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Discussing immunization with vaccine-hesitant parents requires caring, individualized approach
ORLANDO – Putting parents at ease, making vaccination the default option during discussions, appealing to their identity as a good parent, and focusing on positive word choice during discussions are the techniques two pediatricians have recommended using to get vaccine-hesitant parents to immunize their children.
“Your goal is to get parents to immunize their kids,” Katrina Saba, MD, of the Permanente Medical Group in Oakland, Calif., said during an interactive group panel at the annual meeting of the American Academy of Pediatrics. “Our goal is not to win a debate. You don’t have to correct every mistaken idea.”
“And really importantly, as we know, belief trumps science,” she added. “Their belief is so much stronger than our proof, and their belief will not be changed by evidence.”
Many parents who are vaccine- hesitant also belong to a social network that forms or reinforces their beliefs, and attacking those beliefs is the same as attacking their identity, Dr. Saba noted. “When you attack someone’s identity, you are immediately seen as not like them, and if you’re not like them, you’ve lost your strength in persuading them.”
Dr. Saba; Kenneth Hempstead, MD; and other pediatricians and educators in the Permanente Medical Group developed a framework for pediatricians and educators to talk with their patients about immunization at their center after California passed a law in 2013 that required health care professionals to discuss vaccines with patients and sign off that they had that discussion.
“We felt that, if we were going to be by law required to have that discussion, maybe we needed some new tools to have [the discussion] more effectively,” Dr. Saba said. “Because clearly, [what we were doing ] wasn’t working or there wouldn’t have been a need for that law.”
Dr. Hempstead explained the concerns of three major categories of vaccine-hesitant parents: those patients who are unsure of whether they should vaccinate, parents who wish to delay vaccination, and parents who refuse vaccination of their children.
Each parent requires a different approach for discussing the importance of vaccination based on their level of vaccine hesitancy, he said. For parents who are unsure, they may require general information about the safety and importance of vaccines.
Parents who delay immunization may have less trust in vaccines, have done research in their own social networks, and may present alternatives to a standard immunization schedule or want to omit certain vaccines from their child’s immunization schedule, he noted. Using the analogy of a car seat is one approach to identify the importance of vaccination to these parents: “Waiting to give the shots is like putting your baby in the car seat after you’ve already arrived at the store – the protection isn’t there for the most important part of the journey!”
In cases where parents refuse vaccination, you should not expect to change a parent’s mind in a single visit, but instead focus on building the patient-provider bond. However, presenting information the parent may have already seen, such as vaccination data from the Food and Drug Administration or Centers for Disease Control and Prevention, may alienate parents who identify with groups that share vaccine-hesitant viewpoints and erode your ability to persuade a parent’s intent to vaccinate.
A study by Nyhan et al. randomized parents to receive one of four pieces of interventions about the MMR vaccine: information from the CDC explaining the lack of evidence linking autism and the vaccine, information about the dangers of the diseases prevented by the vaccine, images of children who have had diseases prevented by the vaccine, and a “dramatic narrative” from a CDC fact sheet about a child who nearly died of measles. The researchers found no informational intervention helped in persuading to vaccinate in parents who had the “least favorable” attitudes toward the vaccine. And in the case of the dramatic narrative, there was an increased misperception about the MMR vaccine (Pediatrics. 2014;133[4]:e835-e842).
Dr. Hempstead and Dr. Saba outlined four rhetorical devices to include in conversations with patients about vaccination: cognitive ease, natural assumption, appeal to identity, and using advantageous terms.
Cognitive ease
Cognitive ease means creating an environment in which the patient is relaxed, comfortable, and more likely to be agreeable. Recognize when the tone shifts, and strive to maintain this calm and comfortable environment throughout the discussion. “If your blood pressure is coming up, that means theirs is, too,” Dr. Hempstead said.
Natural assumption
How you are offering the vaccination also matters, he added. Rather than asking whether a patient wants to vaccinate (“Have you thought about your flu vaccine this year?”), instead frame the discussion with vaccination as the default option (“Is your child due for a flu vaccination this year? Yes, he is. Let’s get that taken care of today”). Equating inaction with vaccination prevents the risk fallacy phenomenon from occurring in which, when given multiple options, people give equal weight to each option and may choose not to vaccinate, Dr. Hempstead noted.
Dr. Saba cited research that backed this approach. In a study by Opel et al., using a “presumptive” approach instead of a “participatory” approach when discussing a provider’s recommendation to vaccinate helped: The presumptive conversations had an odds ratio of 17.5, compared with the participatory approach. In cases in which parents resisted the provider’s recommendations, 50% of providers persisted with their original recommendations, and 47% of parents who initially resisted the recommendations agreed to vaccinate (Pediatrics. 2013;132[6]:1037-46).
Appeal to identity
Another strategy to use is appealing to the patient’s identity as a good parent and link the concept of vaccination with the good parent identity. Forging a new common identity with the parents through common beliefs – such as recognizing that networks to which parents belong are an important part of his or her identify – and reemphasizing the mutual desire to protect the child is another strategy.
Using advantageous terms
Positive terms, such as “protection,” “health,” “safety,” and “what’s best,” are much better words to use in conversation with parents and have more staying power than negative terms, like “autism” and “side effects,” Dr. Hempstead said.
“Stay with positive messaging,” he said. “Immediately coming back to the positive impact of this vaccine, why we care so much, why we’re doing this vaccine, is absolutely critical.”
Dr. Hempstead and Dr. Saba reported no relevant conflicts of interest.
ORLANDO – Putting parents at ease, making vaccination the default option during discussions, appealing to their identity as a good parent, and focusing on positive word choice during discussions are the techniques two pediatricians have recommended using to get vaccine-hesitant parents to immunize their children.
“Your goal is to get parents to immunize their kids,” Katrina Saba, MD, of the Permanente Medical Group in Oakland, Calif., said during an interactive group panel at the annual meeting of the American Academy of Pediatrics. “Our goal is not to win a debate. You don’t have to correct every mistaken idea.”
“And really importantly, as we know, belief trumps science,” she added. “Their belief is so much stronger than our proof, and their belief will not be changed by evidence.”
Many parents who are vaccine- hesitant also belong to a social network that forms or reinforces their beliefs, and attacking those beliefs is the same as attacking their identity, Dr. Saba noted. “When you attack someone’s identity, you are immediately seen as not like them, and if you’re not like them, you’ve lost your strength in persuading them.”
Dr. Saba; Kenneth Hempstead, MD; and other pediatricians and educators in the Permanente Medical Group developed a framework for pediatricians and educators to talk with their patients about immunization at their center after California passed a law in 2013 that required health care professionals to discuss vaccines with patients and sign off that they had that discussion.
“We felt that, if we were going to be by law required to have that discussion, maybe we needed some new tools to have [the discussion] more effectively,” Dr. Saba said. “Because clearly, [what we were doing ] wasn’t working or there wouldn’t have been a need for that law.”
Dr. Hempstead explained the concerns of three major categories of vaccine-hesitant parents: those patients who are unsure of whether they should vaccinate, parents who wish to delay vaccination, and parents who refuse vaccination of their children.
Each parent requires a different approach for discussing the importance of vaccination based on their level of vaccine hesitancy, he said. For parents who are unsure, they may require general information about the safety and importance of vaccines.
Parents who delay immunization may have less trust in vaccines, have done research in their own social networks, and may present alternatives to a standard immunization schedule or want to omit certain vaccines from their child’s immunization schedule, he noted. Using the analogy of a car seat is one approach to identify the importance of vaccination to these parents: “Waiting to give the shots is like putting your baby in the car seat after you’ve already arrived at the store – the protection isn’t there for the most important part of the journey!”
In cases where parents refuse vaccination, you should not expect to change a parent’s mind in a single visit, but instead focus on building the patient-provider bond. However, presenting information the parent may have already seen, such as vaccination data from the Food and Drug Administration or Centers for Disease Control and Prevention, may alienate parents who identify with groups that share vaccine-hesitant viewpoints and erode your ability to persuade a parent’s intent to vaccinate.
A study by Nyhan et al. randomized parents to receive one of four pieces of interventions about the MMR vaccine: information from the CDC explaining the lack of evidence linking autism and the vaccine, information about the dangers of the diseases prevented by the vaccine, images of children who have had diseases prevented by the vaccine, and a “dramatic narrative” from a CDC fact sheet about a child who nearly died of measles. The researchers found no informational intervention helped in persuading to vaccinate in parents who had the “least favorable” attitudes toward the vaccine. And in the case of the dramatic narrative, there was an increased misperception about the MMR vaccine (Pediatrics. 2014;133[4]:e835-e842).
Dr. Hempstead and Dr. Saba outlined four rhetorical devices to include in conversations with patients about vaccination: cognitive ease, natural assumption, appeal to identity, and using advantageous terms.
Cognitive ease
Cognitive ease means creating an environment in which the patient is relaxed, comfortable, and more likely to be agreeable. Recognize when the tone shifts, and strive to maintain this calm and comfortable environment throughout the discussion. “If your blood pressure is coming up, that means theirs is, too,” Dr. Hempstead said.
Natural assumption
How you are offering the vaccination also matters, he added. Rather than asking whether a patient wants to vaccinate (“Have you thought about your flu vaccine this year?”), instead frame the discussion with vaccination as the default option (“Is your child due for a flu vaccination this year? Yes, he is. Let’s get that taken care of today”). Equating inaction with vaccination prevents the risk fallacy phenomenon from occurring in which, when given multiple options, people give equal weight to each option and may choose not to vaccinate, Dr. Hempstead noted.
Dr. Saba cited research that backed this approach. In a study by Opel et al., using a “presumptive” approach instead of a “participatory” approach when discussing a provider’s recommendation to vaccinate helped: The presumptive conversations had an odds ratio of 17.5, compared with the participatory approach. In cases in which parents resisted the provider’s recommendations, 50% of providers persisted with their original recommendations, and 47% of parents who initially resisted the recommendations agreed to vaccinate (Pediatrics. 2013;132[6]:1037-46).
Appeal to identity
Another strategy to use is appealing to the patient’s identity as a good parent and link the concept of vaccination with the good parent identity. Forging a new common identity with the parents through common beliefs – such as recognizing that networks to which parents belong are an important part of his or her identify – and reemphasizing the mutual desire to protect the child is another strategy.
Using advantageous terms
Positive terms, such as “protection,” “health,” “safety,” and “what’s best,” are much better words to use in conversation with parents and have more staying power than negative terms, like “autism” and “side effects,” Dr. Hempstead said.
“Stay with positive messaging,” he said. “Immediately coming back to the positive impact of this vaccine, why we care so much, why we’re doing this vaccine, is absolutely critical.”
Dr. Hempstead and Dr. Saba reported no relevant conflicts of interest.
ORLANDO – Putting parents at ease, making vaccination the default option during discussions, appealing to their identity as a good parent, and focusing on positive word choice during discussions are the techniques two pediatricians have recommended using to get vaccine-hesitant parents to immunize their children.
“Your goal is to get parents to immunize their kids,” Katrina Saba, MD, of the Permanente Medical Group in Oakland, Calif., said during an interactive group panel at the annual meeting of the American Academy of Pediatrics. “Our goal is not to win a debate. You don’t have to correct every mistaken idea.”
“And really importantly, as we know, belief trumps science,” she added. “Their belief is so much stronger than our proof, and their belief will not be changed by evidence.”
Many parents who are vaccine- hesitant also belong to a social network that forms or reinforces their beliefs, and attacking those beliefs is the same as attacking their identity, Dr. Saba noted. “When you attack someone’s identity, you are immediately seen as not like them, and if you’re not like them, you’ve lost your strength in persuading them.”
Dr. Saba; Kenneth Hempstead, MD; and other pediatricians and educators in the Permanente Medical Group developed a framework for pediatricians and educators to talk with their patients about immunization at their center after California passed a law in 2013 that required health care professionals to discuss vaccines with patients and sign off that they had that discussion.
“We felt that, if we were going to be by law required to have that discussion, maybe we needed some new tools to have [the discussion] more effectively,” Dr. Saba said. “Because clearly, [what we were doing ] wasn’t working or there wouldn’t have been a need for that law.”
Dr. Hempstead explained the concerns of three major categories of vaccine-hesitant parents: those patients who are unsure of whether they should vaccinate, parents who wish to delay vaccination, and parents who refuse vaccination of their children.
Each parent requires a different approach for discussing the importance of vaccination based on their level of vaccine hesitancy, he said. For parents who are unsure, they may require general information about the safety and importance of vaccines.
Parents who delay immunization may have less trust in vaccines, have done research in their own social networks, and may present alternatives to a standard immunization schedule or want to omit certain vaccines from their child’s immunization schedule, he noted. Using the analogy of a car seat is one approach to identify the importance of vaccination to these parents: “Waiting to give the shots is like putting your baby in the car seat after you’ve already arrived at the store – the protection isn’t there for the most important part of the journey!”
In cases where parents refuse vaccination, you should not expect to change a parent’s mind in a single visit, but instead focus on building the patient-provider bond. However, presenting information the parent may have already seen, such as vaccination data from the Food and Drug Administration or Centers for Disease Control and Prevention, may alienate parents who identify with groups that share vaccine-hesitant viewpoints and erode your ability to persuade a parent’s intent to vaccinate.
A study by Nyhan et al. randomized parents to receive one of four pieces of interventions about the MMR vaccine: information from the CDC explaining the lack of evidence linking autism and the vaccine, information about the dangers of the diseases prevented by the vaccine, images of children who have had diseases prevented by the vaccine, and a “dramatic narrative” from a CDC fact sheet about a child who nearly died of measles. The researchers found no informational intervention helped in persuading to vaccinate in parents who had the “least favorable” attitudes toward the vaccine. And in the case of the dramatic narrative, there was an increased misperception about the MMR vaccine (Pediatrics. 2014;133[4]:e835-e842).
Dr. Hempstead and Dr. Saba outlined four rhetorical devices to include in conversations with patients about vaccination: cognitive ease, natural assumption, appeal to identity, and using advantageous terms.
Cognitive ease
Cognitive ease means creating an environment in which the patient is relaxed, comfortable, and more likely to be agreeable. Recognize when the tone shifts, and strive to maintain this calm and comfortable environment throughout the discussion. “If your blood pressure is coming up, that means theirs is, too,” Dr. Hempstead said.
Natural assumption
How you are offering the vaccination also matters, he added. Rather than asking whether a patient wants to vaccinate (“Have you thought about your flu vaccine this year?”), instead frame the discussion with vaccination as the default option (“Is your child due for a flu vaccination this year? Yes, he is. Let’s get that taken care of today”). Equating inaction with vaccination prevents the risk fallacy phenomenon from occurring in which, when given multiple options, people give equal weight to each option and may choose not to vaccinate, Dr. Hempstead noted.
Dr. Saba cited research that backed this approach. In a study by Opel et al., using a “presumptive” approach instead of a “participatory” approach when discussing a provider’s recommendation to vaccinate helped: The presumptive conversations had an odds ratio of 17.5, compared with the participatory approach. In cases in which parents resisted the provider’s recommendations, 50% of providers persisted with their original recommendations, and 47% of parents who initially resisted the recommendations agreed to vaccinate (Pediatrics. 2013;132[6]:1037-46).
Appeal to identity
Another strategy to use is appealing to the patient’s identity as a good parent and link the concept of vaccination with the good parent identity. Forging a new common identity with the parents through common beliefs – such as recognizing that networks to which parents belong are an important part of his or her identify – and reemphasizing the mutual desire to protect the child is another strategy.
Using advantageous terms
Positive terms, such as “protection,” “health,” “safety,” and “what’s best,” are much better words to use in conversation with parents and have more staying power than negative terms, like “autism” and “side effects,” Dr. Hempstead said.
“Stay with positive messaging,” he said. “Immediately coming back to the positive impact of this vaccine, why we care so much, why we’re doing this vaccine, is absolutely critical.”
Dr. Hempstead and Dr. Saba reported no relevant conflicts of interest.
EXPERT ANALYSIS FROM AAP 18
Study confirms advice to halt methotrexate when giving flu vaccine to RA patients
CHICAGO – Discontinuing methotrexate for 2 weeks in patients with RA starting the day they receive the seasonal influenza vaccine significantly improves the vaccine’s immunogenicity without aggravating disease activity, Kevin L. Winthrop, MD, reported at the annual meeting of the American College of Rheumatology.
