prior to the 1990s, you probably were taught that D. fragilis is merely a harmless commensal and doesn't need to be treated. However, it has become apparent in the last decade or so that this parasite can cause symptoms, including chronic loose stools, cramps, and flatulence. The child usually doesn't look especially ill but complains of abdominal upset and may have up to three to four loose, mucus-containing stools per day.

And D. fragilis hangs on—after the second week or so, you can be fairly certain it's not rotavirus or another acute gastrointestinal virus. Along with giardia, also think of D. fragilis.

Interestingly, D. fragilis will often piggyback with pinworms, literally sticking itself to the pinworm eggs. Therefore, if you've already treated the child for pinworms and the GI symptoms continue, you might want to order another ova and parasite stool exam. This time, however, special procedures are required. Because this organism is so fragile—hence the name—it deteriorates rapidly at room temperature. Parents should be instructed to collect a fresh stool sample and immediately place it in a preservative-containing pack (we use ParaPak). For the greatest sensitivity, three samples must be collected on separate days. Sensitivity of the test is about 85%–90% for three samples taken on consecutive days, and up to 95% if collected on alternate days.

The order to the lab should request a microscopic exam, not just an antigen screen. Microscopy will pick up not only D. fragilis, but other less common parasitic creatures that you don't want to miss, such as Entamoeba histolytica. Parents must also be told to stop any over-the-counter antidiarrheals such as Kaopectate or Pepto-Bismol 24–48 hours prior to the first stool collection, as these agents will make it difficult to visualize the parasites.

If D. fragilis is identified, treatment is metronidazole three times a day for 10 days. Because of fecal-oral transmission, consider asking the parents if they're experiencing loose stools as well. Symptoms tend not to be as dramatic in adults as in kids, but if they've got D. fragilis and you treat them, they often feel better.

▸ Blastocystis hominis. Although similar to D. fragilis in structure, B. hominis is still considered a commensal and not pathogenic. However, if present in high enough quantities, it can still cause nonspecific abdominal symptoms, loose stools, flatulence, and mucus in the stool. If you do a work-up and find no other explanation for the symptoms, it's not unreasonable to treat using the 10-day metronidazole regimen. Here, too, a microscopic exam is necessary to visualize the cysts in the stool.

Although not known to produce any toxins or direct irritants to the colon, it's possible that B. hominis just has not been investigated closely enough to prove its pathogenicity. New data suggest this may be the case.

We've been seeing more lab reports of both D. fragilis and B. hominis in the last few years. It's not clear whether that's because of increased use of preservative packs or actual increased prevalence.

But we definitely seem to get more calls from parents and physicians about parasites as the weather gets warmer.

Just in time for summer, I thought I'd offer some pointers on parasites.

Of course, parasites exist year round. But as the weather gets warmer and our patients head outside to play in the dirt or splash around in the toddler pool, the possibility that they'll pick up one of the following five organisms increases.

Here they are in approximate order of the frequency that we see them in central Kentucky:

▸ Pinworms. By far the most common parasite seen in preschool children, the diagnosis is usually made by a parent who finds a little wriggling rice-sized creature in the child's diaper, underwear, or bedding. Treatment—liquid mebendazole or chewable pyrantel pamoate—is given once, then repeated about 10–14 days later.

Families should be advised to wash all bed linens in hot water to get rid of any residual eggs and to prevent reinfestation.

If the problem recurs, retreat the child and consider treating the whole family and the child's playmates. If the parent reports a third sighting after two rounds of treatment, I will ask that they actually bring the worm in.

Some parents become so excessively concerned that they misinterpret many things as pinworms. It's been quite interesting—I've seen husks of corn, pea shells, and little bits of mucus that aren't even organisms.

Once, we got back a housefly larvae from a child's stool. I'm not sure how it got there.

We've also seen the proglottid of a tapeworm—these often fold up on themselves, and can almost look like a pinworm. That child had been treated several times for pinworms before referral.

Another pinworm-related problem is that the child may continue to experience perianal or vulvar itching and continue to scratch even after the pinworms are eradicated. Sitz baths may be helpful in easing the irritation. If itching continues, applying 1% hydrocortisone cream to the area for no more than 1 week can often break the itch-scratch cycle.

Pinworms are often an emotional issue for families. It's important to convince parents that it's not because they or their child is dirty, but, rather, that they picked up pinworms from their friends. To diffuse the worry, I often tell parents that the upside of pinworms is that their child likely has good social skills.

