Infectious Diseases

The US Department of Veterans Affairs (VA) is the largest health care organization in the US, staffing more than 1,200 facilities and servicing about 9 million veterans.¹ Identifying VA practices that promote effective health care delivery has the potential to impact thousands of patients every day. The Surgical service at the Minneapolis VA Medical Center (MVAMC) in Minnesota often questioned colleagues whether many of the ordered tests, including blood cultures for patients with suspected infections, were clinically necessary. Despite recommendations for utilizing culture-driven results in choosing appropriate antimicrobials, it was debated whether these additional tests were simply drawn and ignored resulting only in increased costs and venipuncture discomfort for the patient. Thus, the purpose of this quality improvement study was to determine whether positive blood culture results actually influence clinical management at MVAMC.

Background

Accepted best practice when responding to positive blood culture results entails empiric treatment with broad-spectrum antibiotics that subsequently narrows in breadth of coverage once the pathogen has been identified.^2-4 This strategy has been labeled deescalation. Despite the acceptance of these standards, surveys of clinician attitudes towards antibiotics showed that 90% of physicians and residents stated they wanted more education on antimicrobials and 80% desired better schooling on antibiotic choices.^5,6 Additionally, in an online survey 18% of 402 inpatient and emergency department providers, including residents, fellows, intensive care unit (ICU) and emergency department attending physicians, hospitalists, physician assistants, and nurse practitioners, described a lack of confidence when deescalating antibiotic therapy and 45% reported that they had received training on antimicrobial prescribing that was not fully adequate.⁷

These surveys hint at a potential gap in provider education or confidence, which may serve as a barrier to ideal care, further confounding other individualized considerations taken into account when deescalating care. These considerations include patient renal toxicity profiles, the potential for missed pathogens not identified in culture results, unknown sources of infection, and the mindset of many providers to remain on broad therapy if the patient’s condition is improving.^8-10 A specific barrier to deescalation within the VA is the variance in antimicrobial stewardship practices between facilities. In a recent widespread survey of VA practices, Chou and colleagues identified that only 29 of 130 (22.3%) responding facilities had a formal policy to establish an antimicrobial stewardship program.¹¹

Overcoming these barriers to deescalation through effective stewardship practices can help to promote improved clinical outcomes. Most studies have demonstrated that outcomes of deescalation strategies have equivalent or improved mortalityand equivalent or even decreased length of ICU stay.^12-26 Although a 2014 study by Leone and colleagues reported longer overall ICU stay in deescalation treatment groups with equivalent mortality outcomes, newer data do not support these findings.^16,20,22

Furthermore, antibiotics can be expensive. Deescalation, particularly in response to positive blood culture results, has been associated with reduced antibiotic cost due to both a decrease in overall antibiotic usage and the utilization of less expensive choices.^22,24,26,27 The findings of these individual studies were corroborated in 2013 by a meta-analysis, including 89 additional studies.²⁸ Besides the direct costs of the drugs, the development of regional antibiotic resistance has been labeled as one of the most pressing concerns in public health, and major initiatives have been undertaken to stem its spread.^29,30 The majority of clinicians believe that deescalation of antibiotics would reduce antibiotic resistance. Thus, deescalation is widely cited as one of the primary goals in the management of resistance development.^{5,24,26,28,31,32}

Due to the proposed benefits and challenges of implementation, MVAMC instituted a program where the electronic health records (EHR) for all patients with positive blood culture results were reviewed by the on-call infectious disease attending physician to advise the primary care team on antibiotic administration. The MVAMC system for notification of positive blood culture results has 2 components. The first is phone notification to the on-call resident when the positive result of the pathogen identification is noted by the microbiology laboratory staff. Notably, this protocol of phone notification is only performed when identifying the pathogen and not for the subsequent sensitivity profile. The second component occurs each morning when the on-call infectious disease attending physician reviews all positive blood culture results and the current therapy. If the infectious disease attending physician feels some alterations in management are warranted, the physician calls the primary service. Additionally, the primary service may always request a formal consult with the infectious disease team. This quality improvement study was initiated to examine the success of this deescalation/stewardship program to determine whether positive blood culture results influenced clinical management.

Methods

From July 1, 2015 to June 30, 2016, 212 positive blood cultures at the MVAMC were analyzed. Four cases that did not have an antibiotic spectrum score were excluded, leaving 208 cases reviewed. Duplicate blood cultures were excluded from analysis. The microbiology laboratory used the BD Bactec automated blood culture system using the Plus aerobic and Lytic anaerobic media (Becton, Dickinson and Company).

Antibiotic alterations in response to culture results were classified as either deescalation or escalation, using a spectrum score developed by Madaras-Kelly and colleagues.³³ These investigators performed a 3-round modified Delphi survey of infectious disease staff of physicians and pharmacists. The resulting consensus spectrum score for each respective antibiotic reflected the relative susceptibilities of various pathogens to antibiotics and the intrinsic resistance of the pathogens. It is a nonlinear scale from 0 to 60 with a score of 0 indicating no antibacterial activity and a score of 60 indicating complete coverage of all critically identified pathogens. For example, a narrow-spectrum antibiotic such as metronidazole received a spectrum score of 4.0 and a broad-spectrum antibiotic such as piperacillin/tazobactam received a 42.3 score.