“I think this is potentially clinically practice changing because now there are two studies showing the same thing,” said Dr. Winthrop, a professor of public health and preventive medicine at Oregon Health & Science University, Portland.
Based upon these prospective randomized studies, which he conducted together with investigators at Seoul National University in South Korea, initiating a 2-week halt of methotrexate on the day the influenza vaccine is given to patients with RA is now his routine practice, and he recommends other physicians do the same.
The first prospective, randomized trial included 199 RA patients on stable doses of methotrexate who were assigned to one of four groups in conjunction with seasonal influenza vaccination. One group continued their methotrexate as usual, the second stopped the drug for 1 month prior to vaccination and then restarted it at the time of vaccination, the third group halted methotrexate for 2 weeks before and 2 weeks after vaccination, and the fourth suspended methotrexate for 4 weeks starting on the day they got their flu shot. Everyone received trivalent influenza vaccine containing H1N1, H3N2, and B/Yamagata.
The lowest rate of satisfactory vaccine response as defined by at least a 300% titer increase 1 month after vaccination occurred in the group that continued their methotrexate as usual. The group that halted the drug for 2 weeks before and 2 weeks after influenza vaccination had a 51% satisfactory vaccine response against all three antigens, compared with a 31.5% rate in the methotrexate-as-usual group. RA flare rates ranged from 21% to 39% across the four study arms, differences that weren’t statistically significant (Ann Rheum Dis. 2017 Sep;76[9]:1559-65).
Next Dr. Winthrop and his colleagues conducted a confirmatory prospective, multicenter, randomized trial in which they sought to nail down the optimal duration and timing of methotrexate discontinuation. A total of 320 RA patients on stable doses of methotrexate were assigned to halt the drug for 2 weeks starting at the time they received a quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains, or to continue their methotrexate throughout.
A satisfactory vaccine response was achieved in 75.5% of the group that discontinued the drug, significantly better than the 54.5% rate in the methotrexate continuers. The absolute difference in seroprotection was greater in patients who halted their methotrexate for 2 weeks after vaccination for all four antigens: an absolute 11% difference for H1N1, 16% for H3N2, 12% for B/Yamagata, and 15% for B/Victoria (Ann Rheum Dis. 2018 Jun;77[6]:898-904).
“It does seem to be a nice strategy. The percentage of people who flared their RA during their 2 weeks off methotrexate was very low, so there seems to be a good reason to do this,” according to Dr. Winthrop.
Some rheumatologists he has spoken with initially balked at the plausibility of the results.
“I had the same thought about these studies: It doesn’t make sense to me in terms of how methotrexate works, and why we would see this effect acutely by stopping methotrexate for just 2 weeks?” he said.
But then a coinvestigator drilled down deeper into the data and came up with the explanation: The benefit in terms of enhanced flu vaccine immunogenicity through temporary withholding of methotrexate was confined to the subgroup of RA patients with high baseline levels of B-cell activation factor (BAFF). In contrast, withholding methotrexate didn’t affect the vaccine response in patients with low or normal baseline BAFF (Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214025).
“I don’t know how to check anyone’s BAFF levels. I don’t think there’s a commercial test out there. But this does help explain why we saw this observation. So I think I would still hold everyone’s methotrexate for 2 weeks. That’s how I approach it. And they may get benefit from it, and they may not,” he said.
Dr. Winthrop reported having no financial conflicts regarding the study, which was funded by GC Pharma.
CHICAGO – Discontinuing methotrexate for 2 weeks in patients with RA starting the day they receive the seasonal influenza vaccine significantly improves the vaccine’s immunogenicity without aggravating disease activity, Kevin L. Winthrop, MD, reported at the annual meeting of the American College of Rheumatology.
“I think this is potentially clinically practice changing because now there are two studies showing the same thing,” said Dr. Winthrop, a professor of public health and preventive medicine at Oregon Health & Science University, Portland.
Based upon these prospective randomized studies, which he conducted together with investigators at Seoul National University in South Korea, initiating a 2-week halt of methotrexate on the day the influenza vaccine is given to patients with RA is now his routine practice, and he recommends other physicians do the same.
The first prospective, randomized trial included 199 RA patients on stable doses of methotrexate who were assigned to one of four groups in conjunction with seasonal influenza vaccination. One group continued their methotrexate as usual, the second stopped the drug for 1 month prior to vaccination and then restarted it at the time of vaccination, the third group halted methotrexate for 2 weeks before and 2 weeks after vaccination, and the fourth suspended methotrexate for 4 weeks starting on the day they got their flu shot. Everyone received trivalent influenza vaccine containing H1N1, H3N2, and B/Yamagata.
The lowest rate of satisfactory vaccine response as defined by at least a 300% titer increase 1 month after vaccination occurred in the group that continued their methotrexate as usual. The group that halted the drug for 2 weeks before and 2 weeks after influenza vaccination had a 51% satisfactory vaccine response against all three antigens, compared with a 31.5% rate in the methotrexate-as-usual group. RA flare rates ranged from 21% to 39% across the four study arms, differences that weren’t statistically significant (Ann Rheum Dis. 2017 Sep;76[9]:1559-65).
Next Dr. Winthrop and his colleagues conducted a confirmatory prospective, multicenter, randomized trial in which they sought to nail down the optimal duration and timing of methotrexate discontinuation. A total of 320 RA patients on stable doses of methotrexate were assigned to halt the drug for 2 weeks starting at the time they received a quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains, or to continue their methotrexate throughout.
A satisfactory vaccine response was achieved in 75.5% of the group that discontinued the drug, significantly better than the 54.5% rate in the methotrexate continuers. The absolute difference in seroprotection was greater in patients who halted their methotrexate for 2 weeks after vaccination for all four antigens: an absolute 11% difference for H1N1, 16% for H3N2, 12% for B/Yamagata, and 15% for B/Victoria (Ann Rheum Dis. 2018 Jun;77[6]:898-904).
“It does seem to be a nice strategy. The percentage of people who flared their RA during their 2 weeks off methotrexate was very low, so there seems to be a good reason to do this,” according to Dr. Winthrop.
Some rheumatologists he has spoken with initially balked at the plausibility of the results.
“I had the same thought about these studies: It doesn’t make sense to me in terms of how methotrexate works, and why we would see this effect acutely by stopping methotrexate for just 2 weeks?” he said.
But then a coinvestigator drilled down deeper into the data and came up with the explanation: The benefit in terms of enhanced flu vaccine immunogenicity through temporary withholding of methotrexate was confined to the subgroup of RA patients with high baseline levels of B-cell activation factor (BAFF). In contrast, withholding methotrexate didn’t affect the vaccine response in patients with low or normal baseline BAFF (Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214025).
“I don’t know how to check anyone’s BAFF levels. I don’t think there’s a commercial test out there. But this does help explain why we saw this observation. So I think I would still hold everyone’s methotrexate for 2 weeks. That’s how I approach it. And they may get benefit from it, and they may not,” he said.
Dr. Winthrop reported having no financial conflicts regarding the study, which was funded by GC Pharma.
CHICAGO – Discontinuing methotrexate for 2 weeks in patients with RA starting the day they receive the seasonal influenza vaccine significantly improves the vaccine’s immunogenicity without aggravating disease activity, Kevin L. Winthrop, MD, reported at the annual meeting of the American College of Rheumatology.
“I think this is potentially clinically practice changing because now there are two studies showing the same thing,” said Dr. Winthrop, a professor of public health and preventive medicine at Oregon Health & Science University, Portland.
Based upon these prospective randomized studies, which he conducted together with investigators at Seoul National University in South Korea, initiating a 2-week halt of methotrexate on the day the influenza vaccine is given to patients with RA is now his routine practice, and he recommends other physicians do the same.
The first prospective, randomized trial included 199 RA patients on stable doses of methotrexate who were assigned to one of four groups in conjunction with seasonal influenza vaccination. One group continued their methotrexate as usual, the second stopped the drug for 1 month prior to vaccination and then restarted it at the time of vaccination, the third group halted methotrexate for 2 weeks before and 2 weeks after vaccination, and the fourth suspended methotrexate for 4 weeks starting on the day they got their flu shot. Everyone received trivalent influenza vaccine containing H1N1, H3N2, and B/Yamagata.
The lowest rate of satisfactory vaccine response as defined by at least a 300% titer increase 1 month after vaccination occurred in the group that continued their methotrexate as usual. The group that halted the drug for 2 weeks before and 2 weeks after influenza vaccination had a 51% satisfactory vaccine response against all three antigens, compared with a 31.5% rate in the methotrexate-as-usual group. RA flare rates ranged from 21% to 39% across the four study arms, differences that weren’t statistically significant (Ann Rheum Dis. 2017 Sep;76[9]:1559-65).
Next Dr. Winthrop and his colleagues conducted a confirmatory prospective, multicenter, randomized trial in which they sought to nail down the optimal duration and timing of methotrexate discontinuation. A total of 320 RA patients on stable doses of methotrexate were assigned to halt the drug for 2 weeks starting at the time they received a quadrivalent seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains, or to continue their methotrexate throughout.
A satisfactory vaccine response was achieved in 75.5% of the group that discontinued the drug, significantly better than the 54.5% rate in the methotrexate continuers. The absolute difference in seroprotection was greater in patients who halted their methotrexate for 2 weeks after vaccination for all four antigens: an absolute 11% difference for H1N1, 16% for H3N2, 12% for B/Yamagata, and 15% for B/Victoria (Ann Rheum Dis. 2018 Jun;77[6]:898-904).
“It does seem to be a nice strategy. The percentage of people who flared their RA during their 2 weeks off methotrexate was very low, so there seems to be a good reason to do this,” according to Dr. Winthrop.
Some rheumatologists he has spoken with initially balked at the plausibility of the results.
“I had the same thought about these studies: It doesn’t make sense to me in terms of how methotrexate works, and why we would see this effect acutely by stopping methotrexate for just 2 weeks?” he said.
But then a coinvestigator drilled down deeper into the data and came up with the explanation: The benefit in terms of enhanced flu vaccine immunogenicity through temporary withholding of methotrexate was confined to the subgroup of RA patients with high baseline levels of B-cell activation factor (BAFF). In contrast, withholding methotrexate didn’t affect the vaccine response in patients with low or normal baseline BAFF (Ann Rheum Dis. 2018 Oct 8. doi: 10.1136/annrheumdis-2018-214025).
“I don’t know how to check anyone’s BAFF levels. I don’t think there’s a commercial test out there. But this does help explain why we saw this observation. So I think I would still hold everyone’s methotrexate for 2 weeks. That’s how I approach it. And they may get benefit from it, and they may not,” he said.
Dr. Winthrop reported having no financial conflicts regarding the study, which was funded by GC Pharma.
REPORTING FROM THE ACR ANNUAL MEETING
Struggling to reach an HCV vaccine
Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.
In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.
One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.
Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.
“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.
The authors reported having no conflicts.
SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.
Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.
In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.
One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.
Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.
“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.
The authors reported having no conflicts.
SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.
Currently, there is no effective hepatitis C virus (HCV) vaccine available despite numerous ongoing studies, according to the results of a review published in Gastroenterology.
In their article, Justin R. Bailey, MD, of Johns Hopkins University, Baltimore, and his colleagues reviewed the limited feasibility of applying traditional vaccine design to HCV and the problem of genetic diversity in the virus, as well as trials of vaccines designed to elicit T-cell responses.
One profound difficulty in the development and testing of an HCV vaccine is that the cohort most predictably at risk for high infection levels, people who inject drugs, are notoriously difficult to recruit, maintain consistent treatment, and follow up on – all necessary aspects of an appropriate vaccine trial.
Thus, at present, adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested only in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins remain the only vaccine strategy tested in truly at-risk individuals, according to Dr. Bailey and his colleagues.
“Although pharmaceutical companies invest in drug development, vaccine development requires investment from sources beyond government and charitable foundations. A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” Dr. Bailey and his colleagues concluded.
The authors reported having no conflicts.
SOURCE: Bailey JR et al. Gastroenterology. 2018 Sep 27. doi: 10.1053/j.gastro.2018.08.060.
FROM GASTROENTEROLOGY
Reviewing the state of HCV and HBV in children
The natural histories of hepatitis B virus (HBV) and hepatitis C virus (HCV) are very different in children, compared with their progress in adults, and depends on age at time of infection, mode of acquisition, ethnicity, and genotype, according to a review in a special pediatric issue of Clinics in Liver Disease.
Most children infected perinatally or vertically continue to be asymptomatic but are at uniquely higher risk of developing chronic viral hepatitis and progressing to liver cirrhosis and hepatocellular carcinoma (HCC), according to Krupa R. Mysore, MD, and Daniel H. Leung, MD, both of the Baylor College of Medicine, Houston. In addition, because the risk of progression to cancer along with such other liver damage is high in children, the reviewers stated that HCV and HBV can be classified as oncoviruses.
Their article assessed overall epidemiology, viral characteristics, and immune responses, as well as prevention, clinical manifestations, and current advances in the treatment of hepatitis B and C in children.
Because of the introduction of universal infant vaccination for HBV in the United States in 1991, the incidence of acute hepatitis B in U.S. children (those aged less than 19 years) has decreased from approximately 13.80/100,000 population (in children aged 10-19 years) in the 1980s to 0.34/100,000 population in 2002, Dr. Mysore and Dr. Leung wrote.
However, they added that those children who have chronic HBV remain at high risk for HCC, with a 100-fold greater incidence, compared with the HBV-negative population.
Similarly, HCV is a significant problem in children, with an estimated prevalence in the United States of 0.2% and 0.4% for children aged 6-11 years and 12-19 years, respectively. Vertical transmission from the mother is responsible for more than 60% of pediatric HCV infection and adds approximately 7,200 new cases in the United States yearly. Older children can acquire the virus through intravenous and intranasal drug use and high-risk sexual activity, they stated.
“Our understanding of the pathobiology and immunology of hepatitis B and C is unprecedented. As new antiviral therapies are being developed for the pediatric population, the differences in management and monitoring between children and adults with HBV and HCV are beginning to narrow but are still important,” the authors wrote.
They pointed out that soon-to-be-available treatments for HCV will be curative in children aged as young as 3 years. “[T]his will change the natural history of HCV and the prevalence of hepatocellular carcinoma over the next several decades for the better,” Dr. Mysore and Dr. Leung concluded.
They reported that they had no conflicts of interest to disclose.
SOURCE: Mysore KR et al. Clin Liver Dis. 2018; 22:703-22.
The natural histories of hepatitis B virus (HBV) and hepatitis C virus (HCV) are very different in children, compared with their progress in adults, and depends on age at time of infection, mode of acquisition, ethnicity, and genotype, according to a review in a special pediatric issue of Clinics in Liver Disease.
Most children infected perinatally or vertically continue to be asymptomatic but are at uniquely higher risk of developing chronic viral hepatitis and progressing to liver cirrhosis and hepatocellular carcinoma (HCC), according to Krupa R. Mysore, MD, and Daniel H. Leung, MD, both of the Baylor College of Medicine, Houston. In addition, because the risk of progression to cancer along with such other liver damage is high in children, the reviewers stated that HCV and HBV can be classified as oncoviruses.
Their article assessed overall epidemiology, viral characteristics, and immune responses, as well as prevention, clinical manifestations, and current advances in the treatment of hepatitis B and C in children.
Because of the introduction of universal infant vaccination for HBV in the United States in 1991, the incidence of acute hepatitis B in U.S. children (those aged less than 19 years) has decreased from approximately 13.80/100,000 population (in children aged 10-19 years) in the 1980s to 0.34/100,000 population in 2002, Dr. Mysore and Dr. Leung wrote.
However, they added that those children who have chronic HBV remain at high risk for HCC, with a 100-fold greater incidence, compared with the HBV-negative population.
Similarly, HCV is a significant problem in children, with an estimated prevalence in the United States of 0.2% and 0.4% for children aged 6-11 years and 12-19 years, respectively. Vertical transmission from the mother is responsible for more than 60% of pediatric HCV infection and adds approximately 7,200 new cases in the United States yearly. Older children can acquire the virus through intravenous and intranasal drug use and high-risk sexual activity, they stated.