▸ Giardia. Toddler pools are a frequent yet underrecognized source of giardia, which are more familiarly associated with food-borne outbreaks or with transmission via fresh water, such as mountain springs.

But “kiddy pools” in the backyard or even at professionally maintained pool complexes are a particularly likely source of giardia transmission. Because they're shallow, sunlight can degrade the chlorine to below the giardia-inhibiting levels, which are higher than needed for coliforms.

If you see more than one giardia patient from the same swim club or backyard pool, advise the swim club pool staff or pool owners to make sure the chlorine level is being monitored more often. We had a giardia outbreak in an upscale country club's pool, and the parents were mortified. Acquisition of giardia in the pool is likely due to other toddlers using the pool in diapers.

Giardia typically presents with diarrhea, cramps, an extreme amount of flatulence, and stools with a characteristic green bubbly appearance. Once you've seen a giardia stool, you will know it again. The diagnosis is made with a routine laboratory ova and parasite screen.

Furazolidone is the treatment of choice, but metronidazole also works. Of course, these are two of the worst-tasting medicines around. You might advise parents to try chasing it with a spoonful of Hershey's syrup. In older kids, a Hershey's Kiss works. No, I receive no funding from Hershey's.

▸ Ascaris. In a typical scenario with ascaris, the parent reports finding a 2- to 4-inch long “fishing worm” in the child's diaper. This is the easy diagnosis.

However, we had a case last year of a 4-year-old who had been diagnosed with asthma and who continued wheezing over an 8-month period despite all the usual asthma medications including a couple rounds of steroids. He had eosinophilia, which had been attributed to allergies.

As it turned out, this child did not have asthma at all, but rather a classic case of Loeffler's pneumonia, in which the ascaris larvae had migrated to his lungs, triggering eosinophilia and an asthma-like picture. We treated the child with mebendazole twice a day for 3 days, and both the wheezing and the eosinophilia disappeared. The child didn't wheeze thereafter.

Ascaris was far more common in years past. These days we've become such a clean society we just don't see it as much as we used to and it's dropped off the radar screen. Yet, in addition to the pulmonary case, we've actually had two more classical ascaris cases just in the last month—one was spotted by the mother in the child's diaper, the other in the toilet.

Ascaris can produce abdominal pain and discomfort, and may lead to malabsorption syndrome, weight loss, or vitamin deficiency. Very large infestations can sometimes lead to intestinal obstruction—I saw a case of this a few years ago, when I was working in Omaha, Neb. The parasite also can migrate to the bile duct and obstruct the liver.

With lower-level infestations, however, the nonspecific epigastric and diffuse abdominal discomfort may be indistinguishable from functional abdominal pain.

However, if the problem persists—or if the child has wheezing or pneumonia symptoms, get a complete blood count. If you see eosinophilia, order an ova and parasite stool exam.

▸ Dientamoeba fragilis. If you trained prior to the 1990s, you probably were taught that D. fragilis is merely a harmless commensal and doesn't need to be treated. However, it has become apparent in the last decade or so that this parasite can cause symptoms, including chronic loose stools, cramps, and flatulence. The child usually doesn't look especially ill but complains of abdominal upset and may have up to three to four loose, mucus-containing stools per day.

And D. fragilis hangs on—after the second week or so, you can be fairly certain it's not rotavirus or another acute gastrointestinal virus. Along with giardia, also think of D. fragilis.

Interestingly, D. fragilis will often piggyback with pinworms, literally sticking itself to the pinworm eggs. Therefore, if you've already treated the child for pinworms and the GI symptoms continue, you might want to order another ova and parasite stool exam. This time, however, special procedures are required. Because this organism is so fragile—hence the name—it deteriorates rapidly at room temperature. Parents should be instructed to collect a fresh stool sample and immediately place it in a preservative-containing pack (we use ParaPak). For the greatest sensitivity, three samples must be collected on separate days. Sensitivity of the test is about 85%–90% for three samples taken on consecutive days, and up to 95% if collected on alternate days.

The order to the lab should request a microscopic exam, not just an antigen screen. Microscopy will pick up not only D. fragilis, but other less common parasitic creatures that you don't want to miss, such as Entamoeba histolytica. Parents must also be told to stop any over-the-counter antidiarrheals such as Kaopectate or Pepto-Bismol 24–48 hours prior to the first stool collection, as these agents will make it difficult to visualize the parasites.