Data Recording and Analysis

Charts for review were flagged based on positive blood culture results from the microbiology laboratory. EHRs were manually reviewed to determine when antibiotics were started/stopped and when a member of the primary care team, usually a resident, was notified of culture results as documented by the microbiology laboratory personnel. Any alteration in antibiotics that fit the criteria of deescalation or escalation that occurred within 24 hours of notification of either critical laboratory value was recorded. The identity of infectious pathogens and the primary site of infection were not recorded as these data were not within the scope of the purpose of this study. We did not control for possible contaminants within positive blood cultures.

There were 3 time frames considered when determining culture driven alterations to the antibiotic regimen. The first 2 were changes within the 24 hours after notification of either (1) pathogen identification or (2) pathogen sensitivity. These were defined as culture-driven alterations in response to those particular laboratory findings. The third—whole case time frame—spanned from pathogen identification to 24 hours after sensitivity information was recorded. In cases where ≥ 1 antibiotic alteration was noted within a respective time frame, a classification of deescalation or escalation was still assigned. This was done by summing each change in spectrum score that occurred from antibiotic regimen alterations within the time frame, and classifying the net effect on the spectrum of coverage as either deescalation or escalation. Data were recorded in spreadsheet. RStudio 3.5.3 was used for statistical analysis.

Results

Of 208 cases assigned a spectrum score, 47 (22.6%) had the breadth of antibiotic coverage deescalated by the primary care team within 24 hours of pathogen identification with a mean (SD) physician response time of 8.0 (7.3) hours. Fourteen cases (6.7%) had the breadth of antibiotic coverage escalated from pathogen identification with a mean (SD) response time of 8.0 (7.4) hours. When taken together, within 24 hours of pathogen identification from positive blood cultures 61 cases (29.3%) had altered antibiotics, leaving 70.7% of cases unaltered (Tables 1 and 2). In this nonquantitative spectrum score method, deescalations typically involved larger changes in spectrum score than escalations.

Physician notification of pathogen sensitivities resulted in deescalation in 69 cases (33.2%) within 24 hours, with a mean (SD) response time of 10.4 (7) hours. The mean time to deescalation in response to pathogen identification was significantly shorter than the mean time to deescalation in response to sensitivities (P = .049). Broadening of coverage based on sensitivity information was reported for 17 cases (8.2%) within 24 hours, with a mean (SD) response time of 7.6 (6) hours (Table 3). In response to pathogen sensitivity results from positive blood cultures, 58.6% of cases had no antibiotic alterations. Deescalations involved notably larger changes in spectrum score than escalations.

More than half (58.6%) of cases resulted in an antibiotic alteration from empiric treatment when considering the time frame from empiric antibiotics to 24 hours after receiving sensitivity information. These were deemed the whole-case, culture-driven results. In addition to antibiotic alterations that occurred within 24 hours of either pathogen identification or sensitivity information, the whole-case category also considered antibiotic alterations that occurred more than 24 hours after pathogen identification was known and before sensitivity information was available, although this was rare. Some of these patients may have had their antibiotics altered twice, first after pathogen identification and later once sensitivities became available with the net effect recorded as the whole-case administration. Of those that had their antibiotics modified in response to laboratory results, by a ratio of 6.4:1, the change was a deescalation rather than an escalation.

Discussion

The strategy of the infectious disease team at MVAMC is one of deescalation. One challenge of quantifying deescalation was to make a reliable and agreed-upon definition of just what deescalation entails. In 2003, the pharmaceutical company Merck was granted a trademark for the phrase “De-Escalation Therapy” under the international class code 41 for educational and entertainment services. This seemed to correspond to marketing efforts for the antibiotic imipenem/cilastatin. Although the company trademarked the term, it was never defined. The usage of the phrase evolved from a reduction of the dosage of a specific antibiotic to a reduction in the number of antibiotics prescribed to that of monotherapy. The phrase continues to evolve and has now become associated with a change from combination therapy or broad-spectrum antibiotics to monotherapy, switching to an antibiotic that covers fewer pathogens, or even shortening the duration of antibiotic therapy.³⁴ The trademark expired at about the same time the imipenem/cilastatin patent expired. Notably, this drug had initially been marketed for use in empiric antibiotic therapy.³⁵

Barriers

The goal of the stewardship program was not to see a narrowing of the antibiotic spectrum in all patients. Some diseases such as diverticulitis or diabetic foot infections are usually associated with multiple pathogens where relatively broad-spectrum antibiotics seem to be preferred.^36,37 Heenen and colleagues reported that infectious disease specialists recommended deescalation in < 50% of cases they examined.³⁸

Comparing different institutions’ deescalation rates can be confusing due to varying definitions, differing patient populations, and health care provider behavior. Thus, the published rates of deescalation range widely from 10 to 70%.^2,39,40 In addition to the varied definitions of deescalation, it is challenging to directly compare the rate of deescalation between studies due to institutional variation in empirical broad-spectrum antibiotic usage. A hospital that uses broad-spectrum antibiotics at a higher rate than another has the potential to deescalate more often than one that has low rates of empirical broad-spectrum antibiotic use. Some studies use a conservative definition of deescalation such as narrowing the spectrum of coverage, while others use a more general definition, including both the narrowing of spectrum and/or the discontinuation of antibiotics from empirical therapy.^41-45 The more specific and validated definition of deescalation used in this study may allow for standardized comparisons. Another unique feature of this study is that all positive blood cultures were followed, not only those of a particular disease.