“Our understanding of the pathobiology and immunology of hepatitis B and C is unprecedented. As new antiviral therapies are being developed for the pediatric population, the differences in management and monitoring between children and adults with HBV and HCV are beginning to narrow but are still important,” the authors wrote.
They pointed out that soon-to-be-available treatments for HCV will be curative in children aged as young as 3 years. “[T]his will change the natural history of HCV and the prevalence of hepatocellular carcinoma over the next several decades for the better,” Dr. Mysore and Dr. Leung concluded.
They reported that they had no conflicts of interest to disclose.
SOURCE: Mysore KR et al. Clin Liver Dis. 2018; 22:703-22.
The natural histories of hepatitis B virus (HBV) and hepatitis C virus (HCV) are very different in children, compared with their progress in adults, and depends on age at time of infection, mode of acquisition, ethnicity, and genotype, according to a review in a special pediatric issue of Clinics in Liver Disease.
Most children infected perinatally or vertically continue to be asymptomatic but are at uniquely higher risk of developing chronic viral hepatitis and progressing to liver cirrhosis and hepatocellular carcinoma (HCC), according to Krupa R. Mysore, MD, and Daniel H. Leung, MD, both of the Baylor College of Medicine, Houston. In addition, because the risk of progression to cancer along with such other liver damage is high in children, the reviewers stated that HCV and HBV can be classified as oncoviruses.
Their article assessed overall epidemiology, viral characteristics, and immune responses, as well as prevention, clinical manifestations, and current advances in the treatment of hepatitis B and C in children.
Because of the introduction of universal infant vaccination for HBV in the United States in 1991, the incidence of acute hepatitis B in U.S. children (those aged less than 19 years) has decreased from approximately 13.80/100,000 population (in children aged 10-19 years) in the 1980s to 0.34/100,000 population in 2002, Dr. Mysore and Dr. Leung wrote.
However, they added that those children who have chronic HBV remain at high risk for HCC, with a 100-fold greater incidence, compared with the HBV-negative population.
Similarly, HCV is a significant problem in children, with an estimated prevalence in the United States of 0.2% and 0.4% for children aged 6-11 years and 12-19 years, respectively. Vertical transmission from the mother is responsible for more than 60% of pediatric HCV infection and adds approximately 7,200 new cases in the United States yearly. Older children can acquire the virus through intravenous and intranasal drug use and high-risk sexual activity, they stated.
“Our understanding of the pathobiology and immunology of hepatitis B and C is unprecedented. As new antiviral therapies are being developed for the pediatric population, the differences in management and monitoring between children and adults with HBV and HCV are beginning to narrow but are still important,” the authors wrote.
They pointed out that soon-to-be-available treatments for HCV will be curative in children aged as young as 3 years. “[T]his will change the natural history of HCV and the prevalence of hepatocellular carcinoma over the next several decades for the better,” Dr. Mysore and Dr. Leung concluded.
They reported that they had no conflicts of interest to disclose.
SOURCE: Mysore KR et al. Clin Liver Dis. 2018; 22:703-22.
FROM CLINICS IN LIVER DISEASE
Pneumonia, COPD most common emergency care–sensitive conditions
SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.
In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.
Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.
Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.
Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.
Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).
The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”
The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.
Dr. Vashi reported having no financial disclosures.
Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.
SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.
In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.
Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.
Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.
Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.
Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).
The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”
The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.
Dr. Vashi reported having no financial disclosures.
Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.
SAN DIEGO – Emergency care–sensitive conditions – those for which timely access to high-quality emergency care impact morbidity and mortality—account for 14% of all ED visits, results from a large analysis of national data showed.
In previously published work, an eight-member expert panel identified 51 condition groups as emergency care–sensitive conditions (ECSCs), including asthma, cardiac arrest, cerebral infarction, and pneumonia. The purpose of the current study, published in Annals of Emergency Medicine and presented by Anita Vashi, MD, MPH, at the annual meeting of the American College of Emergency Physicians, was to provide the first national estimates of acute care utilization and the demographic characteristics of adults experiencing ECSCs, compare ECSC and non-ECSC ED visits, and assess patient- and hospital-level characteristics predictive of an ECSC-related ED visit.
Using the Nationwide Emergency Department Sample data set, Dr. Vashi, a physician investigator at the Center for Innovation to Implementation at the VA Palo Alto Health Care System, and her colleagues retrospectively evaluated all ED visits for patients aged 18 years and older from 2009 to 2014. The researchers used summary statistics to compare population characteristics across groups and multivariable logistic regression models to assess the odds of an ECSC-related ED visit with patient- and hospital-level characteristics.
Of the 622,725,542 estimated ED visits evaluated during the study period, 86,577,041 (14%) were ECSCs. Among these ECSC visits, 58% of patients were admitted for an average length of 3.2 days and an average charge of $2,240. The most frequent ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), asthma (7%), heart failure (7%), and sepsis (5%), but varied by age group.
Dr. Vashi and her colleagues found that ECSCs were more common among older adults, males, those who reside in low-income areas, those who reside in the South, and among metropolitan-based hospitals and nontrauma center hospitals. ECSCs also accounted for about 45% of all inpatient admissions.
Multivariate logistic regression analysis revealed that the odds of having an ECSC-related visit was highest among patients aged 65 years and older (odds ratio, 3.84), those on Medicare (OR, 1.37), those who resided in rural counties (OR, 1.21), and those who reside in the Western portion of the United States (OR, 1.11). Significant hospital-related factors related to ECSC visits included trauma centers (OR, 1.09), nonteaching hospitals (OR, 1.04), and EDs located in the wealthiest counties (OR, 1.02).
The researchers also found that 40% of patients who made ECSC-related ED visits were treated and discharged back to the community. “There is evidence of regional variability, suggesting the need for future research,” said Dr. Vashi, who also holds a faculty position in the department of emergency medicine at Stanford (Calif.) University. “We found no consistent relationship between insurance, income, and ED use for ECSC-related conditions. This suggests that ECSCs are not significantly influenced by socioeconomic factor and can serve as a reliable marker for acuity.”
The next steps in this research area, she added, are to create condition-specific measures related to morbidity, mortality, and posthospital events, as well as to analyze regional and hospital variations including correlation across conditions, and to compare performance across conditions and hospitals.
Dr. Vashi reported having no financial disclosures.
Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.
REPORTING FROM ACEP18
Key clinical point: Emergency care–sensitive conditions (ECSCs) make up a significant proportion of ED visits.
Major finding: The most common ECSC-related visits were for pneumonia (9%), chronic obstructive pulmonary disease (9%), and asthma (7%).
Study details: A retrospective cohort study of more than 86.5 million ECSC-related ED visits.
Disclosures: Dr. Vashi reported having no financial disclosures.
Source: Vashi A et al. Ann Emerg Med. 2018 Oct;72;4:S38. doi. 10.1016/j.annemergmed.2018.08.091.
Antibiotics, antacids before age 2 linked to obesity
Acid-suppressing medications were also associated with childhood obesity, although to a lesser extent, according to results of the study, which included more than a quarter of a million children receiving care in the U.S. military health system.
Antibiotics and antacids are both microbiota-altering medications, researchers said, noting that obesity has been linked to variations in the native gut microbiota.
While the evidence from previous studies is conflicting on whether microbiota-altering medications may play a role in development of childhood obesity, this study does suggest such medications may lead to weight gain early in life, they said in the journal Gut.
“Providers should practice appropriate stewardship as the first-line response to these findings,” said Christopher M. Stark, MD, of the William Beaumont Army Medical Center, El Paso, Tex., and his co-authors.
This retrospective analysis included the largest cohort of pediatric patients ever studied for the link between antibiotics and obesity, according to Dr. Stark and colleagues, and was the first to look at the link between acid-suppressing medications and obesity in that age group.
The analysis included a total of 333,353 U.S. Department of Defense TRICARE beneficiaries born between October 2006 and September 2013 who were exposed to antibiotics, histamine-2-receptor antagonists (H2RAs), or proton pump inhibitors (PPIs) within the first 2 years of life.
Patients were followed past their initial exposure period, up to 8 years of age in some cases, investigators said.
Antibiotics were prescribed in 72.4% of those children, while H2RAs and PPIs were prescribed in 11.8% and 3.3%, respectively, with a substantial number of children receiving more than one of the medications of interest for this study.
A total of 46,993 (14.1%) of the children developed obesity. Of those obese children only 9,268, or 11%, had no antibiotic or acid suppressant prescriptions on record in the first 2 years of life, the reported data show.
Antibiotic prescriptions were associated with a 26% increase in obesity risk (unadjusted hazard ratio, 1.26; 95% CI, 1.23-1.28), investigators reported. That association strengthened steadily with the number of antibiotic prescriptions, with adjusted hazard ratios of 1.12 (95% CI, 1.09-1.15) for a single prescription, up to 1.42 (95% CI, 1.37-1.46) for 4 or more prescriptions
Likewise, H2RAs and PPIs were associated, albeit weakly, with an increased hazard of obesity, investigators said. The adjusted hazard ratios and 95% confidence intervals were 1.02 (1.01-1.03) for PPIs and 1.01 (1.004-1.02) for H2RA prescriptions.
The risk of obesity steadily climbed for those receiving multiple medications, researchers added, from a hazard ratio of 1.21 for one medication, 1.31 for two, and 1.42 for three, data show.
Dr. Stark and co-authors declared no competing interests related to the study.
SOURCE: Stark CM, et al. Gut. 2018 Oct 30. pii: gutjnl-2017-314971.
Acid-suppressing medications were also associated with childhood obesity, although to a lesser extent, according to results of the study, which included more than a quarter of a million children receiving care in the U.S. military health system.
Antibiotics and antacids are both microbiota-altering medications, researchers said, noting that obesity has been linked to variations in the native gut microbiota.
While the evidence from previous studies is conflicting on whether microbiota-altering medications may play a role in development of childhood obesity, this study does suggest such medications may lead to weight gain early in life, they said in the journal Gut.
“Providers should practice appropriate stewardship as the first-line response to these findings,” said Christopher M. Stark, MD, of the William Beaumont Army Medical Center, El Paso, Tex., and his co-authors.
This retrospective analysis included the largest cohort of pediatric patients ever studied for the link between antibiotics and obesity, according to Dr. Stark and colleagues, and was the first to look at the link between acid-suppressing medications and obesity in that age group.
The analysis included a total of 333,353 U.S. Department of Defense TRICARE beneficiaries born between October 2006 and September 2013 who were exposed to antibiotics, histamine-2-receptor antagonists (H2RAs), or proton pump inhibitors (PPIs) within the first 2 years of life.
Patients were followed past their initial exposure period, up to 8 years of age in some cases, investigators said.
Antibiotics were prescribed in 72.4% of those children, while H2RAs and PPIs were prescribed in 11.8% and 3.3%, respectively, with a substantial number of children receiving more than one of the medications of interest for this study.
A total of 46,993 (14.1%) of the children developed obesity. Of those obese children only 9,268, or 11%, had no antibiotic or acid suppressant prescriptions on record in the first 2 years of life, the reported data show.
Antibiotic prescriptions were associated with a 26% increase in obesity risk (unadjusted hazard ratio, 1.26; 95% CI, 1.23-1.28), investigators reported. That association strengthened steadily with the number of antibiotic prescriptions, with adjusted hazard ratios of 1.12 (95% CI, 1.09-1.15) for a single prescription, up to 1.42 (95% CI, 1.37-1.46) for 4 or more prescriptions
Likewise, H2RAs and PPIs were associated, albeit weakly, with an increased hazard of obesity, investigators said. The adjusted hazard ratios and 95% confidence intervals were 1.02 (1.01-1.03) for PPIs and 1.01 (1.004-1.02) for H2RA prescriptions.
The risk of obesity steadily climbed for those receiving multiple medications, researchers added, from a hazard ratio of 1.21 for one medication, 1.31 for two, and 1.42 for three, data show.
Dr. Stark and co-authors declared no competing interests related to the study.
SOURCE: Stark CM, et al. Gut. 2018 Oct 30. pii: gutjnl-2017-314971.
Acid-suppressing medications were also associated with childhood obesity, although to a lesser extent, according to results of the study, which included more than a quarter of a million children receiving care in the U.S. military health system.
Antibiotics and antacids are both microbiota-altering medications, researchers said, noting that obesity has been linked to variations in the native gut microbiota.
While the evidence from previous studies is conflicting on whether microbiota-altering medications may play a role in development of childhood obesity, this study does suggest such medications may lead to weight gain early in life, they said in the journal Gut.
“Providers should practice appropriate stewardship as the first-line response to these findings,” said Christopher M. Stark, MD, of the William Beaumont Army Medical Center, El Paso, Tex., and his co-authors.
This retrospective analysis included the largest cohort of pediatric patients ever studied for the link between antibiotics and obesity, according to Dr. Stark and colleagues, and was the first to look at the link between acid-suppressing medications and obesity in that age group.
The analysis included a total of 333,353 U.S. Department of Defense TRICARE beneficiaries born between October 2006 and September 2013 who were exposed to antibiotics, histamine-2-receptor antagonists (H2RAs), or proton pump inhibitors (PPIs) within the first 2 years of life.
Patients were followed past their initial exposure period, up to 8 years of age in some cases, investigators said.
Antibiotics were prescribed in 72.4% of those children, while H2RAs and PPIs were prescribed in 11.8% and 3.3%, respectively, with a substantial number of children receiving more than one of the medications of interest for this study.
A total of 46,993 (14.1%) of the children developed obesity. Of those obese children only 9,268, or 11%, had no antibiotic or acid suppressant prescriptions on record in the first 2 years of life, the reported data show.
Antibiotic prescriptions were associated with a 26% increase in obesity risk (unadjusted hazard ratio, 1.26; 95% CI, 1.23-1.28), investigators reported. That association strengthened steadily with the number of antibiotic prescriptions, with adjusted hazard ratios of 1.12 (95% CI, 1.09-1.15) for a single prescription, up to 1.42 (95% CI, 1.37-1.46) for 4 or more prescriptions
Likewise, H2RAs and PPIs were associated, albeit weakly, with an increased hazard of obesity, investigators said. The adjusted hazard ratios and 95% confidence intervals were 1.02 (1.01-1.03) for PPIs and 1.01 (1.004-1.02) for H2RA prescriptions.
The risk of obesity steadily climbed for those receiving multiple medications, researchers added, from a hazard ratio of 1.21 for one medication, 1.31 for two, and 1.42 for three, data show.
Dr. Stark and co-authors declared no competing interests related to the study.
SOURCE: Stark CM, et al. Gut. 2018 Oct 30. pii: gutjnl-2017-314971.
FROM GUT
Key clinical point: When prescribed early in life, antibiotics, and to a lesser extent antacids, were associated with childhood obesity.
Major finding: Antibiotic prescriptions were associated with a 26% increase in obesity risk (unadjusted hazard ratio, 1.26; 95% CI, 1.23-1.28).
Study details: Retrospective study of 333,353 children in the U.S. military health system exposed in the first two years of life to antibiotics, histamine-2-receptor antagonists, or proton pump inhibitors.
Disclosures: Study authors declared no competing interests related to the work.
Source: Stark CM, et al. Gut. 2018 Oct 30. pii: gutjnl-2017-314971.
How do you evaluate and treat a patient with C. difficile–associated disease?
Metronidazole is no longer recommended
Case
A 45-year-old woman on omeprazole for gastroesophageal reflux disease and recent treatment with ciprofloxacin for a urinary tract infection (UTI), who also has had several days of frequent watery stools, is admitted. She does not appear ill, and her abdominal exam is benign. She has normal renal function and white blood cell count. How should she be evaluated and treated for Clostridium difficile–associated disease (CDAD)?