If D. fragilis is identified, treatment is metronidazole three times a day for 10 days. Because of fecal-oral transmission, consider asking the parents if they're experiencing loose stools as well. Symptoms tend not to be as dramatic in adults as in kids, but if they've got D. fragilis and you treat them, they often feel better.

▸ Blastocystis hominis. Although similar to D. fragilis in structure, B. hominis is still considered a commensal and not pathogenic. However, if present in high enough quantities, it can still cause nonspecific abdominal symptoms, loose stools, flatulence, and mucus in the stool. If you do a work-up and find no other explanation for the symptoms, it's not unreasonable to treat using the 10-day metronidazole regimen. Here, too, a microscopic exam is necessary to visualize the cysts in the stool.

Although not known to produce any toxins or direct irritants to the colon, it's possible that B. hominis just has not been investigated closely enough to prove its pathogenicity. New data suggest this may be the case.

We've been seeing more lab reports of both D. fragilis and B. hominis in the last few years. It's not clear whether that's because of increased use of preservative packs or actual increased prevalence.

But we definitely seem to get more calls from parents and physicians about parasites as the weather gets warmer.

For your viewing pleasure …” as Rod Serling once said, I invite you to peruse four alternative group A streptococcus presentations that might not be so obvious at first and for which the approach may be controversial:

▸ Urticaria. Hives may be due to group A streptococcus (GAS), developing even while the patient is on effective anti-GAS treatment. This appears to be an atypical host-specific response and often occurs in children who develop hives in response to other stimuli as well. Unfortunately, the literature on this is mostly anecdotal.

We recently saw a 15-year-old who developed hives 3 days into amoxicillin therapy for GAS pharyngitis. Amoxicillin was changed to azithromycin, but the urticaria intensified. After switching her to two other classes of antibiotics, we deduced that the urticaria wasn't a drug reaction, but a reaction to GAS itself.

Another scenario is the child with recurrent urticaria. Elevated antistreptolysin-O (ASO) or anti-DNase B titers or evidence of GAS in the pharynx via a rapid antigen test or throat culture are indications to try empiric GAS therapy. If the urticaria goes away and stays away, you've solved the problem.

Look for GAS if hives occur more than three times in 6 months without another known trigger, even if the child has no signs of pharyngitis. If it looks like GAS is involved, consider 3 months of prophylactic penicillin in these select patients, particularly during the winter months, when reexposure is most likely.

▸ Movement disorders. It's not very common, but if a child suddenly develops tics or obsessive-compulsive behaviors, check for GAS.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) was first described in the 1990's by Susan Swedo, M.D., and her colleagues at the National Institute of Mental Health based on five criteria: presence of obsessive-compulsive disorder (OCD) and/or a tic disorder; prepubertal symptom onset; episodic symptom severity; GAS association; and associated neurologic abnormalities (Am. J. Psychiatry 1998;155:264-71).

We recently saw a child with a sudden onset of tics after a febrile illness. Rheumatic fever was considered and the anti-DNase B was elevated. He did not meet the familiar modified Jones criteria. His repetitive hand movements were not really chorea and he had facial tics as well. After 10 days of penicillin, his tics went away, but some unusual facial movements remained for another month.

Six weeks after stopping penicillin, he developed OCD symptoms, which in turn disappeared after 6 weeks of amoxicillin prophylaxis. He continues symptom free on amoxicillin.

One wonders if he might have been reexposed to streptococcus after the initial penicillin; and, while he didn't subsequently develop clinical pharyngitis, GAS reacquisition may have triggered an antibody response that cross-reacted with neural tissues.

The theory that if you can prevent GAS stimulus, you may prevent neuropsychiatric symptoms is supported by a prospective study published in 2002 by Marie Lynd Murphy, M.D., and Michael Pichichero, M.D. (Arch. Pediatr. Adolesc. Med. 2002;156:356-61).

Both the diagnosis and empiric treatment of PANDAS are still controversial. It seems to me that an antibiotic trial could be justified in the face of symptoms that are quite lifestyle altering for the child and family—even if only some of the small subset with evidence of GAS improve.

However, I'm not yet ready to give intravenous immunoglobulin or order plasmapheresis without a defined investigational protocol.