Clinical Response

This quality improvement study was initiated to determine whether positive blood culture results actually affect clinical management at MVAMC. The answer seems to be yes, with blood culture results altering antibiotic administration in about 60% of cases with the predominant change being deescalation. This overall rate of deescalation is toward the higher end of previously documented rates and coincides with the upper bound of the clinically advised deescalation rate described by Heenen and colleagues.³⁸

As noted, the spectrum score is not quantitative. Still, one may be able to contend that the values may provide some insight into the magnitude of the changes in antibiotic selection. Deescalations were on average much larger changes in spectrum than escalations. The larger magnitude of deescalations reflects that when already starting with a very broad spectrum of coverage, it is much easier to get narrower than even broader. Stated another way, when starting therapy using piperacillin/tazobactam at a spectrum score of 42.3 on a 60-point scale, there is much more room for deescalation to 0 than escalation to 60. Additionally, escalations were more likely with much smaller of a spectrum change due to accurate empirical judgment of the suspected pathogens with new findings only necessitating a minor expansion of the spectrum of coverage.

Future Study

Similar studies designed using the spectrum score methodology would allow for more meaningful interinstitutional comparison of antibiotic administration through the use of a unified definition of deescalation and escalation. Comparison of deescalation and escalation rates between hospital systems with similar patient populations with and without prompt infectious disease review and phone notification of blood culture results could further verify the value of such a protocol. It could also help determine which empiric antibiotics may be most effective in individual patient morbidity and mortality outcomes, length of stay, costs, and the development of antibiotic resistance. Chou and colleagues found that only 49 of 130 responding VA facilities had antimicrobial stewardship teams in place with even fewer (29) having a formal policy to establish an antimicrobial stewardship program.¹¹ This significant variation in the practices of VA facilities across the nation underscores the benefit to be gained from implementation of value-added protocols such as daily infectious disease case monitoring and microbiology laboratory phone notification of positive blood culture results as it occurs at MVAMC.

They also noted that systems of patient-level antibiotic review, and the presence of at least one full-time infectious disease physician were both associated with a statistically significant decrease in the use of antimicrobials, corroborating the results of this analysis.¹¹ Adapting the current system of infectious disease specialist review of positive blood culture results to use remote monitoring through the EHR could help to defer some of the cost of needing an in-house specialist while retaining the benefit of the oversite.

Another option for study would be a before and after design to determine whether the program of infectious disease specialist review led to increased use of deescalation strategies similar to studies investigating the efficacy of antimicrobial subcommittee implementation.^{13,20,23,24,26}

Conclusions

This analysis of empiric antibiotic use at the MVAMC indicates promising rates of deescalation. The results indicate that the medical service may be right and that positive blood culture results appear to affect clinical decision making in an appropriate and timely fashion. The VA is the largest health care organization in the US. Thus, identifying and propagating effective stewardship practices on a widespread basis can have a significant effect on the public health of the nation.

These data suggest that the program implemented at the MVAMC of phone notification to the primary care team along with daily infectious disease staff monitoring of blood culture information should be widely adopted at sister institutions using either in-house or remote specialist review.

The US Department of Veterans Affairs (VA) is the largest health care organization in the US, staffing more than 1,200 facilities and servicing about 9 million veterans.¹ Identifying VA practices that promote effective health care delivery has the potential to impact thousands of patients every day. The Surgical service at the Minneapolis VA Medical Center (MVAMC) in Minnesota often questioned colleagues whether many of the ordered tests, including blood cultures for patients with suspected infections, were clinically necessary. Despite recommendations for utilizing culture-driven results in choosing appropriate antimicrobials, it was debated whether these additional tests were simply drawn and ignored resulting only in increased costs and venipuncture discomfort for the patient. Thus, the purpose of this quality improvement study was to determine whether positive blood culture results actually influence clinical management at MVAMC.

Background

Accepted best practice when responding to positive blood culture results entails empiric treatment with broad-spectrum antibiotics that subsequently narrows in breadth of coverage once the pathogen has been identified.^2-4 This strategy has been labeled deescalation. Despite the acceptance of these standards, surveys of clinician attitudes towards antibiotics showed that 90% of physicians and residents stated they wanted more education on antimicrobials and 80% desired better schooling on antibiotic choices.^5,6 Additionally, in an online survey 18% of 402 inpatient and emergency department providers, including residents, fellows, intensive care unit (ICU) and emergency department attending physicians, hospitalists, physician assistants, and nurse practitioners, described a lack of confidence when deescalating antibiotic therapy and 45% reported that they had received training on antimicrobial prescribing that was not fully adequate.⁷

These surveys hint at a potential gap in provider education or confidence, which may serve as a barrier to ideal care, further confounding other individualized considerations taken into account when deescalating care. These considerations include patient renal toxicity profiles, the potential for missed pathogens not identified in culture results, unknown sources of infection, and the mindset of many providers to remain on broad therapy if the patient’s condition is improving.^8-10 A specific barrier to deescalation within the VA is the variance in antimicrobial stewardship practices between facilities. In a recent widespread survey of VA practices, Chou and colleagues identified that only 29 of 130 (22.3%) responding facilities had a formal policy to establish an antimicrobial stewardship program.¹¹