Brief overview
C. difficile, a gram-positive anaerobic bacillus that exists in vegetative and spore forms, is a leading cause of hospital-associated diarrhea. C. difficile has a variety of presentations, ranging from asymptomatic colonization to CDAD, including severe diarrhea, ileus, and megacolon, and may be associated with a fatal outcome on rare occasions. The incidence of CDAD has been rising since the emergence of a hypervirulent strain (NAP1/BI/027) in the early 2000s and, not surprisingly, the number of deaths attributed to CDAD has also increased.1
CDAD requires acquisition of C. difficile as well as alteration in the colonic microbiota, often precipitated by antibiotics. The vegetative form of C. difficile can produce up to three toxins that are responsible for a cascade of reactions beginning with intestinal epithelial cell death followed by a significant inflammatory response and migration of neutrophils that eventually lead to the formation of the characteristic pseudomembranes.2
Until recently, the mainstay treatment for CDAD consisted of metronidazole and oral preparations of vancomycin. Recent results from randomized controlled trials and the increasing popularity of fecal microbiota transplant (FMT), however, have changed the therapeutic landscape of CDAD dramatically. Not surprisingly, the 2017 Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America joint guidelines for CDAD represent a significant change to the treatment of CDAD, compared with previous guidelines.3
Overview of data
The hallmark of CDAD is a watery, nonbloody diarrhea. Given many other causes of diarrhea in hospitalized patients (e.g., direct effect of antibiotics, laxative use, tube feeding, etc.), hospitalists should focus on testing those patients who have three or more episodes of diarrhea in 24 hours and risk factors for CDAD (See Table 1).
Exposure to antibiotics remains the greatest risk factor. It’s important to note that, while most patients develop CDAD within the first month after receiving systemic antibiotics, many patients remain at risk for up to 3 months.4 Although exposure to antibiotics, particularly in health care settings, is a significant risk factor for CDAD, up to 30%-40% of community-associated cases may not have a substantial antibiotic or health care facility exposure.5
Hospitalists should also not overlook the association between proton pump inhibitor (PPI) use and the development of CDAD.3 Although the IDSA/SHEA guidelines do not recommend discontinuation of PPIs solely for treatment or prevention of CDAD, at the minimum, the indication for their continued use in patients with CDAD should be revisited.
Testing for CDAD ranges from immunoassays that detect an enzyme common to all strains of C. difficile, glutamate dehydrogenase antigen (GDH), or toxins to nucleic acid amplification tests (NAATs), such as polymerase chain reaction [PCR]).1,6 GDH tests have high sensitivity but poor specificity, while testing for the toxin has high specificity but lower sensitivity (40%-80%) for CDAD.1 Although NAATs are highly sensitive and specific, they often have a poor positive predictive value in low-risk populations (e.g., those who do not have true diarrhea or whose diarrhea resolves before test results return). In these patients, a positive NAAT test may reflect colonization with toxigenic C. difficile, not necessarily CDAD. Except in rare instances, laboratories should only accept unformed stools for testing. Since the choice of testing for C. difficile varies by institution, hospitalists should understand the algorithm used by their respective hospitals and familiarize themselves with the sensitivity and specificity of each test.
Once a patient is diagnosed with CDAD, the hospitalist should assess the severity of the disease. The IDSA/SHEA guidelines still use leukocytosis and creatinine to separate mild from severe cases; the presence of fever and hypoalbuminemia also points to a more complicated course.3
The treatment of CDAD involves a strategy of withdrawing the putative culprit antibiotic(s) whenever possible and initiating of antibiotics effective against C. difficile. Following the publication of two randomized controlled trials demonstrating the inferiority of metronidazole to vancomycin in clinical cure of CDAD,2,7 the IDSA/SHEA guidelines no longer recommend metronidazole for the treatment of CDAD. Instead, a 10-day course of oral vancomycin or fidaxomicin has been recommended.2 Although fidaxomicin is associated with lower rates of recurrence of CDAD, it is also substantially more expensive than oral vancomycin, with a 10-day course often costing over $3,000.8 When choosing oral vancomycin for completion of therapy following discharge, hospitalists should also consider whether the dispensing outpatient pharmacy can provide the less-expensive liquid preparation of vancomycin. In resource-poor settings, consideration can still be given to metronidazole, an inexpensive drug, compared with both oral vancomycin and fidaxomicin. “Test of cure” with follow-up stool testing is not recommended.
For patients who require systemic antibiotics that precipitated their CDAD, it is common practice to extend CDAD treatment by providing a “tail” coverage with an agent effective against CDAD for 7-10 days following the completion of the inciting antibiotic. A common clinical question relates to the management of patients with prior history of CDAD but in need of a new round of systemic antibiotic therapy. In these patients, concurrent prophylactic doses of oral vancomycin have been found to be effective in preventing recurrence.9 The IDSA/SHEA guidelines conclude that “it may be prudent to administer low doses of vancomycin or fidaxomicin (e.g., 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered.”3
For patients whose presentation extends beyond diarrhea, the IDSA/SHEA guidelines have changed the nomenclature for CDAD from “severe, complicated” to “fulminant.” Although there are no strict definitions, the IDSA/SHEA guidelines suggest that fulminant CDAD is characterized by “hypotension or shock, ileus, or megacolon.” In these patients, surgical intervention can be life saving, though mortality rates may remain over 50%.10 Hospitalists whose patients with CDAD are experiencing an acute abdomen or concern for colonic perforation, megacolon, shock, or organ system failure should obtain prompt surgical consultation. Antibiotic treatment should consist of a combination of higher doses of oral vancomycin and intravenous metronidazole (See Table 2).
In addition to occasional treatment failures, a vexing characteristic of CDAD is its frequent recurrence rate, which may range from 15% to 30% or higher.11 The approach to recurrences is twofold: treatment of the C. difficile itself, and attempts to restore the colonic microbiome. The antibiotic treatment of the first recurrence of CDAD consists of either a 10-day course of fidaxomicin or a tapered, pulsed dose of vancomycin, which may be more effective than a repeat 10-day course of oral vancomycin.12 Although the treatment is unchanged for subsequent recurrences, the guidelines suggest consideration of rifaximin after a course of vancomycin (See Table 2).
Probiotics have been investigated as a means of restoring the colonic microbiome. Use of probiotics for both primary and secondary prevention of CDAD has resulted in conflicting data, with pooled analyses showing some benefit, while randomized controlled trials demonstrate less benefit.13 In addition, reports of bloodstream infections with Lactobacillus in frail patients and Saccharomyces in immunocompromised patients and those with central venous catheters raise doubts regarding their safety in certain patient populations.13 The IDSA/SHEA guidelines make no recommendations about the use of probiotics for the prevention of CDAD at this time.
Fecal microbiota transplant (FMT), however, does appear to be effective, especially in comparison to antibiotics alone in patients with multiple recurrences of CDAD.13 The IDSA/SHEA guidelines recommend consideration for FMT after the second recurrence of CDAD. The Fecal Microbiota Transplantation Workgroup has also proposed a set of guidelines for consideration of FMT when available (See Table 3).
Application of data
The recent IDSA/SHEA guidelines have revised the treatment paradigm for CDAD. Most notably, metronidazole is no longer recommended for treatment of either initial or subsequent episodes of mild to severe CDAD, except when the cost of treatment may preclude the use of more effective therapies.
Initial episodes of mild to severe infection should be treated with either oral vancomycin or fidaxomicin. Recurrent episodes of CDAD should be treated with an agent different from that used for the initial episode, or with a pulsed, tapered regimen of oral vancomycin. FMT, where available, should be considered with multiple recurrences, or with moderate to severe infection not responding to standard therapy.
Fulminant CDAD, characterized by hypotension, shock, severe ileus, or megacolon, is a life-threatening medical emergency with a high mortality rate. Treatment should include high-dose oral vancomycin and intravenous metronidazole, with consideration of rectal vancomycin in patients with ileus. Immediate surgical consultation should be obtained to weigh the benefits of colectomy.
Back to our case
Our patient was treated with a 10-day course of vancomycin because this was uncomplicated CDAD and was her initial episode. Were she to develop a recurrence, she could be treated with a pulsed, tapered vancomycin regimen or fidaxomicin.
Bottom line
Vancomycin and fidaxomicin are recommended for the initial episode as well as recurrent CDAD. FMT should be considered for patients with multiple episodes of CDAD or treatment failures.
Dr. Roberts, Dr. Hillman, and Dr. Manian are hospitalists at Massachusetts General Hospital in Boston.
References
1. Louie TJ et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364:422-31. doi: 10.1056/NEJMoa0910812.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
4. Hensgens MP et al. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012 Mar;67:742-8. doi: 10.1093/jac/dkr508. Epub 2011 Dec 6.
5. Chitnis AS et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013 Jul 22;173:1359-67. doi: 10.1001/jamainternmed.2013.7056.
6. Solomon DA et al. ID learning unit: Understanding and interpreting testing for Clostridium difficile. Open Forum Infectious Diseases. 2014 Mar;1(1);ofu007. doi: 10.1093/ofid/ofu007.
7. Johnson S et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug 1;59(3):345-54. doi: 10.1093/cid/ciu313. Epub 2014 May 5.
8. https://m.goodrx.com/fidaxomicin, accessed June 24, 2018.
9. Van Hise NW et al. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis. 2016 Sep 1;63:651-3. doi: 10.1093/cid/ciw401. Epub 2016 Jun 17.
10. Sailhamer EA et al. Fulminant Clostridium difficile colitis: Patterns of care and predictors of mortality. Arch Surg. 2009;144:433-9. doi: 10.1001/archsurg.2009.51.
11. Zar FA et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-7. doi: 10.1086/519265. Epub 2007 Jun 19.
12. Bakken JS et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-9. doi: 10.1016/j.cgh.2011.08.014. Epub 2011 Aug 24.
13. Crow JR et al. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov;35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2.
Additional reading
1. McDonald LC et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. Crow JR, Davis SL, Chaykosky DM, Smith TT, Smith JM. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov; 35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2. Review.
Key points
1. Metronidazole is inferior to oral vancomycin and fidaxomicin for clinical cure of CDAD. The IDSA/SHEA guidelines now recommend a 10-day course of oral vancomycin or fidaxomicin for nonfulminant cases of CDAD.
2. For fulminant CDAD, the IDSA/SHEA guidelines suggest an increased dose of vancomycin and the addition of IV metronidazole. In such cases, surgical consultation should also be obtained.
3. After the second recurrence of Clostridium difficile infection, hospitalists should consider referral for FMT where available.
Quiz
The recent IDSA/SHEA guidelines no longer recommend metronidazole in the treatment of CDAD, except for which of the following scenarios (best answer)?
A. Treatment of a first episode of nonfulminant CDAD.
B. Treatment of recurrent CDAD following an initial course of oral vancomycin.
C. Treatment of fulminant infection with IV metronidazole in addition to oral or rectal vancomycin.
D. For prophylaxis following fecal microbiota transplant.
Answer: C. In fulminant infection, concurrent ileus may interfere with appropriate delivery of oral vancomycin to the colon. Adding intravenous metronidazole can allow this antibiotic to reach the bowel. Adding intravenous metronidazole to oral vancomycin is also recommended by IDSA/SHEA guidelines in cases of fulminant CDAD. Evidence from high-quality randomized controlled trials has shown that vancomycin is superior to oral metronidazole for treatment of initial and recurrent episodes of CDAD. There is no evidence to support the use of metronidazole for recurrent CDAD following an initial course of oral vancomycin or for prophylaxis following FMT.
Metronidazole is no longer recommended
Metronidazole is no longer recommended
Case
A 45-year-old woman on omeprazole for gastroesophageal reflux disease and recent treatment with ciprofloxacin for a urinary tract infection (UTI), who also has had several days of frequent watery stools, is admitted. She does not appear ill, and her abdominal exam is benign. She has normal renal function and white blood cell count. How should she be evaluated and treated for Clostridium difficile–associated disease (CDAD)?
Brief overview
C. difficile, a gram-positive anaerobic bacillus that exists in vegetative and spore forms, is a leading cause of hospital-associated diarrhea. C. difficile has a variety of presentations, ranging from asymptomatic colonization to CDAD, including severe diarrhea, ileus, and megacolon, and may be associated with a fatal outcome on rare occasions. The incidence of CDAD has been rising since the emergence of a hypervirulent strain (NAP1/BI/027) in the early 2000s and, not surprisingly, the number of deaths attributed to CDAD has also increased.1
CDAD requires acquisition of C. difficile as well as alteration in the colonic microbiota, often precipitated by antibiotics. The vegetative form of C. difficile can produce up to three toxins that are responsible for a cascade of reactions beginning with intestinal epithelial cell death followed by a significant inflammatory response and migration of neutrophils that eventually lead to the formation of the characteristic pseudomembranes.2
Until recently, the mainstay treatment for CDAD consisted of metronidazole and oral preparations of vancomycin. Recent results from randomized controlled trials and the increasing popularity of fecal microbiota transplant (FMT), however, have changed the therapeutic landscape of CDAD dramatically. Not surprisingly, the 2017 Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America joint guidelines for CDAD represent a significant change to the treatment of CDAD, compared with previous guidelines.3
Overview of data
The hallmark of CDAD is a watery, nonbloody diarrhea. Given many other causes of diarrhea in hospitalized patients (e.g., direct effect of antibiotics, laxative use, tube feeding, etc.), hospitalists should focus on testing those patients who have three or more episodes of diarrhea in 24 hours and risk factors for CDAD (See Table 1).
Exposure to antibiotics remains the greatest risk factor. It’s important to note that, while most patients develop CDAD within the first month after receiving systemic antibiotics, many patients remain at risk for up to 3 months.4 Although exposure to antibiotics, particularly in health care settings, is a significant risk factor for CDAD, up to 30%-40% of community-associated cases may not have a substantial antibiotic or health care facility exposure.5
Hospitalists should also not overlook the association between proton pump inhibitor (PPI) use and the development of CDAD.3 Although the IDSA/SHEA guidelines do not recommend discontinuation of PPIs solely for treatment or prevention of CDAD, at the minimum, the indication for their continued use in patients with CDAD should be revisited.
Testing for CDAD ranges from immunoassays that detect an enzyme common to all strains of C. difficile, glutamate dehydrogenase antigen (GDH), or toxins to nucleic acid amplification tests (NAATs), such as polymerase chain reaction [PCR]).1,6 GDH tests have high sensitivity but poor specificity, while testing for the toxin has high specificity but lower sensitivity (40%-80%) for CDAD.1 Although NAATs are highly sensitive and specific, they often have a poor positive predictive value in low-risk populations (e.g., those who do not have true diarrhea or whose diarrhea resolves before test results return). In these patients, a positive NAAT test may reflect colonization with toxigenic C. difficile, not necessarily CDAD. Except in rare instances, laboratories should only accept unformed stools for testing. Since the choice of testing for C. difficile varies by institution, hospitalists should understand the algorithm used by their respective hospitals and familiarize themselves with the sensitivity and specificity of each test.
Once a patient is diagnosed with CDAD, the hospitalist should assess the severity of the disease. The IDSA/SHEA guidelines still use leukocytosis and creatinine to separate mild from severe cases; the presence of fever and hypoalbuminemia also points to a more complicated course.3
The treatment of CDAD involves a strategy of withdrawing the putative culprit antibiotic(s) whenever possible and initiating of antibiotics effective against C. difficile. Following the publication of two randomized controlled trials demonstrating the inferiority of metronidazole to vancomycin in clinical cure of CDAD,2,7 the IDSA/SHEA guidelines no longer recommend metronidazole for the treatment of CDAD. Instead, a 10-day course of oral vancomycin or fidaxomicin has been recommended.2 Although fidaxomicin is associated with lower rates of recurrence of CDAD, it is also substantially more expensive than oral vancomycin, with a 10-day course often costing over $3,000.8 When choosing oral vancomycin for completion of therapy following discharge, hospitalists should also consider whether the dispensing outpatient pharmacy can provide the less-expensive liquid preparation of vancomycin. In resource-poor settings, consideration can still be given to metronidazole, an inexpensive drug, compared with both oral vancomycin and fidaxomicin. “Test of cure” with follow-up stool testing is not recommended.
For patients who require systemic antibiotics that precipitated their CDAD, it is common practice to extend CDAD treatment by providing a “tail” coverage with an agent effective against CDAD for 7-10 days following the completion of the inciting antibiotic. A common clinical question relates to the management of patients with prior history of CDAD but in need of a new round of systemic antibiotic therapy. In these patients, concurrent prophylactic doses of oral vancomycin have been found to be effective in preventing recurrence.9 The IDSA/SHEA guidelines conclude that “it may be prudent to administer low doses of vancomycin or fidaxomicin (e.g., 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered.”3
For patients whose presentation extends beyond diarrhea, the IDSA/SHEA guidelines have changed the nomenclature for CDAD from “severe, complicated” to “fulminant.” Although there are no strict definitions, the IDSA/SHEA guidelines suggest that fulminant CDAD is characterized by “hypotension or shock, ileus, or megacolon.” In these patients, surgical intervention can be life saving, though mortality rates may remain over 50%.10 Hospitalists whose patients with CDAD are experiencing an acute abdomen or concern for colonic perforation, megacolon, shock, or organ system failure should obtain prompt surgical consultation. Antibiotic treatment should consist of a combination of higher doses of oral vancomycin and intravenous metronidazole (See Table 2).