▸ Fever and petechiae. We immediately think of meningococcemia in a child with fever and petechiae (and so we should), even though GAS is actually more likely. Ray Baker, M.D., and his colleagues found Neisseria meningitides in 13 (6.8%) of 190 children with fever and petechial rash (8/13 had meningitis), compared with GAS in 10%. No pathogen was found in 72% (Pediatrics 1989;84:1051-5).

Using these data can be tricky. I think we should consider GAS in relatively well-looking febrile children with only a few scattered petechiae and tonsillitis or pharyngitis. If a throat culture or rapid antigen test is positive, immediate hospitalization may not be necessary. Of course, hospitalization and full work-up are necessary if the child looks sick, has more than scattered petechiae or any purpura, or if meningococcus has been in the community lately.

The main clinical use of these data may be to obtain a throat culture before starting antibiotics for presumed meningococcus in the fever/petechiae case.

▸Joint pain and fever. It seems that we are seeing more children who have fever, arthralgias and elevated sedimentation rates and C-reactive protein values, but who don't meet the Jones criteria for rheumatic fever. That doesn't mean they don't have poststreptococcal disease.

The Jones criteria for rheumatic fever, first established in 1944 and revised most recently in 1992 (JAMA 1992;268:2069-73), require evidence of antecedent GAS infection along with either two or more major criteria (carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules), or one major criterion plus at least two minor criteria (fever, arthralgia, previous rheumatic fever or rheumatic heart disease, elevated acute phase reactants, prolonged PR interval).

This definition leaves us with a conundrum: what to do with the child who has two or more of the minor criteria but none of the major ones, particularly if the child has a single joint arthritis. These may be post-GAS syndromes. Or could the child have some other arthritis that coincidentally occurred following GAS?

Further, do these children need more than 10 days of penicillin (up to a year)? Without prophylaxis, some who initially had an autoimmune joint flare-up without classic carditis or polyarthritis may convert to full-blown rheumatic fever the next time they're exposed to GAS.

It seems reasonable to put such children on prophylaxis for 12 months, especially during the winter GAS season. If the joint symptoms recur on adequate GAS prophylaxis, you can be more confident that it's not due to GAS and therefore should be referred to a rheumatologist. If the child develops some evidence of valvular abnormality over the year of prophylaxis, then it's an atypical case of rheumatic fever.

For your viewing pleasure …” as Rod Serling once said, I invite you to peruse four alternative group A streptococcus presentations that might not be so obvious at first and for which the approach may be controversial:

▸ Urticaria. Hives may be due to group A streptococcus (GAS), developing even while the patient is on effective anti-GAS treatment. This appears to be an atypical host-specific response and often occurs in children who develop hives in response to other stimuli as well. Unfortunately, the literature on this is mostly anecdotal.

We recently saw a 15-year-old who developed hives 3 days into amoxicillin therapy for GAS pharyngitis. Amoxicillin was changed to azithromycin, but the urticaria intensified. After switching her to two other classes of antibiotics, we deduced that the urticaria wasn't a drug reaction, but a reaction to GAS itself.

Another scenario is the child with recurrent urticaria. Elevated antistreptolysin-O (ASO) or anti-DNase B titers or evidence of GAS in the pharynx via a rapid antigen test or throat culture are indications to try empiric GAS therapy. If the urticaria goes away and stays away, you've solved the problem.

Look for GAS if hives occur more than three times in 6 months without another known trigger, even if the child has no signs of pharyngitis. If it looks like GAS is involved, consider 3 months of prophylactic penicillin in these select patients, particularly during the winter months, when reexposure is most likely.

▸ Movement disorders. It's not very common, but if a child suddenly develops tics or obsessive-compulsive behaviors, check for GAS.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) was first described in the 1990's by Susan Swedo, M.D., and her colleagues at the National Institute of Mental Health based on five criteria: presence of obsessive-compulsive disorder (OCD) and/or a tic disorder; prepubertal symptom onset; episodic symptom severity; GAS association; and associated neurologic abnormalities (Am. J. Psychiatry 1998;155:264-71).

We recently saw a child with a sudden onset of tics after a febrile illness. Rheumatic fever was considered and the anti-DNase B was elevated. He did not meet the familiar modified Jones criteria. His repetitive hand movements were not really chorea and he had facial tics as well. After 10 days of penicillin, his tics went away, but some unusual facial movements remained for another month.