Overcoming these barriers to deescalation through effective stewardship practices can help to promote improved clinical outcomes. Most studies have demonstrated that outcomes of deescalation strategies have equivalent or improved mortalityand equivalent or even decreased length of ICU stay.^12-26 Although a 2014 study by Leone and colleagues reported longer overall ICU stay in deescalation treatment groups with equivalent mortality outcomes, newer data do not support these findings.^16,20,22

Furthermore, antibiotics can be expensive. Deescalation, particularly in response to positive blood culture results, has been associated with reduced antibiotic cost due to both a decrease in overall antibiotic usage and the utilization of less expensive choices.^22,24,26,27 The findings of these individual studies were corroborated in 2013 by a meta-analysis, including 89 additional studies.²⁸ Besides the direct costs of the drugs, the development of regional antibiotic resistance has been labeled as one of the most pressing concerns in public health, and major initiatives have been undertaken to stem its spread.^29,30 The majority of clinicians believe that deescalation of antibiotics would reduce antibiotic resistance. Thus, deescalation is widely cited as one of the primary goals in the management of resistance development.^{5,24,26,28,31,32}

Due to the proposed benefits and challenges of implementation, MVAMC instituted a program where the electronic health records (EHR) for all patients with positive blood culture results were reviewed by the on-call infectious disease attending physician to advise the primary care team on antibiotic administration. The MVAMC system for notification of positive blood culture results has 2 components. The first is phone notification to the on-call resident when the positive result of the pathogen identification is noted by the microbiology laboratory staff. Notably, this protocol of phone notification is only performed when identifying the pathogen and not for the subsequent sensitivity profile. The second component occurs each morning when the on-call infectious disease attending physician reviews all positive blood culture results and the current therapy. If the infectious disease attending physician feels some alterations in management are warranted, the physician calls the primary service. Additionally, the primary service may always request a formal consult with the infectious disease team. This quality improvement study was initiated to examine the success of this deescalation/stewardship program to determine whether positive blood culture results influenced clinical management.

Methods

From July 1, 2015 to June 30, 2016, 212 positive blood cultures at the MVAMC were analyzed. Four cases that did not have an antibiotic spectrum score were excluded, leaving 208 cases reviewed. Duplicate blood cultures were excluded from analysis. The microbiology laboratory used the BD Bactec automated blood culture system using the Plus aerobic and Lytic anaerobic media (Becton, Dickinson and Company).

Antibiotic alterations in response to culture results were classified as either deescalation or escalation, using a spectrum score developed by Madaras-Kelly and colleagues.³³ These investigators performed a 3-round modified Delphi survey of infectious disease staff of physicians and pharmacists. The resulting consensus spectrum score for each respective antibiotic reflected the relative susceptibilities of various pathogens to antibiotics and the intrinsic resistance of the pathogens. It is a nonlinear scale from 0 to 60 with a score of 0 indicating no antibacterial activity and a score of 60 indicating complete coverage of all critically identified pathogens. For example, a narrow-spectrum antibiotic such as metronidazole received a spectrum score of 4.0 and a broad-spectrum antibiotic such as piperacillin/tazobactam received a 42.3 score.

Data Recording and Analysis

Charts for review were flagged based on positive blood culture results from the microbiology laboratory. EHRs were manually reviewed to determine when antibiotics were started/stopped and when a member of the primary care team, usually a resident, was notified of culture results as documented by the microbiology laboratory personnel. Any alteration in antibiotics that fit the criteria of deescalation or escalation that occurred within 24 hours of notification of either critical laboratory value was recorded. The identity of infectious pathogens and the primary site of infection were not recorded as these data were not within the scope of the purpose of this study. We did not control for possible contaminants within positive blood cultures.

There were 3 time frames considered when determining culture driven alterations to the antibiotic regimen. The first 2 were changes within the 24 hours after notification of either (1) pathogen identification or (2) pathogen sensitivity. These were defined as culture-driven alterations in response to those particular laboratory findings. The third—whole case time frame—spanned from pathogen identification to 24 hours after sensitivity information was recorded. In cases where ≥ 1 antibiotic alteration was noted within a respective time frame, a classification of deescalation or escalation was still assigned. This was done by summing each change in spectrum score that occurred from antibiotic regimen alterations within the time frame, and classifying the net effect on the spectrum of coverage as either deescalation or escalation. Data were recorded in spreadsheet. RStudio 3.5.3 was used for statistical analysis.

Results

Of 208 cases assigned a spectrum score, 47 (22.6%) had the breadth of antibiotic coverage deescalated by the primary care team within 24 hours of pathogen identification with a mean (SD) physician response time of 8.0 (7.3) hours. Fourteen cases (6.7%) had the breadth of antibiotic coverage escalated from pathogen identification with a mean (SD) response time of 8.0 (7.4) hours. When taken together, within 24 hours of pathogen identification from positive blood cultures 61 cases (29.3%) had altered antibiotics, leaving 70.7% of cases unaltered (Tables 1 and 2). In this nonquantitative spectrum score method, deescalations typically involved larger changes in spectrum score than escalations.