In addition to occasional treatment failures, a vexing characteristic of CDAD is its frequent recurrence rate, which may range from 15% to 30% or higher.11 The approach to recurrences is twofold: treatment of the C. difficile itself, and attempts to restore the colonic microbiome. The antibiotic treatment of the first recurrence of CDAD consists of either a 10-day course of fidaxomicin or a tapered, pulsed dose of vancomycin, which may be more effective than a repeat 10-day course of oral vancomycin.12 Although the treatment is unchanged for subsequent recurrences, the guidelines suggest consideration of rifaximin after a course of vancomycin (See Table 2).
Probiotics have been investigated as a means of restoring the colonic microbiome. Use of probiotics for both primary and secondary prevention of CDAD has resulted in conflicting data, with pooled analyses showing some benefit, while randomized controlled trials demonstrate less benefit.13 In addition, reports of bloodstream infections with Lactobacillus in frail patients and Saccharomyces in immunocompromised patients and those with central venous catheters raise doubts regarding their safety in certain patient populations.13 The IDSA/SHEA guidelines make no recommendations about the use of probiotics for the prevention of CDAD at this time.
Fecal microbiota transplant (FMT), however, does appear to be effective, especially in comparison to antibiotics alone in patients with multiple recurrences of CDAD.13 The IDSA/SHEA guidelines recommend consideration for FMT after the second recurrence of CDAD. The Fecal Microbiota Transplantation Workgroup has also proposed a set of guidelines for consideration of FMT when available (See Table 3).
Application of data
The recent IDSA/SHEA guidelines have revised the treatment paradigm for CDAD. Most notably, metronidazole is no longer recommended for treatment of either initial or subsequent episodes of mild to severe CDAD, except when the cost of treatment may preclude the use of more effective therapies.
Initial episodes of mild to severe infection should be treated with either oral vancomycin or fidaxomicin. Recurrent episodes of CDAD should be treated with an agent different from that used for the initial episode, or with a pulsed, tapered regimen of oral vancomycin. FMT, where available, should be considered with multiple recurrences, or with moderate to severe infection not responding to standard therapy.
Fulminant CDAD, characterized by hypotension, shock, severe ileus, or megacolon, is a life-threatening medical emergency with a high mortality rate. Treatment should include high-dose oral vancomycin and intravenous metronidazole, with consideration of rectal vancomycin in patients with ileus. Immediate surgical consultation should be obtained to weigh the benefits of colectomy.
Back to our case
Our patient was treated with a 10-day course of vancomycin because this was uncomplicated CDAD and was her initial episode. Were she to develop a recurrence, she could be treated with a pulsed, tapered vancomycin regimen or fidaxomicin.
Bottom line
Vancomycin and fidaxomicin are recommended for the initial episode as well as recurrent CDAD. FMT should be considered for patients with multiple episodes of CDAD or treatment failures.
Dr. Roberts, Dr. Hillman, and Dr. Manian are hospitalists at Massachusetts General Hospital in Boston.
References
1. Louie TJ et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364:422-31. doi: 10.1056/NEJMoa0910812.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
4. Hensgens MP et al. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012 Mar;67:742-8. doi: 10.1093/jac/dkr508. Epub 2011 Dec 6.
5. Chitnis AS et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013 Jul 22;173:1359-67. doi: 10.1001/jamainternmed.2013.7056.
6. Solomon DA et al. ID learning unit: Understanding and interpreting testing for Clostridium difficile. Open Forum Infectious Diseases. 2014 Mar;1(1);ofu007. doi: 10.1093/ofid/ofu007.
7. Johnson S et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug 1;59(3):345-54. doi: 10.1093/cid/ciu313. Epub 2014 May 5.
8. https://m.goodrx.com/fidaxomicin, accessed June 24, 2018.
9. Van Hise NW et al. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis. 2016 Sep 1;63:651-3. doi: 10.1093/cid/ciw401. Epub 2016 Jun 17.
10. Sailhamer EA et al. Fulminant Clostridium difficile colitis: Patterns of care and predictors of mortality. Arch Surg. 2009;144:433-9. doi: 10.1001/archsurg.2009.51.
11. Zar FA et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-7. doi: 10.1086/519265. Epub 2007 Jun 19.
12. Bakken JS et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-9. doi: 10.1016/j.cgh.2011.08.014. Epub 2011 Aug 24.
13. Crow JR et al. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov;35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2.
Additional reading
1. McDonald LC et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. Crow JR, Davis SL, Chaykosky DM, Smith TT, Smith JM. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov; 35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2. Review.
Key points
1. Metronidazole is inferior to oral vancomycin and fidaxomicin for clinical cure of CDAD. The IDSA/SHEA guidelines now recommend a 10-day course of oral vancomycin or fidaxomicin for nonfulminant cases of CDAD.
2. For fulminant CDAD, the IDSA/SHEA guidelines suggest an increased dose of vancomycin and the addition of IV metronidazole. In such cases, surgical consultation should also be obtained.
3. After the second recurrence of Clostridium difficile infection, hospitalists should consider referral for FMT where available.
Quiz
The recent IDSA/SHEA guidelines no longer recommend metronidazole in the treatment of CDAD, except for which of the following scenarios (best answer)?
A. Treatment of a first episode of nonfulminant CDAD.
B. Treatment of recurrent CDAD following an initial course of oral vancomycin.
C. Treatment of fulminant infection with IV metronidazole in addition to oral or rectal vancomycin.
D. For prophylaxis following fecal microbiota transplant.
Answer: C. In fulminant infection, concurrent ileus may interfere with appropriate delivery of oral vancomycin to the colon. Adding intravenous metronidazole can allow this antibiotic to reach the bowel. Adding intravenous metronidazole to oral vancomycin is also recommended by IDSA/SHEA guidelines in cases of fulminant CDAD. Evidence from high-quality randomized controlled trials has shown that vancomycin is superior to oral metronidazole for treatment of initial and recurrent episodes of CDAD. There is no evidence to support the use of metronidazole for recurrent CDAD following an initial course of oral vancomycin or for prophylaxis following FMT.
Case
A 45-year-old woman on omeprazole for gastroesophageal reflux disease and recent treatment with ciprofloxacin for a urinary tract infection (UTI), who also has had several days of frequent watery stools, is admitted. She does not appear ill, and her abdominal exam is benign. She has normal renal function and white blood cell count. How should she be evaluated and treated for Clostridium difficile–associated disease (CDAD)?
Brief overview
C. difficile, a gram-positive anaerobic bacillus that exists in vegetative and spore forms, is a leading cause of hospital-associated diarrhea. C. difficile has a variety of presentations, ranging from asymptomatic colonization to CDAD, including severe diarrhea, ileus, and megacolon, and may be associated with a fatal outcome on rare occasions. The incidence of CDAD has been rising since the emergence of a hypervirulent strain (NAP1/BI/027) in the early 2000s and, not surprisingly, the number of deaths attributed to CDAD has also increased.1
CDAD requires acquisition of C. difficile as well as alteration in the colonic microbiota, often precipitated by antibiotics. The vegetative form of C. difficile can produce up to three toxins that are responsible for a cascade of reactions beginning with intestinal epithelial cell death followed by a significant inflammatory response and migration of neutrophils that eventually lead to the formation of the characteristic pseudomembranes.2
Until recently, the mainstay treatment for CDAD consisted of metronidazole and oral preparations of vancomycin. Recent results from randomized controlled trials and the increasing popularity of fecal microbiota transplant (FMT), however, have changed the therapeutic landscape of CDAD dramatically. Not surprisingly, the 2017 Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America joint guidelines for CDAD represent a significant change to the treatment of CDAD, compared with previous guidelines.3
Overview of data
The hallmark of CDAD is a watery, nonbloody diarrhea. Given many other causes of diarrhea in hospitalized patients (e.g., direct effect of antibiotics, laxative use, tube feeding, etc.), hospitalists should focus on testing those patients who have three or more episodes of diarrhea in 24 hours and risk factors for CDAD (See Table 1).
Exposure to antibiotics remains the greatest risk factor. It’s important to note that, while most patients develop CDAD within the first month after receiving systemic antibiotics, many patients remain at risk for up to 3 months.4 Although exposure to antibiotics, particularly in health care settings, is a significant risk factor for CDAD, up to 30%-40% of community-associated cases may not have a substantial antibiotic or health care facility exposure.5
Hospitalists should also not overlook the association between proton pump inhibitor (PPI) use and the development of CDAD.3 Although the IDSA/SHEA guidelines do not recommend discontinuation of PPIs solely for treatment or prevention of CDAD, at the minimum, the indication for their continued use in patients with CDAD should be revisited.
Testing for CDAD ranges from immunoassays that detect an enzyme common to all strains of C. difficile, glutamate dehydrogenase antigen (GDH), or toxins to nucleic acid amplification tests (NAATs), such as polymerase chain reaction [PCR]).1,6 GDH tests have high sensitivity but poor specificity, while testing for the toxin has high specificity but lower sensitivity (40%-80%) for CDAD.1 Although NAATs are highly sensitive and specific, they often have a poor positive predictive value in low-risk populations (e.g., those who do not have true diarrhea or whose diarrhea resolves before test results return). In these patients, a positive NAAT test may reflect colonization with toxigenic C. difficile, not necessarily CDAD. Except in rare instances, laboratories should only accept unformed stools for testing. Since the choice of testing for C. difficile varies by institution, hospitalists should understand the algorithm used by their respective hospitals and familiarize themselves with the sensitivity and specificity of each test.
Once a patient is diagnosed with CDAD, the hospitalist should assess the severity of the disease. The IDSA/SHEA guidelines still use leukocytosis and creatinine to separate mild from severe cases; the presence of fever and hypoalbuminemia also points to a more complicated course.3
The treatment of CDAD involves a strategy of withdrawing the putative culprit antibiotic(s) whenever possible and initiating of antibiotics effective against C. difficile. Following the publication of two randomized controlled trials demonstrating the inferiority of metronidazole to vancomycin in clinical cure of CDAD,2,7 the IDSA/SHEA guidelines no longer recommend metronidazole for the treatment of CDAD. Instead, a 10-day course of oral vancomycin or fidaxomicin has been recommended.2 Although fidaxomicin is associated with lower rates of recurrence of CDAD, it is also substantially more expensive than oral vancomycin, with a 10-day course often costing over $3,000.8 When choosing oral vancomycin for completion of therapy following discharge, hospitalists should also consider whether the dispensing outpatient pharmacy can provide the less-expensive liquid preparation of vancomycin. In resource-poor settings, consideration can still be given to metronidazole, an inexpensive drug, compared with both oral vancomycin and fidaxomicin. “Test of cure” with follow-up stool testing is not recommended.
For patients who require systemic antibiotics that precipitated their CDAD, it is common practice to extend CDAD treatment by providing a “tail” coverage with an agent effective against CDAD for 7-10 days following the completion of the inciting antibiotic. A common clinical question relates to the management of patients with prior history of CDAD but in need of a new round of systemic antibiotic therapy. In these patients, concurrent prophylactic doses of oral vancomycin have been found to be effective in preventing recurrence.9 The IDSA/SHEA guidelines conclude that “it may be prudent to administer low doses of vancomycin or fidaxomicin (e.g., 125 mg or 200 mg, respectively, once daily) while systemic antibiotics are administered.”3
For patients whose presentation extends beyond diarrhea, the IDSA/SHEA guidelines have changed the nomenclature for CDAD from “severe, complicated” to “fulminant.” Although there are no strict definitions, the IDSA/SHEA guidelines suggest that fulminant CDAD is characterized by “hypotension or shock, ileus, or megacolon.” In these patients, surgical intervention can be life saving, though mortality rates may remain over 50%.10 Hospitalists whose patients with CDAD are experiencing an acute abdomen or concern for colonic perforation, megacolon, shock, or organ system failure should obtain prompt surgical consultation. Antibiotic treatment should consist of a combination of higher doses of oral vancomycin and intravenous metronidazole (See Table 2).
In addition to occasional treatment failures, a vexing characteristic of CDAD is its frequent recurrence rate, which may range from 15% to 30% or higher.11 The approach to recurrences is twofold: treatment of the C. difficile itself, and attempts to restore the colonic microbiome. The antibiotic treatment of the first recurrence of CDAD consists of either a 10-day course of fidaxomicin or a tapered, pulsed dose of vancomycin, which may be more effective than a repeat 10-day course of oral vancomycin.12 Although the treatment is unchanged for subsequent recurrences, the guidelines suggest consideration of rifaximin after a course of vancomycin (See Table 2).
Probiotics have been investigated as a means of restoring the colonic microbiome. Use of probiotics for both primary and secondary prevention of CDAD has resulted in conflicting data, with pooled analyses showing some benefit, while randomized controlled trials demonstrate less benefit.13 In addition, reports of bloodstream infections with Lactobacillus in frail patients and Saccharomyces in immunocompromised patients and those with central venous catheters raise doubts regarding their safety in certain patient populations.13 The IDSA/SHEA guidelines make no recommendations about the use of probiotics for the prevention of CDAD at this time.
Fecal microbiota transplant (FMT), however, does appear to be effective, especially in comparison to antibiotics alone in patients with multiple recurrences of CDAD.13 The IDSA/SHEA guidelines recommend consideration for FMT after the second recurrence of CDAD. The Fecal Microbiota Transplantation Workgroup has also proposed a set of guidelines for consideration of FMT when available (See Table 3).
Application of data
The recent IDSA/SHEA guidelines have revised the treatment paradigm for CDAD. Most notably, metronidazole is no longer recommended for treatment of either initial or subsequent episodes of mild to severe CDAD, except when the cost of treatment may preclude the use of more effective therapies.
Initial episodes of mild to severe infection should be treated with either oral vancomycin or fidaxomicin. Recurrent episodes of CDAD should be treated with an agent different from that used for the initial episode, or with a pulsed, tapered regimen of oral vancomycin. FMT, where available, should be considered with multiple recurrences, or with moderate to severe infection not responding to standard therapy.
Fulminant CDAD, characterized by hypotension, shock, severe ileus, or megacolon, is a life-threatening medical emergency with a high mortality rate. Treatment should include high-dose oral vancomycin and intravenous metronidazole, with consideration of rectal vancomycin in patients with ileus. Immediate surgical consultation should be obtained to weigh the benefits of colectomy.
Back to our case
Our patient was treated with a 10-day course of vancomycin because this was uncomplicated CDAD and was her initial episode. Were she to develop a recurrence, she could be treated with a pulsed, tapered vancomycin regimen or fidaxomicin.
Bottom line
Vancomycin and fidaxomicin are recommended for the initial episode as well as recurrent CDAD. FMT should be considered for patients with multiple episodes of CDAD or treatment failures.
Dr. Roberts, Dr. Hillman, and Dr. Manian are hospitalists at Massachusetts General Hospital in Boston.
References
1. Louie TJ et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364:422-31. doi: 10.1056/NEJMoa0910812.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
4. Hensgens MP et al. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012 Mar;67:742-8. doi: 10.1093/jac/dkr508. Epub 2011 Dec 6.
5. Chitnis AS et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013 Jul 22;173:1359-67. doi: 10.1001/jamainternmed.2013.7056.
6. Solomon DA et al. ID learning unit: Understanding and interpreting testing for Clostridium difficile. Open Forum Infectious Diseases. 2014 Mar;1(1);ofu007. doi: 10.1093/ofid/ofu007.
7. Johnson S et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014 Aug 1;59(3):345-54. doi: 10.1093/cid/ciu313. Epub 2014 May 5.
8. https://m.goodrx.com/fidaxomicin, accessed June 24, 2018.
9. Van Hise NW et al. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis. 2016 Sep 1;63:651-3. doi: 10.1093/cid/ciw401. Epub 2016 Jun 17.
10. Sailhamer EA et al. Fulminant Clostridium difficile colitis: Patterns of care and predictors of mortality. Arch Surg. 2009;144:433-9. doi: 10.1001/archsurg.2009.51.