Six weeks after stopping penicillin, he developed OCD symptoms, which in turn disappeared after 6 weeks of amoxicillin prophylaxis. He continues symptom free on amoxicillin.

One wonders if he might have been reexposed to streptococcus after the initial penicillin; and, while he didn't subsequently develop clinical pharyngitis, GAS reacquisition may have triggered an antibody response that cross-reacted with neural tissues.

The theory that if you can prevent GAS stimulus, you may prevent neuropsychiatric symptoms is supported by a prospective study published in 2002 by Marie Lynd Murphy, M.D., and Michael Pichichero, M.D. (Arch. Pediatr. Adolesc. Med. 2002;156:356-61).

Both the diagnosis and empiric treatment of PANDAS are still controversial. It seems to me that an antibiotic trial could be justified in the face of symptoms that are quite lifestyle altering for the child and family—even if only some of the small subset with evidence of GAS improve.

However, I'm not yet ready to give intravenous immunoglobulin or order plasmapheresis without a defined investigational protocol.

▸ Fever and petechiae. We immediately think of meningococcemia in a child with fever and petechiae (and so we should), even though GAS is actually more likely. Ray Baker, M.D., and his colleagues found Neisseria meningitides in 13 (6.8%) of 190 children with fever and petechial rash (8/13 had meningitis), compared with GAS in 10%. No pathogen was found in 72% (Pediatrics 1989;84:1051-5).

Using these data can be tricky. I think we should consider GAS in relatively well-looking febrile children with only a few scattered petechiae and tonsillitis or pharyngitis. If a throat culture or rapid antigen test is positive, immediate hospitalization may not be necessary. Of course, hospitalization and full work-up are necessary if the child looks sick, has more than scattered petechiae or any purpura, or if meningococcus has been in the community lately.

The main clinical use of these data may be to obtain a throat culture before starting antibiotics for presumed meningococcus in the fever/petechiae case.

▸Joint pain and fever. It seems that we are seeing more children who have fever, arthralgias and elevated sedimentation rates and C-reactive protein values, but who don't meet the Jones criteria for rheumatic fever. That doesn't mean they don't have poststreptococcal disease.

The Jones criteria for rheumatic fever, first established in 1944 and revised most recently in 1992 (JAMA 1992;268:2069-73), require evidence of antecedent GAS infection along with either two or more major criteria (carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules), or one major criterion plus at least two minor criteria (fever, arthralgia, previous rheumatic fever or rheumatic heart disease, elevated acute phase reactants, prolonged PR interval).

This definition leaves us with a conundrum: what to do with the child who has two or more of the minor criteria but none of the major ones, particularly if the child has a single joint arthritis. These may be post-GAS syndromes. Or could the child have some other arthritis that coincidentally occurred following GAS?

Further, do these children need more than 10 days of penicillin (up to a year)? Without prophylaxis, some who initially had an autoimmune joint flare-up without classic carditis or polyarthritis may convert to full-blown rheumatic fever the next time they're exposed to GAS.

It seems reasonable to put such children on prophylaxis for 12 months, especially during the winter GAS season. If the joint symptoms recur on adequate GAS prophylaxis, you can be more confident that it's not due to GAS and therefore should be referred to a rheumatologist. If the child develops some evidence of valvular abnormality over the year of prophylaxis, then it's an atypical case of rheumatic fever.

For your viewing pleasure …” as Rod Serling once said, I invite you to peruse four alternative group A streptococcus presentations that might not be so obvious at first and for which the approach may be controversial:

▸ Urticaria. Hives may be due to group A streptococcus (GAS), developing even while the patient is on effective anti-GAS treatment. This appears to be an atypical host-specific response and often occurs in children who develop hives in response to other stimuli as well. Unfortunately, the literature on this is mostly anecdotal.

We recently saw a 15-year-old who developed hives 3 days into amoxicillin therapy for GAS pharyngitis. Amoxicillin was changed to azithromycin, but the urticaria intensified. After switching her to two other classes of antibiotics, we deduced that the urticaria wasn't a drug reaction, but a reaction to GAS itself.

Another scenario is the child with recurrent urticaria. Elevated antistreptolysin-O (ASO) or anti-DNase B titers or evidence of GAS in the pharynx via a rapid antigen test or throat culture are indications to try empiric GAS therapy. If the urticaria goes away and stays away, you've solved the problem.