Physician notification of pathogen sensitivities resulted in deescalation in 69 cases (33.2%) within 24 hours, with a mean (SD) response time of 10.4 (7) hours. The mean time to deescalation in response to pathogen identification was significantly shorter than the mean time to deescalation in response to sensitivities (P = .049). Broadening of coverage based on sensitivity information was reported for 17 cases (8.2%) within 24 hours, with a mean (SD) response time of 7.6 (6) hours (Table 3). In response to pathogen sensitivity results from positive blood cultures, 58.6% of cases had no antibiotic alterations. Deescalations involved notably larger changes in spectrum score than escalations.

More than half (58.6%) of cases resulted in an antibiotic alteration from empiric treatment when considering the time frame from empiric antibiotics to 24 hours after receiving sensitivity information. These were deemed the whole-case, culture-driven results. In addition to antibiotic alterations that occurred within 24 hours of either pathogen identification or sensitivity information, the whole-case category also considered antibiotic alterations that occurred more than 24 hours after pathogen identification was known and before sensitivity information was available, although this was rare. Some of these patients may have had their antibiotics altered twice, first after pathogen identification and later once sensitivities became available with the net effect recorded as the whole-case administration. Of those that had their antibiotics modified in response to laboratory results, by a ratio of 6.4:1, the change was a deescalation rather than an escalation.

Discussion

The strategy of the infectious disease team at MVAMC is one of deescalation. One challenge of quantifying deescalation was to make a reliable and agreed-upon definition of just what deescalation entails. In 2003, the pharmaceutical company Merck was granted a trademark for the phrase “De-Escalation Therapy” under the international class code 41 for educational and entertainment services. This seemed to correspond to marketing efforts for the antibiotic imipenem/cilastatin. Although the company trademarked the term, it was never defined. The usage of the phrase evolved from a reduction of the dosage of a specific antibiotic to a reduction in the number of antibiotics prescribed to that of monotherapy. The phrase continues to evolve and has now become associated with a change from combination therapy or broad-spectrum antibiotics to monotherapy, switching to an antibiotic that covers fewer pathogens, or even shortening the duration of antibiotic therapy.³⁴ The trademark expired at about the same time the imipenem/cilastatin patent expired. Notably, this drug had initially been marketed for use in empiric antibiotic therapy.³⁵

Barriers

The goal of the stewardship program was not to see a narrowing of the antibiotic spectrum in all patients. Some diseases such as diverticulitis or diabetic foot infections are usually associated with multiple pathogens where relatively broad-spectrum antibiotics seem to be preferred.^36,37 Heenen and colleagues reported that infectious disease specialists recommended deescalation in < 50% of cases they examined.³⁸

Comparing different institutions’ deescalation rates can be confusing due to varying definitions, differing patient populations, and health care provider behavior. Thus, the published rates of deescalation range widely from 10 to 70%.^2,39,40 In addition to the varied definitions of deescalation, it is challenging to directly compare the rate of deescalation between studies due to institutional variation in empirical broad-spectrum antibiotic usage. A hospital that uses broad-spectrum antibiotics at a higher rate than another has the potential to deescalate more often than one that has low rates of empirical broad-spectrum antibiotic use. Some studies use a conservative definition of deescalation such as narrowing the spectrum of coverage, while others use a more general definition, including both the narrowing of spectrum and/or the discontinuation of antibiotics from empirical therapy.^41-45 The more specific and validated definition of deescalation used in this study may allow for standardized comparisons. Another unique feature of this study is that all positive blood cultures were followed, not only those of a particular disease.

Clinical Response

This quality improvement study was initiated to determine whether positive blood culture results actually affect clinical management at MVAMC. The answer seems to be yes, with blood culture results altering antibiotic administration in about 60% of cases with the predominant change being deescalation. This overall rate of deescalation is toward the higher end of previously documented rates and coincides with the upper bound of the clinically advised deescalation rate described by Heenen and colleagues.³⁸

As noted, the spectrum score is not quantitative. Still, one may be able to contend that the values may provide some insight into the magnitude of the changes in antibiotic selection. Deescalations were on average much larger changes in spectrum than escalations. The larger magnitude of deescalations reflects that when already starting with a very broad spectrum of coverage, it is much easier to get narrower than even broader. Stated another way, when starting therapy using piperacillin/tazobactam at a spectrum score of 42.3 on a 60-point scale, there is much more room for deescalation to 0 than escalation to 60. Additionally, escalations were more likely with much smaller of a spectrum change due to accurate empirical judgment of the suspected pathogens with new findings only necessitating a minor expansion of the spectrum of coverage.

Future Study

Similar studies designed using the spectrum score methodology would allow for more meaningful interinstitutional comparison of antibiotic administration through the use of a unified definition of deescalation and escalation. Comparison of deescalation and escalation rates between hospital systems with similar patient populations with and without prompt infectious disease review and phone notification of blood culture results could further verify the value of such a protocol. It could also help determine which empiric antibiotics may be most effective in individual patient morbidity and mortality outcomes, length of stay, costs, and the development of antibiotic resistance. Chou and colleagues found that only 49 of 130 responding VA facilities had antimicrobial stewardship teams in place with even fewer (29) having a formal policy to establish an antimicrobial stewardship program.¹¹ This significant variation in the practices of VA facilities across the nation underscores the benefit to be gained from implementation of value-added protocols such as daily infectious disease case monitoring and microbiology laboratory phone notification of positive blood culture results as it occurs at MVAMC.