11. Zar FA et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-7. doi: 10.1086/519265. Epub 2007 Jun 19.
12. Bakken JS et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-9. doi: 10.1016/j.cgh.2011.08.014. Epub 2011 Aug 24.
13. Crow JR et al. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov;35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2.
Additional reading
1. McDonald LC et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66:987-94. doi: 10.1093/cid/ciy149.
2. Burnham CA et al. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013 Jul;26:604-30. doi: 10.1128/CMR.00016-13.
3. Crow JR, Davis SL, Chaykosky DM, Smith TT, Smith JM. Probiotics and fecal microbiota transplant for primary and secondary prevention of Clostridium difficile infection. Pharmacotherapy. 2015 Nov; 35:1016-25. doi: 10.1002/phar.1644. Epub 2015 Nov 2. Review.
Key points
1. Metronidazole is inferior to oral vancomycin and fidaxomicin for clinical cure of CDAD. The IDSA/SHEA guidelines now recommend a 10-day course of oral vancomycin or fidaxomicin for nonfulminant cases of CDAD.
2. For fulminant CDAD, the IDSA/SHEA guidelines suggest an increased dose of vancomycin and the addition of IV metronidazole. In such cases, surgical consultation should also be obtained.
3. After the second recurrence of Clostridium difficile infection, hospitalists should consider referral for FMT where available.
Quiz
The recent IDSA/SHEA guidelines no longer recommend metronidazole in the treatment of CDAD, except for which of the following scenarios (best answer)?
A. Treatment of a first episode of nonfulminant CDAD.
B. Treatment of recurrent CDAD following an initial course of oral vancomycin.
C. Treatment of fulminant infection with IV metronidazole in addition to oral or rectal vancomycin.
D. For prophylaxis following fecal microbiota transplant.
Answer: C. In fulminant infection, concurrent ileus may interfere with appropriate delivery of oral vancomycin to the colon. Adding intravenous metronidazole can allow this antibiotic to reach the bowel. Adding intravenous metronidazole to oral vancomycin is also recommended by IDSA/SHEA guidelines in cases of fulminant CDAD. Evidence from high-quality randomized controlled trials has shown that vancomycin is superior to oral metronidazole for treatment of initial and recurrent episodes of CDAD. There is no evidence to support the use of metronidazole for recurrent CDAD following an initial course of oral vancomycin or for prophylaxis following FMT.
HIV superinfection: No boost to broadly neutralizing antibodies
Infection by a second HIV strain after established primary infection (HIV superinfection) has been associated with broader antibody production, and such events are analogous to heterologous prime-boost immunizations, according to a report published in Cell Host & Microbe.
This phenomenon offers an opportunity to assess how the human immune system responds to sequential exposure to two distinct HIV envelope (Env) antigens, according to the authors, Daniel J. Sheward, a PhD student and scientific officer at the University of Cape Town, South Africa, and his colleagues.
Mr. Sheward and his colleagues followed 108 women recruited in acute/early infection and screened for superinfection over approximately 2 years in the Centre for the AIDS Programme of Research in South Africa (CAPRISA 002 cohort). In a previous study, they identified five superinfected participants, all of whom were superinfected between 3 and 10 months following primary infection. Only two of these patients developed antibodies capable of neutralizing heterologous viruses at 2 years, and one individual developed extremely potent broadly neutralizing antibodies (bnAbs). However, the contribution of superinfection itself to the development of antibody breadth in these individuals was not clear, prompting the current study (Cell Host Microbe. 2018 Oct 10;24[4]:593-9).
The researchers compared neutralization breadth (defined as the percent of heterologous viruses neutralized) present in plasma sampled 2 years post infection between the previously identified superinfected participants and the remaining CAPRISA 002 cohort participants. Four virus strains accounted for the superinfections. Antibody breadth was compared at 2 years post infection to four of the five of the superinfected participants, as they all had at least 2 years of antiretroviral-naive follow-up.
The researchers compared the peak neutralizing antibody (nAb) titers against all four superinfecting viruses with their matched primary infecting virus, as well as with the nAb titers that increased against early/founder viruses in 22 other participants in the CAPRISA 002 cohort.
They found that titers to the superinfecting virus strains were comparable with those seen in single infections from the rest of the cohort. In contrast, two other superinfecting virus strains developed exceedingly high neutralizing titers against themselves. Also, HIV superinfection did not appear to boost nAb memory responses primed by the initial infection.
Notably, superinfection did not elicit bnAB responses to epitopes conserved in both infecting viruses. The one individual who appeared to have developed a bnAB response, upon analysis, was found to have breadth of response attributable to a single antibody lineage that only affected the superinfecting virus. This indicated that superinfection did not facilitate breadth by directing responses to an Env conserved in both infecting viruses, according to Mr. Sheward and his colleagues.
“HIV superinfection fails to efficiently recruit neutralizing memory B cells and, at best, results in additive nAb responses rather than a synergistic effect leading to cross-neutralization; a distinction that is highly relevant for vaccine design. ... [W]hile sequential immunizations with heterologous Env immunogens may be able to improve the potency of elicited responses, alone, they are unlikely to promote the development of bnAbs,” the researchers concluded.
The study was funded by the Centre for the AIDS Programme of Research in South Africa and the South African Medical Research Council. The authors reported that they had no disclosures.
SOURCE: Sheward DJ et al. Cell Host Microbe. 2018 Oct 10;24[4]:593-9.
Infection by a second HIV strain after established primary infection (HIV superinfection) has been associated with broader antibody production, and such events are analogous to heterologous prime-boost immunizations, according to a report published in Cell Host & Microbe.
This phenomenon offers an opportunity to assess how the human immune system responds to sequential exposure to two distinct HIV envelope (Env) antigens, according to the authors, Daniel J. Sheward, a PhD student and scientific officer at the University of Cape Town, South Africa, and his colleagues.
Mr. Sheward and his colleagues followed 108 women recruited in acute/early infection and screened for superinfection over approximately 2 years in the Centre for the AIDS Programme of Research in South Africa (CAPRISA 002 cohort). In a previous study, they identified five superinfected participants, all of whom were superinfected between 3 and 10 months following primary infection. Only two of these patients developed antibodies capable of neutralizing heterologous viruses at 2 years, and one individual developed extremely potent broadly neutralizing antibodies (bnAbs). However, the contribution of superinfection itself to the development of antibody breadth in these individuals was not clear, prompting the current study (Cell Host Microbe. 2018 Oct 10;24[4]:593-9).
The researchers compared neutralization breadth (defined as the percent of heterologous viruses neutralized) present in plasma sampled 2 years post infection between the previously identified superinfected participants and the remaining CAPRISA 002 cohort participants. Four virus strains accounted for the superinfections. Antibody breadth was compared at 2 years post infection to four of the five of the superinfected participants, as they all had at least 2 years of antiretroviral-naive follow-up.
The researchers compared the peak neutralizing antibody (nAb) titers against all four superinfecting viruses with their matched primary infecting virus, as well as with the nAb titers that increased against early/founder viruses in 22 other participants in the CAPRISA 002 cohort.
They found that titers to the superinfecting virus strains were comparable with those seen in single infections from the rest of the cohort. In contrast, two other superinfecting virus strains developed exceedingly high neutralizing titers against themselves. Also, HIV superinfection did not appear to boost nAb memory responses primed by the initial infection.
Notably, superinfection did not elicit bnAB responses to epitopes conserved in both infecting viruses. The one individual who appeared to have developed a bnAB response, upon analysis, was found to have breadth of response attributable to a single antibody lineage that only affected the superinfecting virus. This indicated that superinfection did not facilitate breadth by directing responses to an Env conserved in both infecting viruses, according to Mr. Sheward and his colleagues.
“HIV superinfection fails to efficiently recruit neutralizing memory B cells and, at best, results in additive nAb responses rather than a synergistic effect leading to cross-neutralization; a distinction that is highly relevant for vaccine design. ... [W]hile sequential immunizations with heterologous Env immunogens may be able to improve the potency of elicited responses, alone, they are unlikely to promote the development of bnAbs,” the researchers concluded.
The study was funded by the Centre for the AIDS Programme of Research in South Africa and the South African Medical Research Council. The authors reported that they had no disclosures.
SOURCE: Sheward DJ et al. Cell Host Microbe. 2018 Oct 10;24[4]:593-9.
Infection by a second HIV strain after established primary infection (HIV superinfection) has been associated with broader antibody production, and such events are analogous to heterologous prime-boost immunizations, according to a report published in Cell Host & Microbe.
This phenomenon offers an opportunity to assess how the human immune system responds to sequential exposure to two distinct HIV envelope (Env) antigens, according to the authors, Daniel J. Sheward, a PhD student and scientific officer at the University of Cape Town, South Africa, and his colleagues.
Mr. Sheward and his colleagues followed 108 women recruited in acute/early infection and screened for superinfection over approximately 2 years in the Centre for the AIDS Programme of Research in South Africa (CAPRISA 002 cohort). In a previous study, they identified five superinfected participants, all of whom were superinfected between 3 and 10 months following primary infection. Only two of these patients developed antibodies capable of neutralizing heterologous viruses at 2 years, and one individual developed extremely potent broadly neutralizing antibodies (bnAbs). However, the contribution of superinfection itself to the development of antibody breadth in these individuals was not clear, prompting the current study (Cell Host Microbe. 2018 Oct 10;24[4]:593-9).
The researchers compared neutralization breadth (defined as the percent of heterologous viruses neutralized) present in plasma sampled 2 years post infection between the previously identified superinfected participants and the remaining CAPRISA 002 cohort participants. Four virus strains accounted for the superinfections. Antibody breadth was compared at 2 years post infection to four of the five of the superinfected participants, as they all had at least 2 years of antiretroviral-naive follow-up.
The researchers compared the peak neutralizing antibody (nAb) titers against all four superinfecting viruses with their matched primary infecting virus, as well as with the nAb titers that increased against early/founder viruses in 22 other participants in the CAPRISA 002 cohort.
They found that titers to the superinfecting virus strains were comparable with those seen in single infections from the rest of the cohort. In contrast, two other superinfecting virus strains developed exceedingly high neutralizing titers against themselves. Also, HIV superinfection did not appear to boost nAb memory responses primed by the initial infection.
Notably, superinfection did not elicit bnAB responses to epitopes conserved in both infecting viruses. The one individual who appeared to have developed a bnAB response, upon analysis, was found to have breadth of response attributable to a single antibody lineage that only affected the superinfecting virus. This indicated that superinfection did not facilitate breadth by directing responses to an Env conserved in both infecting viruses, according to Mr. Sheward and his colleagues.
“HIV superinfection fails to efficiently recruit neutralizing memory B cells and, at best, results in additive nAb responses rather than a synergistic effect leading to cross-neutralization; a distinction that is highly relevant for vaccine design. ... [W]hile sequential immunizations with heterologous Env immunogens may be able to improve the potency of elicited responses, alone, they are unlikely to promote the development of bnAbs,” the researchers concluded.
The study was funded by the Centre for the AIDS Programme of Research in South Africa and the South African Medical Research Council. The authors reported that they had no disclosures.
SOURCE: Sheward DJ et al. Cell Host Microbe. 2018 Oct 10;24[4]:593-9.
FROM CELL HOST & MICROBE
Key clinical point: Sequential immunizations with heterologous HIV Env immunogens are unlikely to promote broadly neutralizing antibodies.
Major finding: HIV superinfection does not efficiently recruit cross-reactive memory B cells.
Study details: Neutralizing antibody responses were compared between 4 superinfected individuals and 22 singly infected individuals in the CAPRISA 002 cohort.
Disclosures: The study was funded by the Centre for the AIDS Programme of Research in South Africa and the South African Medical Research Council. The authors reported that they had no disclosures.
Source: Sheward DJ et al. Cell Host Microbe. 2018 Oct 10;24[4]:593-9.
Pediatric Primary Cutaneous Blastomycosis Clinically Responsive to Itraconazole
Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.3
We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.
Case Report
A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.
Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.
Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.
The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.
Comment
Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.4 Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.1 Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.
Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.5 The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.6,7
Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.2,6,7 Transmission does not occur from person to person.7 Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.3,8-14
Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.14 Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.7 Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.4 Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.2
Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.19 To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.4
Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.7 Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.19
Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.4 Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.19 Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.19 Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.
Conclusion
Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.
Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.
- Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:1801-1812.
- Smith JA, Riddell Jt, Kauffman CA. Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. 2013;15:440-449.
- Fisher KR, Baselski V, Beard G, et al. Pustular blastomycosis. J Am Acad Dermatol. 2009;6:355-358.
- Mason AR, Cortes GY, Cook J, et al. Cutaneous blastomycosis: a diagnostic challenge. Int J Dermatol. 2008;47:824-830.
- Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6:194-203.
- Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17:21-40, vii.
- Blastomycosis. In: Kimberlin DW, ed. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:263-264.
- Brick KE, Drolet BA, Lyon VB, et al. Cutaneous and disseminated blastomycosis: a pediatric case series. Pediatr Dermatol. 2013;30:23-28.
- Fanella S, Skinner S, Trepman E, et al. Blastomycosis in children and adolescents: a 30-year experience from Manitoba. Med Mycol. 2011;49:627-632.
- Frost HM, Anderson J, Ivacic L, et al. Blastomycosis in children: an analysis of clinical, epidemiologic, and genetic features. J Pediatr Infect Dis Soc. 2017;6:49-56.
- Shukla S, Singh S, Jain M, et al. Paediatric cutaneous blastomycosis: a rare case diagnosed on FNAC. Diagn Cytopathol. 2009;37:119-121.
- Smith RJ, Boos MD, Burnham JM, et al. Atypical cutaneous blastomycosis in a child with juvenile idiopathic arthritis on infliximab. Pediatrics. 2015;136:E1386-E1389.
- Wilson JW, Cawley EP, Weidman FD, et al. Primary cutaneous North American blastomycosis. AMA Arch Derm. 1955;71:39-45.
- Zampogna JC, Hoy MJ, Ramos-Caro FA. Primary cutaneous north american blastomycosis in an immunosuppressed child. Pediatr Dermatol. 2003;20:128-130.
- Balasaraswathy P, Theerthanath. Cutaneous blastomycosis presenting as non-healing ulcer and responding to oral ketoconazole. Dermatol Online J. 2003;9:19.
- Bonifaz A, Morales D, Morales N, et al. Cutaneous blastomycosis. an imported case with good response to itraconazole. Rev Iberoam Micol. 2016;33:51-54.
- Clinton TS, Timko AL. Cutaneous blastomycosis without evidence of pulmonary involvement. Mil Med. 2003;168:651-653.
- Dhamija A, D’Souza P, Salgia P, et al. Blastomycosis presenting as solitary nodule: a rare presentation. Indian J Dermatol. 2012;57:133-135.
- Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin Infect Dis. 2002;34:E44-E49.
- Motswaledi HM, Monyemangene FM, Maloba BR, et al. Blastomycosis: a case report and review of the literature. Int J Dermatol. 2012;51:1090-1093.
- Rodríguez-Mena A, Mayorga J, Solís-Ledesma G, et al. Blastomycosis: report of an imported case in Mexico, with only cutaneous lesions [in Spanish]. Rev Iberoam Micol. 2010;27:210-212.
- Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367-381.
Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.3
We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.
Case Report
A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.
Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.
Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.
The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.
Comment
Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.4 Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.1 Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.
Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.5 The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.6,7
Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.2,6,7 Transmission does not occur from person to person.7 Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.3,8-14
Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.14 Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.7 Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.4 Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.2
Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.19 To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.4
Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.7 Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.19
Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.4 Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.19 Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.19 Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.
Conclusion
Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.
Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.
Blastomycosis is a polymorphic disease caused by the thermally dimorphic fungus Blastomyces dermatitidis, which is naturally occurring worldwide but particularly prominent in the Great Lakes, Mississippi, and Ohio River areas of the United States. The disease was first described by Thomas Caspar Gilchrist in 1894 and historically has been referred to as Gilchrist disease, North American blastomycosis, or Chicago disease.1,2 Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin resulting in primary cutaneous disease. Clinically, the lesions are polymorphic and may appear as well-demarcated verrucous plaques containing foci of pustules or ulcerations. Lesions typically heal centrifugally with a cribriform scar.3
We describe an adolescent with a unique history of inoculation 2 weeks prior to the development of a biopsy-confirmed lesion of cutaneous blastomycosis on the left chest wall that clinically resolved following 6 months of itraconazole.