Look for GAS if hives occur more than three times in 6 months without another known trigger, even if the child has no signs of pharyngitis. If it looks like GAS is involved, consider 3 months of prophylactic penicillin in these select patients, particularly during the winter months, when reexposure is most likely.

▸ Movement disorders. It's not very common, but if a child suddenly develops tics or obsessive-compulsive behaviors, check for GAS.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) was first described in the 1990's by Susan Swedo, M.D., and her colleagues at the National Institute of Mental Health based on five criteria: presence of obsessive-compulsive disorder (OCD) and/or a tic disorder; prepubertal symptom onset; episodic symptom severity; GAS association; and associated neurologic abnormalities (Am. J. Psychiatry 1998;155:264-71).

We recently saw a child with a sudden onset of tics after a febrile illness. Rheumatic fever was considered and the anti-DNase B was elevated. He did not meet the familiar modified Jones criteria. His repetitive hand movements were not really chorea and he had facial tics as well. After 10 days of penicillin, his tics went away, but some unusual facial movements remained for another month.

Six weeks after stopping penicillin, he developed OCD symptoms, which in turn disappeared after 6 weeks of amoxicillin prophylaxis. He continues symptom free on amoxicillin.

One wonders if he might have been reexposed to streptococcus after the initial penicillin; and, while he didn't subsequently develop clinical pharyngitis, GAS reacquisition may have triggered an antibody response that cross-reacted with neural tissues.

The theory that if you can prevent GAS stimulus, you may prevent neuropsychiatric symptoms is supported by a prospective study published in 2002 by Marie Lynd Murphy, M.D., and Michael Pichichero, M.D. (Arch. Pediatr. Adolesc. Med. 2002;156:356-61).

Both the diagnosis and empiric treatment of PANDAS are still controversial. It seems to me that an antibiotic trial could be justified in the face of symptoms that are quite lifestyle altering for the child and family—even if only some of the small subset with evidence of GAS improve.

However, I'm not yet ready to give intravenous immunoglobulin or order plasmapheresis without a defined investigational protocol.

▸ Fever and petechiae. We immediately think of meningococcemia in a child with fever and petechiae (and so we should), even though GAS is actually more likely. Ray Baker, M.D., and his colleagues found Neisseria meningitides in 13 (6.8%) of 190 children with fever and petechial rash (8/13 had meningitis), compared with GAS in 10%. No pathogen was found in 72% (Pediatrics 1989;84:1051-5).

Using these data can be tricky. I think we should consider GAS in relatively well-looking febrile children with only a few scattered petechiae and tonsillitis or pharyngitis. If a throat culture or rapid antigen test is positive, immediate hospitalization may not be necessary. Of course, hospitalization and full work-up are necessary if the child looks sick, has more than scattered petechiae or any purpura, or if meningococcus has been in the community lately.

The main clinical use of these data may be to obtain a throat culture before starting antibiotics for presumed meningococcus in the fever/petechiae case.

▸Joint pain and fever. It seems that we are seeing more children who have fever, arthralgias and elevated sedimentation rates and C-reactive protein values, but who don't meet the Jones criteria for rheumatic fever. That doesn't mean they don't have poststreptococcal disease.

The Jones criteria for rheumatic fever, first established in 1944 and revised most recently in 1992 (JAMA 1992;268:2069-73), require evidence of antecedent GAS infection along with either two or more major criteria (carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules), or one major criterion plus at least two minor criteria (fever, arthralgia, previous rheumatic fever or rheumatic heart disease, elevated acute phase reactants, prolonged PR interval).

This definition leaves us with a conundrum: what to do with the child who has two or more of the minor criteria but none of the major ones, particularly if the child has a single joint arthritis. These may be post-GAS syndromes. Or could the child have some other arthritis that coincidentally occurred following GAS?

Further, do these children need more than 10 days of penicillin (up to a year)? Without prophylaxis, some who initially had an autoimmune joint flare-up without classic carditis or polyarthritis may convert to full-blown rheumatic fever the next time they're exposed to GAS.

It seems reasonable to put such children on prophylaxis for 12 months, especially during the winter GAS season. If the joint symptoms recur on adequate GAS prophylaxis, you can be more confident that it's not due to GAS and therefore should be referred to a rheumatologist. If the child develops some evidence of valvular abnormality over the year of prophylaxis, then it's an atypical case of rheumatic fever.