They also noted that systems of patient-level antibiotic review, and the presence of at least one full-time infectious disease physician were both associated with a statistically significant decrease in the use of antimicrobials, corroborating the results of this analysis.¹¹ Adapting the current system of infectious disease specialist review of positive blood culture results to use remote monitoring through the EHR could help to defer some of the cost of needing an in-house specialist while retaining the benefit of the oversite.

Another option for study would be a before and after design to determine whether the program of infectious disease specialist review led to increased use of deescalation strategies similar to studies investigating the efficacy of antimicrobial subcommittee implementation.^{13,20,23,24,26}

Conclusions

This analysis of empiric antibiotic use at the MVAMC indicates promising rates of deescalation. The results indicate that the medical service may be right and that positive blood culture results appear to affect clinical decision making in an appropriate and timely fashion. The VA is the largest health care organization in the US. Thus, identifying and propagating effective stewardship practices on a widespread basis can have a significant effect on the public health of the nation.

These data suggest that the program implemented at the MVAMC of phone notification to the primary care team along with daily infectious disease staff monitoring of blood culture information should be widely adopted at sister institutions using either in-house or remote specialist review.

The US Department of Veterans Affairs (VA) is the largest health care organization in the US, staffing more than 1,200 facilities and servicing about 9 million veterans.¹ Identifying VA practices that promote effective health care delivery has the potential to impact thousands of patients every day. The Surgical service at the Minneapolis VA Medical Center (MVAMC) in Minnesota often questioned colleagues whether many of the ordered tests, including blood cultures for patients with suspected infections, were clinically necessary. Despite recommendations for utilizing culture-driven results in choosing appropriate antimicrobials, it was debated whether these additional tests were simply drawn and ignored resulting only in increased costs and venipuncture discomfort for the patient. Thus, the purpose of this quality improvement study was to determine whether positive blood culture results actually influence clinical management at MVAMC.

Background

Accepted best practice when responding to positive blood culture results entails empiric treatment with broad-spectrum antibiotics that subsequently narrows in breadth of coverage once the pathogen has been identified.^2-4 This strategy has been labeled deescalation. Despite the acceptance of these standards, surveys of clinician attitudes towards antibiotics showed that 90% of physicians and residents stated they wanted more education on antimicrobials and 80% desired better schooling on antibiotic choices.^5,6 Additionally, in an online survey 18% of 402 inpatient and emergency department providers, including residents, fellows, intensive care unit (ICU) and emergency department attending physicians, hospitalists, physician assistants, and nurse practitioners, described a lack of confidence when deescalating antibiotic therapy and 45% reported that they had received training on antimicrobial prescribing that was not fully adequate.⁷

These surveys hint at a potential gap in provider education or confidence, which may serve as a barrier to ideal care, further confounding other individualized considerations taken into account when deescalating care. These considerations include patient renal toxicity profiles, the potential for missed pathogens not identified in culture results, unknown sources of infection, and the mindset of many providers to remain on broad therapy if the patient’s condition is improving.^8-10 A specific barrier to deescalation within the VA is the variance in antimicrobial stewardship practices between facilities. In a recent widespread survey of VA practices, Chou and colleagues identified that only 29 of 130 (22.3%) responding facilities had a formal policy to establish an antimicrobial stewardship program.¹¹

Overcoming these barriers to deescalation through effective stewardship practices can help to promote improved clinical outcomes. Most studies have demonstrated that outcomes of deescalation strategies have equivalent or improved mortalityand equivalent or even decreased length of ICU stay.^12-26 Although a 2014 study by Leone and colleagues reported longer overall ICU stay in deescalation treatment groups with equivalent mortality outcomes, newer data do not support these findings.^16,20,22

Furthermore, antibiotics can be expensive. Deescalation, particularly in response to positive blood culture results, has been associated with reduced antibiotic cost due to both a decrease in overall antibiotic usage and the utilization of less expensive choices.^22,24,26,27 The findings of these individual studies were corroborated in 2013 by a meta-analysis, including 89 additional studies.²⁸ Besides the direct costs of the drugs, the development of regional antibiotic resistance has been labeled as one of the most pressing concerns in public health, and major initiatives have been undertaken to stem its spread.^29,30 The majority of clinicians believe that deescalation of antibiotics would reduce antibiotic resistance. Thus, deescalation is widely cited as one of the primary goals in the management of resistance development.^{5,24,26,28,31,32}

Due to the proposed benefits and challenges of implementation, MVAMC instituted a program where the electronic health records (EHR) for all patients with positive blood culture results were reviewed by the on-call infectious disease attending physician to advise the primary care team on antibiotic administration. The MVAMC system for notification of positive blood culture results has 2 components. The first is phone notification to the on-call resident when the positive result of the pathogen identification is noted by the microbiology laboratory staff. Notably, this protocol of phone notification is only performed when identifying the pathogen and not for the subsequent sensitivity profile. The second component occurs each morning when the on-call infectious disease attending physician reviews all positive blood culture results and the current therapy. If the infectious disease attending physician feels some alterations in management are warranted, the physician calls the primary service. Additionally, the primary service may always request a formal consult with the infectious disease team. This quality improvement study was initiated to examine the success of this deescalation/stewardship program to determine whether positive blood culture results influenced clinical management.