Case Report
A 16-year-old adolescent boy with a history of morbid obesity, asthma, and seasonal allergies presented for evaluation of a painful, slowly enlarging skin lesion on the left chest wall of 2 months’ duration. According to the patient, a “small pimple” appeared at the site of impact 2 weeks following a fall into a muddy flowerbed in Madison, Wisconsin. The patient recalled that although he had soiled his clothing, there was no identifiable puncture of the skin. Despite daily application of hydrogen peroxide and a 1-week course of trimethoprim-sulfamethoxazole, the lesion gradually enlarged. Complete review of systems as well as exposure and travel history were otherwise negative.
Physical examination revealed a 5.0×2.5-cm exophytic, firm, well-circumscribed plaque with a papillated crusted surface on the left side of the chest near the posterior axillary line (Figure 1). There was no palpable regional lymphadenopathy. Pulmonary examination was unremarkable. Diagnostic workup, including complete blood cell count with differential, hemoglobin A1c, human immunodeficiency virus antibody/antigen testing, interferon-gamma release assay, and chest radiograph were all within normal limits.
Histologic examination of a biopsy specimen showed pseudoepitheliomatous hyperplasia of the epidermis with a brisk mixed inflammatory infiltrate (Figure 2). Displayed in Figure 3 is the Grocott-Gomori methenamine-silver stain that highlighted the thick double-contoured wall-budding yeasts.
The patient was diagnosed with primary cutaneous blastomycosis. Treatment was initiated with itraconazole 200 mg 3 times daily for 3 days, followed by 200 mg 2 times daily for 6 months. Following 3 months of therapy, the lesion had markedly improved with violaceous dyschromia and no residual surface changes. After 5 months of itraconazole, the patient stopped taking the medication for 2 months due to pharmacy issues and then resumed. After 6 total months of therapy, the lesion healed with only residual dyschromia and itraconazole was discontinued.
Comment
Epidemiology
Blastomycosis is a polymorphic pyogranulomatous disease caused by the dimorphic fungus B dermatitidis, naturally occurring in the soil with a worldwide distribution.4 Individuals affected by the disease often reside in locations where the fungus is endemic, specifically in areas that border the Mississippi and Ohio rivers, the Great Lakes, and Canadian provinces near the Saint Lawrence Seaway. More recently there has been an increased incidence of blastomycosis, with the highest proportion found in Wisconsin and Michigan.1,2 Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.1 Despite the ubiquitous presence of B dermatitidis in regions where the species is endemic, it is likely that many individuals who are exposed to the organism do not develop infection.
Pathogenesis
The exact pathogenesis for the development of disease in a particular individual remains unclear. Immunosuppression is not a prerequisite for susceptibility, as evidenced by a review of 123 cases of blastomycosis in which a preceding immunodepressive disorder was present in only 25% of patients. The same study found that it was almost equally common as diabetes mellitus and present in 22% of patients.5 The organism is considered a true pathogen given its ability to affect healthy individuals and the presence of a newly identified novel 120-kD glycoprotein antigen (WI-1) on the cell wall that may confer virulence via extracellular matrix and macrophage binding. Intact cell-mediated immunity that prevents the conversion of conidia (the infectious agent) to yeast (the form that exists at body temperature) plays a key role in conferring natural resistance.6,7
Cutaneous infection may occur by either dissemination of yeast to the skin from systemic disease or less commonly via direct inoculation of the skin, resulting in primary cutaneous disease. With respect to systemic disease, infection occurs through inhalation of conidia from moist soil containing organic debris, with an incubation period of 4 to 6 weeks. In the lungs, in a process largely dependent on host cell-mediated immunity, the mold quickly converts to yeast and may then either multiply or be phagocytized.2,6,7 Transmission does not occur from person to person.7 Asymptomatic infection may occur in at least 50% of patients, often leading to a delay in diagnosis. Symptomatic pulmonary disease may range from mild flulike symptoms to overt pneumonia, clinically indistinguishable from community-acquired bacterial pneumonia, tuberculosis, other fungal infections, and cancer. Of patients with primary pulmonary disease, 25% to 80% have been reported to develop secondary organ involvement via lymphohematogenous spread most commonly to the skin, followed respectively by the skeletal, genitourinary, and central nervous systems. Currently, there are 54 documented cases of secondary disseminated cutaneous blastomycosis in children reported in the literature.3,8-14
Presentation
Primary cutaneous disease resulting from direct cutaneous inoculation is rare, especially among children.14 Of 28 cases of isolated cutaneous blastomycosis reported in the literature, 12 (42%) were pediatric.3,8-21 Inoculation blastomycosis typically presents as a papule that expands to a well-demarcated verrucous plaque, often up to several centimeters in diameter, and is located on the skin at the site of contact. The lesion may exhibit a myriad of features ranging from pustules or nodules to focal ulcerations, either present centrally or within raised borders that ultimately may communicate via sinus tracking.7 Lesions that are purely pustular in morphology also have been reported. Healing typically begins centrally and expands centrifugally, often with cribriform scarring.2,4,22 Histologic features of primary and secondary blastomycosis include pseudoepitheliomatous hyperplasia, intraepidermal microabscesses, and dermal suppurative granulomatous inflammation.4 Classically, broad-based budding yeast are identified with a doubly refractile cell wall that is best visualized on periodic acid–Schiff staining.2
Diagnosis
In approximately 50% of patients with cutaneous blastomycosis resulting from secondary spread, there may be an absence of clinically active pulmonary disease, posing a diagnostic dilemma when differentiating from primary cutaneous disease.1,2,4 Furthermore, the skin findings exhibited in primary and secondary cutaneous blastomycosis cannot be distinguished by clinical inspection.19 To fulfill the criteria for diagnosis of primary cutaneous blastomycosis, there must be an identifiable source of infection from the environment, a lesion at the site of contact, a proven absence of systemic infection, and visualization and/or isolation of fungus from the lesion.4,12 The incubation period of lesions is shorter in primary cutaneous disease (2 weeks) and may aid in its differentiation from secondary disease, which typically is longer with lesions presenting 4 to 6 weeks following initial exposure.4
Treatment
Under the current 2015 guidelines from the American Academy of Pediatrics Committee on Infectious Diseases, 6 to 12 months of itraconazole is the treatment recommendation for mild to moderate pulmonary systemic disease without central nervous system involvement.7 Central nervous system disease and moderate to severe pulmonary and systemic disease are treated with intravenous amphotericin B followed by 12 months of oral itraconazole.1,7 Primary cutaneous disease, unlike secondary disease, may self-resolve; however, primary cutaneous disease usually is treated with 6 months of itraconazole, though successful therapy with surgical excision, radiation therapy, and incision and drainage have been reported.19
Unlike secondary cutaneous blastomycosis, primary inoculation disease may be self-limited; however, as treatment with antifungal therapy has become the standard of care, the disease’s propensity to self-resolve has not been well studied.4 Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.1,22 Effective treatment duration may be difficult to definitively assess because of the self-limited nature of the disease. Our patient showed marked improvement after 3 months and resolution of the skin lesion following 6 months of itraconazole therapy. Our findings support the previously documented observation that systemic therapy might potentially be needed only for the time required to eliminate the clinical evidence of cutaneous disease.19 Our patient received the full 6 months of treatment according to current guidelines. Among a review of 22 cases of primary inoculation blastomycosis, the 5 patients who were treated with an azole agent alone showed disease clearance with an average treatment course of 3.2 months, ranging from 1 to 6 months.19 Further studies that assess the time to clearance with antifungal therapy and subsequent recurrence rates may be warranted.
Conclusion
Pediatric primary cutaneous blastomycosis is a rare cutaneous disease. Identifying sources of probable inoculation from the environment for this patient was unique in that the patient fell into a muddy puddle within a flowerbed. Given the patient’s atopic history, a predominance of humoral over cell-mediated immunity may have placed him at risk. He responded well to 6 months of oral itraconazole and there was no ulceration or scar formation. An increased awareness of this infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.
Acknowledgments
We thank Wenhua Liu, MD (Libertyville, Illinois), for reviewing the pathology and Pravin Muniyappa, MD (Chicago, Illinois), for referring the case.
- Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:1801-1812.
- Smith JA, Riddell Jt, Kauffman CA. Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. 2013;15:440-449.
- Fisher KR, Baselski V, Beard G, et al. Pustular blastomycosis. J Am Acad Dermatol. 2009;6:355-358.
- Mason AR, Cortes GY, Cook J, et al. Cutaneous blastomycosis: a diagnostic challenge. Int J Dermatol. 2008;47:824-830.
- Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6:194-203.
- Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17:21-40, vii.
- Blastomycosis. In: Kimberlin DW, ed. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:263-264.
- Brick KE, Drolet BA, Lyon VB, et al. Cutaneous and disseminated blastomycosis: a pediatric case series. Pediatr Dermatol. 2013;30:23-28.
- Fanella S, Skinner S, Trepman E, et al. Blastomycosis in children and adolescents: a 30-year experience from Manitoba. Med Mycol. 2011;49:627-632.
- Frost HM, Anderson J, Ivacic L, et al. Blastomycosis in children: an analysis of clinical, epidemiologic, and genetic features. J Pediatr Infect Dis Soc. 2017;6:49-56.
- Shukla S, Singh S, Jain M, et al. Paediatric cutaneous blastomycosis: a rare case diagnosed on FNAC. Diagn Cytopathol. 2009;37:119-121.
- Smith RJ, Boos MD, Burnham JM, et al. Atypical cutaneous blastomycosis in a child with juvenile idiopathic arthritis on infliximab. Pediatrics. 2015;136:E1386-E1389.
- Wilson JW, Cawley EP, Weidman FD, et al. Primary cutaneous North American blastomycosis. AMA Arch Derm. 1955;71:39-45.
- Zampogna JC, Hoy MJ, Ramos-Caro FA. Primary cutaneous north american blastomycosis in an immunosuppressed child. Pediatr Dermatol. 2003;20:128-130.
- Balasaraswathy P, Theerthanath. Cutaneous blastomycosis presenting as non-healing ulcer and responding to oral ketoconazole. Dermatol Online J. 2003;9:19.
- Bonifaz A, Morales D, Morales N, et al. Cutaneous blastomycosis. an imported case with good response to itraconazole. Rev Iberoam Micol. 2016;33:51-54.
- Clinton TS, Timko AL. Cutaneous blastomycosis without evidence of pulmonary involvement. Mil Med. 2003;168:651-653.
- Dhamija A, D’Souza P, Salgia P, et al. Blastomycosis presenting as solitary nodule: a rare presentation. Indian J Dermatol. 2012;57:133-135.
- Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin Infect Dis. 2002;34:E44-E49.
- Motswaledi HM, Monyemangene FM, Maloba BR, et al. Blastomycosis: a case report and review of the literature. Int J Dermatol. 2012;51:1090-1093.
- Rodríguez-Mena A, Mayorga J, Solís-Ledesma G, et al. Blastomycosis: report of an imported case in Mexico, with only cutaneous lesions [in Spanish]. Rev Iberoam Micol. 2010;27:210-212.
- Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367-381.
- Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:1801-1812.
- Smith JA, Riddell Jt, Kauffman CA. Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. 2013;15:440-449.
- Fisher KR, Baselski V, Beard G, et al. Pustular blastomycosis. J Am Acad Dermatol. 2009;6:355-358.
- Mason AR, Cortes GY, Cook J, et al. Cutaneous blastomycosis: a diagnostic challenge. Int J Dermatol. 2008;47:824-830.
- Lemos LB, Baliga M, Guo M. Blastomycosis: the great pretender can also be an opportunist. initial clinical diagnosis and underlying diseases in 123 patients. Ann Diagn Pathol. 2002;6:194-203.
- Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am. 2003;17:21-40, vii.
- Blastomycosis. In: Kimberlin DW, ed. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:263-264.
- Brick KE, Drolet BA, Lyon VB, et al. Cutaneous and disseminated blastomycosis: a pediatric case series. Pediatr Dermatol. 2013;30:23-28.
- Fanella S, Skinner S, Trepman E, et al. Blastomycosis in children and adolescents: a 30-year experience from Manitoba. Med Mycol. 2011;49:627-632.
- Frost HM, Anderson J, Ivacic L, et al. Blastomycosis in children: an analysis of clinical, epidemiologic, and genetic features. J Pediatr Infect Dis Soc. 2017;6:49-56.
- Shukla S, Singh S, Jain M, et al. Paediatric cutaneous blastomycosis: a rare case diagnosed on FNAC. Diagn Cytopathol. 2009;37:119-121.
- Smith RJ, Boos MD, Burnham JM, et al. Atypical cutaneous blastomycosis in a child with juvenile idiopathic arthritis on infliximab. Pediatrics. 2015;136:E1386-E1389.
- Wilson JW, Cawley EP, Weidman FD, et al. Primary cutaneous North American blastomycosis. AMA Arch Derm. 1955;71:39-45.
- Zampogna JC, Hoy MJ, Ramos-Caro FA. Primary cutaneous north american blastomycosis in an immunosuppressed child. Pediatr Dermatol. 2003;20:128-130.
- Balasaraswathy P, Theerthanath. Cutaneous blastomycosis presenting as non-healing ulcer and responding to oral ketoconazole. Dermatol Online J. 2003;9:19.
- Bonifaz A, Morales D, Morales N, et al. Cutaneous blastomycosis. an imported case with good response to itraconazole. Rev Iberoam Micol. 2016;33:51-54.
- Clinton TS, Timko AL. Cutaneous blastomycosis without evidence of pulmonary involvement. Mil Med. 2003;168:651-653.
- Dhamija A, D’Souza P, Salgia P, et al. Blastomycosis presenting as solitary nodule: a rare presentation. Indian J Dermatol. 2012;57:133-135.
- Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin Infect Dis. 2002;34:E44-E49.
- Motswaledi HM, Monyemangene FM, Maloba BR, et al. Blastomycosis: a case report and review of the literature. Int J Dermatol. 2012;51:1090-1093.
- Rodríguez-Mena A, Mayorga J, Solís-Ledesma G, et al. Blastomycosis: report of an imported case in Mexico, with only cutaneous lesions [in Spanish]. Rev Iberoam Micol. 2010;27:210-212.
- Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367-381.
Practice Points
- Cutaneous blastomycosis can occur by dissemination of yeast to the skin from systemic and pulmonary disease or rarely via direct inoculation of the skin, resulting in primary cutaneous disease.
- Exposures often are associated with recreational and occupational activities near streams or rivers where there may be decaying vegetation.
- Oral itraconazole for 6 to 12 months is the treatment of choice for mild to moderate cutaneous disease.
- Increased awareness of this rare infection, particularly in geographic areas where its reported incidence is on the rise, could be helpful in reducing delays in diagnosis and treatment.
Hand-foot-and-mouth Disease Caused by Coxsackievirus A6 on the Rise
Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24
Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.
Incidence of CVA6
Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26
The incidence of CVA6 also has been increasing in other areas.28
In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7
Presentation
Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1).
In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24
Clinical Diagnosis
Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.6 In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.40 In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.6,41 CD3+ and CD8+ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.6
Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.43 This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.24 Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.2,24
Treatment
Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.24
Genetic Analysis
Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.44 These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.27,44
Conclusion
With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.
- Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
- Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
- Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
- Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
- Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
- Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
- Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
- Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
- Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
- Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
- Flett K, Youngster I, Huang J, et al. Hand, foot, and mouth disease caused by coxsackievirus A6. Emerg Infect Dis. 2012;18:1702-1704.
- Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep. 2012;61:213-214.
- Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48:49-54.
- Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
- Zeng H, Lu J, Zheng H, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guandong, China. Sci Rep. 2015;5:10550.
- Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 andA10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18:E110-E118.
- Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
- Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18:337-339.
- Bracho MA, Gonzalez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223-2231.
- Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61:420-425.
- Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44:252-257.
- Lu QB, Zhang XA, Wo Y, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7:E52073.
- Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14:E1076-E1081.
- Ventarola D, Bordone L, Silverberg N. Update on hand-foot-and-mouth disease. Clin Dermatol. 2015;33:340-346.
- Li Y, Chang Z, Wu P, et al. Emerging enteroviruses causing hand, foot and mouth disease, China. 2010-2016. Emerg Infect Dis. 2018;24:1902-1906.
- Tan X, Li L, Zhang B, et al. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand, foot, and mouth disease in Tianjin, China, in 2013. Arch Virol. 2015;160:1097-1104.
- Li Y, Bao H, Zhang X, et al. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang City, Henan Province, China, from 2011 to 2015. J Med Virol. 2017;89:1749-1758.
- Guan H, Wang J, Wang C, et al. Etiology of multiple non-EV71 and non-CVA16 enteroviruses associated with hand, foot, and mouth disease in Jinan, China, 2009-2013. PLoS One. 2015;10:E0142733.
- Cabrerizo M, Tarrago´ D, Muñoz-Almagro C, et al. Mollecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20:O150-O156.
- Lønnberg A, Elberling J, Fischer T, et al. Two cases of hand, foot, and mouth disease involving the scalp. Acta Derm Venereol. 2013;93:467-468.
- Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
- Kaminska K, Martinetti G, Lucchini R, et al. Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review. Case Rep Dermatol. 2013;5:203-209.
- Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth disease in an immunocompetent adult. Ann Dermatol. 2010;22:216-218.
- Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
- Feder HM, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 2014;14:83-86.
- Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
- Kim M, Kim B, Byun S, et al. Beau’s lines and onychomadesis after hand-foot-mouth disease. Clin Pediatr Dermatol. 2015;1:1.
- Mathes EF, Oza V, Frieden IJ, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132:E149-E157.
- Lynch M, Sears A, Cookson H, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40:525-528.
- Laga A, Shroba S, Hanna J. Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinicopathologic study. J Cutan Pathol. 2016;43:940-945.
- Schmidt NJ, Ho HH, Lennette EH. Propagation and isolation of group A coxsackieviruses in RD cells. J Clin Microbiol. 1975;2:183-185.
- Oberste MS, Penaranda S, Rogers SL, et al. Comparative evaluation of Taqman real-time PCR and semi-nested VP1 PCR for detection of enteroviruses in clinical specimens. J Clin Virol. 2010;49:73-74.
- Lee MK, Chan PK, Ho II, et al. Enterovirus infection among patients admitted to hospital in Hong Kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis. J Med Virol. 2013;85:1811-1817.
- Yee PTI, Laa Poh C. Impact of genetic changes, pathogenicity and antigenicity on enterovirus A71 vaccine development. Virology. 2017;506:121-129.
Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24
Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.
Incidence of CVA6
Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26
The incidence of CVA6 also has been increasing in other areas.28
In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7
Presentation
Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1).
In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24
Clinical Diagnosis
Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.6 In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.40 In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.6,41 CD3+ and CD8+ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.6
Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.43 This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.24 Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.2,24
Treatment
Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.24
Genetic Analysis
Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.44 These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.27,44
Conclusion
With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.
Hand-foot-and-mouth disease (HFMD) is a viral illness caused by several enteroviruses, most commonly coxsackievirus A16 (CVA16) and enterovirus 71 (EV71). The disease is generally seen in children younger than 5 years, characterized by lesions of the oral mucosa, palms, and soles, usually lasting 7 to 10 days. Other coxsackie type A viruses, including CVA6, CVA9, and CVA10, also are associated with HFMD.1-5 Although CVA16 has traditionally been the primary strain causing HFMD, CVA6 has become a major cause of HFMD outbreaks in the United States and worldwide in recent years.6-12 Interestingly, CVA6 also has been found to be associated with adult HFMD, which has increased in incidence. The CVA6 strain was first identified in association with the disease during HFMD outbreaks in Finland and Singapore in 2008,13,14 with similar strains detected in subsequent outbreaks in Taiwan, Japan, Spain, France, China, India, and the United States.12,15-25 Most cases took place in warmer months, with one winter outbreak in Massachusetts in 2012.24
Herein, we review the incidence of CVA6, as well as its atypical presentation, diagnosis, and treatment to aid dermatologists. Given the increasing incidence of HFMD caused by CVA6 and its often atypical presentation, it is important for dermatologists to be aware of this increasingly notable disease state and its viral cause.
Incidence of CVA6
Coxsackievirus A6 has been identified as the cause of many reported outbreaks of HFMD since it was first identified in 2008, and it is known to cause both pediatric and adult outbreaks.7-12 It may even be surpassing other strains in frequency in certain areas. In Tianjin, China, for example, EV71 and CVA16 were the most common serotypes causing HFMD from 2008 to 2012; however, in 2013, CVA6 was the most prevalent strain.26
The incidence of CVA6 also has been increasing in other areas.28
In 2015, an outbreak of HFMD took place at Lackland Air Force Base in Texas during a basic military training. Eight cases were confirmed and 45 cases were suspected. The rate of infection was 0.4% (50/12,270) among trainees and 0.3% (2/602) among instructors.7 Eight of 12 nasopharyngeal swabs tested positive for EV by way of local real-time reverse transcription–polymerase chain reaction (RT-PCR). Four nasopharyngeal swabs were sent to the CDC for evaluation and all were positive for CVA6.7
Presentation
Because the prevalence of CVA6 has increased, it is important to be able to identify the presentation of HFMD caused by this strain. Coxsackievirus A6 has been found to affect a broader demographic and cause more severe cases of HFMD with its unique constellation of findings compared to other known strains. Patients present with flulike symptoms; higher fever than present in typical HFMD; and a longer duration of disease, typically lasting 2 weeks. Patients also may present with more severe skin disease compared to classic HFMD, not only including vesicles but also large bullae, erosions, and ulcers on the dorsal and plantar feet (Figure 1).
In patients with atopic dermatitis, CVA6 also shows a predilection to appear in areas of skin disease, such as the flexural regions of the arms and legs, and is referred to as eczema coxsackium.24,38,39 It can mimic eczema herpeticum or varicella superinfection, which are important considerations to include in the differential diagnosis. Additionally, CVA6-induced lesions often show up in previously irritated or traumatized areas such as sunburns, fungal infections, and diaper dermatitis in children. Lesions have been described to sometimes mimic Gianotti-Crosti syndrome, with involvement of the extensor surfaces, buttocks, and cheeks, and sparing of the trunk.24
Clinical Diagnosis
Because HFMD is uncommon and atypical in adults, skin biopsies may be used in the initial workup and evaluation of patients. It is important to understand the histologic features associated with HFMD, including spongiosis with exocytosis of neutrophils as well as keratinocyte necrosis and pallor with associated shadow cells.6 In one series, the most extensively involved areas of keratinocyte necrosis were the stratum granulosum and upper half of the stratum spinosum.40 In the dermis, vascular involvement may be present on a spectrum with the extravasation of red blood cells and leukocytoclasis or true leukocytoclastic vasculitis.6,40 Vesicular lesions show severe dermal edema and inflammatory infiltrate.6,41 CD3+ and CD8+ lymphocytes predominate. Cytotoxic T lymphocytes are present and express granzyme B and granulysin, both important mediators of apoptosis in virally infected keratinocytes.6
Adult HFMD primarily is a clinical diagnosis, and histopathologic analysis can be a useful tool in certain cases. Coxsackievirus A6 does not grow well on culture and is not detected by standard serologic testing laboratories, necessitating the use of quantitative RT-PCR analysis.41,42 In one study, culture was able to detect only 14% to 16% of samples that tested positive by quantitative RT-PCR.43 This form of PCR identifies viral subtype through amplification of enterovirus viral protein 1 capsid gene sequence.24 Unfortunately, this testing often is not offered in most readily available laboratories and often necessitates being sent out to more well-equipped laboratories.2,24
Treatment
Hand-foot-and-mouth disease is a self-limited illness and requires only supportive care with a focus on hydration and pain management. Lesions heal without scarring but may leave notable postinflammatory pigment alteration that may last months to years, depending on extent of disease and skin type. Secondarily infected individuals should be treated with appropriate antibiotics or antivirals depending on the infectious agent. Hand hygiene is of great importance, and hospitalized patients should be put on strict contact precautions. It also is important to isolate patients from vulnerable individuals, especially pregnant women, as coxsackievirus has been linked to intrauterine infections and loss of pregnancy.24
Genetic Analysis
Genetic studies of the virus have suggested that nonstructural genes may be playing an interesting role in clinical phenotypes and outcomes of CVA6 infection.44 These genetic studies also are being implemented into the understanding of the virus’ evolution as well as the construction of vaccinations.27,44
Conclusion
With the increasing prevalence of CVA6-associated HFMD, it is important to understand the clinical presentation and histologic findings associated with this atypical presentation of the disease as well as the changing epidemiology of the viral strains causing HFMD.
- Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
- Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
- Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
- Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
- Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
- Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
- Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
- Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
- Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
- Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
- Flett K, Youngster I, Huang J, et al. Hand, foot, and mouth disease caused by coxsackievirus A6. Emerg Infect Dis. 2012;18:1702-1704.
- Centers for Disease Control and Prevention. Notes from the field: severe hand, foot, and mouth disease associated with coxsackievirus A6—Alabama, Connecticut, California, and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly Rep. 2012;61:213-214.
- Blomqvist S, Klemola P, Kaijalainen S, et al. Co-circulation of coxsackieviruses A6 and A10 in hand, foot and mouth disease outbreak in Finland. J Clin Virol. 2010;48:49-54.
- Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
- Zeng H, Lu J, Zheng H, et al. The epidemiological study of coxsackievirus A6 revealing hand, foot and mouth disease epidemic patterns in Guandong, China. Sci Rep. 2015;5:10550.
- Mirand A, Henquell C, Archimbaud C, et al. Outbreak of hand, foot and mouth disease/herpangina associated with coxsackievirus A6 andA10 infections in 2010, France: a large citywide, prospective observational study. Clin Microbiol Infect. 2012;18:E110-E118.
- Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
- Fujimoto T, Iizuka S, Enomoto M, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Japan, 2011. Emerg Infect Dis. 2012;18:337-339.
- Bracho MA, Gonzalez-Candelas F, Valero A, et al. Enterovirus co-infections and onychomadesis after hand, foot, and mouth disease, Spain, 2008. Emerg Infect Dis. 2011;17:2223-2231.
- Gopalkrishna V, Patil PR, Patil GP, et al. Circulation of multiple enterovirus serotypes causing hand, foot and mouth disease in India. J Med Microbiol. 2012;61:420-425.
- Lo SH, Huang YC, Huang CG, et al. Clinical and epidemiologic features of coxsackievirus A6 infection in children in northern Taiwan between 2004 and 2009. J Microbiol Immunol Infect. 2011;44:252-257.
- Lu QB, Zhang XA, Wo Y, et al. Circulation of coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011. PLoS One. 2012;7:E52073.
- Wu Y, Yeo A, Phoon MC, et al. The largest outbreak of hand; foot and mouth disease in Singapore in 2008: the role of enterovirus 71 and coxsackievirus A strains. Int J Infect Dis. 2010;14:E1076-E1081.
- Ventarola D, Bordone L, Silverberg N. Update on hand-foot-and-mouth disease. Clin Dermatol. 2015;33:340-346.
- Li Y, Chang Z, Wu P, et al. Emerging enteroviruses causing hand, foot and mouth disease, China. 2010-2016. Emerg Infect Dis. 2018;24:1902-1906.
- Tan X, Li L, Zhang B, et al. Molecular epidemiology of coxsackievirus A6 associated with outbreaks of hand, foot, and mouth disease in Tianjin, China, in 2013. Arch Virol. 2015;160:1097-1104.
- Li Y, Bao H, Zhang X, et al. Epidemiological and genetic analysis concerning the non-enterovirus 71 and non-coxsackievirus A16 causative agents related to hand, foot and mouth disease in Anyang City, Henan Province, China, from 2011 to 2015. J Med Virol. 2017;89:1749-1758.
- Guan H, Wang J, Wang C, et al. Etiology of multiple non-EV71 and non-CVA16 enteroviruses associated with hand, foot, and mouth disease in Jinan, China, 2009-2013. PLoS One. 2015;10:E0142733.
- Cabrerizo M, Tarrago´ D, Muñoz-Almagro C, et al. Mollecular epidemiology of enterovirus 71, coxsackievirus A16 and A6 associated with hand, foot and mouth disease in Spain. Clin Microbiol Infect. 2014;20:O150-O156.
- Lønnberg A, Elberling J, Fischer T, et al. Two cases of hand, foot, and mouth disease involving the scalp. Acta Derm Venereol. 2013;93:467-468.
- Lott JP, Liu K, Landry ML, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
- Kaminska K, Martinetti G, Lucchini R, et al. Coxsackievirus A6 and hand, foot and mouth disease: three case reports of familial child-to-immunocompetent adult transmission and a literature review. Case Rep Dermatol. 2013;5:203-209.
- Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth disease in an immunocompetent adult. Ann Dermatol. 2010;22:216-218.
- Osterback R, Vuorinen T, Linna M, et al. Coxsackievirus A6 and hand, foot, and mouth disease, Finland. Emerg Infect Dis. 2009;15:1485-1488.
- Feder HM, Bennett N, Modlin JF. Atypical hand, foot, and mouth disease: a vesiculobullous eruption caused by coxsackie virus A6. Lancet Infect Dis. 2014;14:83-86.
- Wei SH, Huang YP, Liu MC, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346.
- Kim M, Kim B, Byun S, et al. Beau’s lines and onychomadesis after hand-foot-mouth disease. Clin Pediatr Dermatol. 2015;1:1.
- Mathes EF, Oza V, Frieden IJ, et al. “Eczema coxsackium” and unusual cutaneous findings in an enterovirus outbreak. Pediatrics. 2013;132:E149-E157.
- Lynch M, Sears A, Cookson H, et al. Disseminated coxsackievirus A6 affecting children with atopic dermatitis. Clin Exp Dermatol. 2015;40:525-528.
- Laga A, Shroba S, Hanna J. Atypical hand, foot and mouth disease in adults associated with coxsackievirus A6: a clinicopathologic study. J Cutan Pathol. 2016;43:940-945.
- Schmidt NJ, Ho HH, Lennette EH. Propagation and isolation of group A coxsackieviruses in RD cells. J Clin Microbiol. 1975;2:183-185.
- Oberste MS, Penaranda S, Rogers SL, et al. Comparative evaluation of Taqman real-time PCR and semi-nested VP1 PCR for detection of enteroviruses in clinical specimens. J Clin Virol. 2010;49:73-74.
- Lee MK, Chan PK, Ho II, et al. Enterovirus infection among patients admitted to hospital in Hong Kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis. J Med Virol. 2013;85:1811-1817.
- Yee PTI, Laa Poh C. Impact of genetic changes, pathogenicity and antigenicity on enterovirus A71 vaccine development. Virology. 2017;506:121-129.
- Galen WK. Cutaneous manifestations of enterovirus infections. In: Tyring SK, ed. Mucocutaneous Manifestations of Viral Diseases. New York, NY: Marcel Dekker; 2002:455-467.
- Ramirez-Fort M, Downing C, Doan H, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381-386.
- Khetsuriani N, Lamonte-Fowlkes A, Oberst S, et al. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ. 2006;55:1-20.
- Yang F, Zhang T, Hu Y, et al. Survey of enterovirus infections from hand, foot and mouth disease outbreak in China, 2009. Virol J. 2011;8:508.
- Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929-935.
- Second J, Velter C, Calès S, et al. Clinicopathologic analysis of atypical hand, foot, and mouth disease in adult patients. J Am Acad Dermatol. 2016;76:722-729.
- Banta J, Lenz B, Pawlak M, et al. Notes from the field: outbreak of hand, foot, and mouth disease caused by coxsackievirus A6 among basic military trainees—Texas, 2015. MMWR Morb Mortal Wkly Rep. 2016;65.26:678-680.
- Bian L, Wang Y, Yao X, et al. Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. Expert Rev Anti Infect Ther. 2015;13:1061-1071.
- Buttery VW, Kenyon C, Grunewald S, et al. Notes from the field: atypical presentations of hand, foot, and mouth disease caused by coxsackievirus A6—Minnesota, 2014. MMWR Morb Mortal Wkly Rep. 2015;64:805.
- Puenpa J, Chieochansin T, Linsuwanon P, et al. Hand, foot, and mouth disease caused by coxsackievirus A6, Thailand, 2012. Emerg Infect Dis. 2013;19:641-643.
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Practice Points
- Coxsackievirus A6 is an increasingly more common cause of hand-foot-and-mouth disease (HFMD), often with atypical presentation, more severe disease, and association with HFMD in adults.
- Coxsackievirus A6 has become a major cause of HFMD outbreak in the United States and worldwide.