Methods

From July 1, 2015 to June 30, 2016, 212 positive blood cultures at the MVAMC were analyzed. Four cases that did not have an antibiotic spectrum score were excluded, leaving 208 cases reviewed. Duplicate blood cultures were excluded from analysis. The microbiology laboratory used the BD Bactec automated blood culture system using the Plus aerobic and Lytic anaerobic media (Becton, Dickinson and Company).

Antibiotic alterations in response to culture results were classified as either deescalation or escalation, using a spectrum score developed by Madaras-Kelly and colleagues.³³ These investigators performed a 3-round modified Delphi survey of infectious disease staff of physicians and pharmacists. The resulting consensus spectrum score for each respective antibiotic reflected the relative susceptibilities of various pathogens to antibiotics and the intrinsic resistance of the pathogens. It is a nonlinear scale from 0 to 60 with a score of 0 indicating no antibacterial activity and a score of 60 indicating complete coverage of all critically identified pathogens. For example, a narrow-spectrum antibiotic such as metronidazole received a spectrum score of 4.0 and a broad-spectrum antibiotic such as piperacillin/tazobactam received a 42.3 score.

Data Recording and Analysis

Charts for review were flagged based on positive blood culture results from the microbiology laboratory. EHRs were manually reviewed to determine when antibiotics were started/stopped and when a member of the primary care team, usually a resident, was notified of culture results as documented by the microbiology laboratory personnel. Any alteration in antibiotics that fit the criteria of deescalation or escalation that occurred within 24 hours of notification of either critical laboratory value was recorded. The identity of infectious pathogens and the primary site of infection were not recorded as these data were not within the scope of the purpose of this study. We did not control for possible contaminants within positive blood cultures.

There were 3 time frames considered when determining culture driven alterations to the antibiotic regimen. The first 2 were changes within the 24 hours after notification of either (1) pathogen identification or (2) pathogen sensitivity. These were defined as culture-driven alterations in response to those particular laboratory findings. The third—whole case time frame—spanned from pathogen identification to 24 hours after sensitivity information was recorded. In cases where ≥ 1 antibiotic alteration was noted within a respective time frame, a classification of deescalation or escalation was still assigned. This was done by summing each change in spectrum score that occurred from antibiotic regimen alterations within the time frame, and classifying the net effect on the spectrum of coverage as either deescalation or escalation. Data were recorded in spreadsheet. RStudio 3.5.3 was used for statistical analysis.

Results

Of 208 cases assigned a spectrum score, 47 (22.6%) had the breadth of antibiotic coverage deescalated by the primary care team within 24 hours of pathogen identification with a mean (SD) physician response time of 8.0 (7.3) hours. Fourteen cases (6.7%) had the breadth of antibiotic coverage escalated from pathogen identification with a mean (SD) response time of 8.0 (7.4) hours. When taken together, within 24 hours of pathogen identification from positive blood cultures 61 cases (29.3%) had altered antibiotics, leaving 70.7% of cases unaltered (Tables 1 and 2). In this nonquantitative spectrum score method, deescalations typically involved larger changes in spectrum score than escalations.

Physician notification of pathogen sensitivities resulted in deescalation in 69 cases (33.2%) within 24 hours, with a mean (SD) response time of 10.4 (7) hours. The mean time to deescalation in response to pathogen identification was significantly shorter than the mean time to deescalation in response to sensitivities (P = .049). Broadening of coverage based on sensitivity information was reported for 17 cases (8.2%) within 24 hours, with a mean (SD) response time of 7.6 (6) hours (Table 3). In response to pathogen sensitivity results from positive blood cultures, 58.6% of cases had no antibiotic alterations. Deescalations involved notably larger changes in spectrum score than escalations.

More than half (58.6%) of cases resulted in an antibiotic alteration from empiric treatment when considering the time frame from empiric antibiotics to 24 hours after receiving sensitivity information. These were deemed the whole-case, culture-driven results. In addition to antibiotic alterations that occurred within 24 hours of either pathogen identification or sensitivity information, the whole-case category also considered antibiotic alterations that occurred more than 24 hours after pathogen identification was known and before sensitivity information was available, although this was rare. Some of these patients may have had their antibiotics altered twice, first after pathogen identification and later once sensitivities became available with the net effect recorded as the whole-case administration. Of those that had their antibiotics modified in response to laboratory results, by a ratio of 6.4:1, the change was a deescalation rather than an escalation.

Discussion

The strategy of the infectious disease team at MVAMC is one of deescalation. One challenge of quantifying deescalation was to make a reliable and agreed-upon definition of just what deescalation entails. In 2003, the pharmaceutical company Merck was granted a trademark for the phrase “De-Escalation Therapy” under the international class code 41 for educational and entertainment services. This seemed to correspond to marketing efforts for the antibiotic imipenem/cilastatin. Although the company trademarked the term, it was never defined. The usage of the phrase evolved from a reduction of the dosage of a specific antibiotic to a reduction in the number of antibiotics prescribed to that of monotherapy. The phrase continues to evolve and has now become associated with a change from combination therapy or broad-spectrum antibiotics to monotherapy, switching to an antibiotic that covers fewer pathogens, or even shortening the duration of antibiotic therapy.³⁴ The trademark expired at about the same time the imipenem/cilastatin patent expired. Notably, this drug had initially been marketed for use in empiric antibiotic therapy.³⁵

Barriers

The goal of the stewardship program was not to see a narrowing of the antibiotic spectrum in all patients. Some diseases such as diverticulitis or diabetic foot infections are usually associated with multiple pathogens where relatively broad-spectrum antibiotics seem to be preferred.^36,37 Heenen and colleagues reported that infectious disease specialists recommended deescalation in < 50% of cases they examined.³⁸

Comparing different institutions’ deescalation rates can be confusing due to varying definitions, differing patient populations, and health care provider behavior. Thus, the published rates of deescalation range widely from 10 to 70%.^2,39,40 In addition to the varied definitions of deescalation, it is challenging to directly compare the rate of deescalation between studies due to institutional variation in empirical broad-spectrum antibiotic usage. A hospital that uses broad-spectrum antibiotics at a higher rate than another has the potential to deescalate more often than one that has low rates of empirical broad-spectrum antibiotic use. Some studies use a conservative definition of deescalation such as narrowing the spectrum of coverage, while others use a more general definition, including both the narrowing of spectrum and/or the discontinuation of antibiotics from empirical therapy.^41-45 The more specific and validated definition of deescalation used in this study may allow for standardized comparisons. Another unique feature of this study is that all positive blood cultures were followed, not only those of a particular disease.

Clinical Response

This quality improvement study was initiated to determine whether positive blood culture results actually affect clinical management at MVAMC. The answer seems to be yes, with blood culture results altering antibiotic administration in about 60% of cases with the predominant change being deescalation. This overall rate of deescalation is toward the higher end of previously documented rates and coincides with the upper bound of the clinically advised deescalation rate described by Heenen and colleagues.³⁸

As noted, the spectrum score is not quantitative. Still, one may be able to contend that the values may provide some insight into the magnitude of the changes in antibiotic selection. Deescalations were on average much larger changes in spectrum than escalations. The larger magnitude of deescalations reflects that when already starting with a very broad spectrum of coverage, it is much easier to get narrower than even broader. Stated another way, when starting therapy using piperacillin/tazobactam at a spectrum score of 42.3 on a 60-point scale, there is much more room for deescalation to 0 than escalation to 60. Additionally, escalations were more likely with much smaller of a spectrum change due to accurate empirical judgment of the suspected pathogens with new findings only necessitating a minor expansion of the spectrum of coverage.

Future Study

Similar studies designed using the spectrum score methodology would allow for more meaningful interinstitutional comparison of antibiotic administration through the use of a unified definition of deescalation and escalation. Comparison of deescalation and escalation rates between hospital systems with similar patient populations with and without prompt infectious disease review and phone notification of blood culture results could further verify the value of such a protocol. It could also help determine which empiric antibiotics may be most effective in individual patient morbidity and mortality outcomes, length of stay, costs, and the development of antibiotic resistance. Chou and colleagues found that only 49 of 130 responding VA facilities had antimicrobial stewardship teams in place with even fewer (29) having a formal policy to establish an antimicrobial stewardship program.¹¹ This significant variation in the practices of VA facilities across the nation underscores the benefit to be gained from implementation of value-added protocols such as daily infectious disease case monitoring and microbiology laboratory phone notification of positive blood culture results as it occurs at MVAMC.

They also noted that systems of patient-level antibiotic review, and the presence of at least one full-time infectious disease physician were both associated with a statistically significant decrease in the use of antimicrobials, corroborating the results of this analysis.¹¹ Adapting the current system of infectious disease specialist review of positive blood culture results to use remote monitoring through the EHR could help to defer some of the cost of needing an in-house specialist while retaining the benefit of the oversite.

Another option for study would be a before and after design to determine whether the program of infectious disease specialist review led to increased use of deescalation strategies similar to studies investigating the efficacy of antimicrobial subcommittee implementation.^{13,20,23,24,26}

Conclusions

This analysis of empiric antibiotic use at the MVAMC indicates promising rates of deescalation. The results indicate that the medical service may be right and that positive blood culture results appear to affect clinical decision making in an appropriate and timely fashion. The VA is the largest health care organization in the US. Thus, identifying and propagating effective stewardship practices on a widespread basis can have a significant effect on the public health of the nation.

These data suggest that the program implemented at the MVAMC of phone notification to the primary care team along with daily infectious disease staff monitoring of blood culture information should be widely adopted at sister institutions using either in-house or remote specialist review.

A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.

The number of new COVID-19 cases in children fell from 64,264 (Feb. 19-25) to 63,562 (Feb. 26 to March 4). That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.

Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.

The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.

Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.

rfranki@mdedge.com

A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.

The number of new COVID-19 cases in children fell from 64,264 (Feb. 19-25) to 63,562 (Feb. 26 to March 4). That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.

Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.

The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.

Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.

rfranki@mdedge.com

A third COVID-19 vaccine is now in circulation and states are starting to drop mask mandates, but the latest decline in weekly child cases barely registers as a decline, according to new data from the American Academy of Pediatrics and the Children’s Hospital Association.

The number of new COVID-19 cases in children fell from 64,264 (Feb. 19-25) to 63,562 (Feb. 26 to March 4). That’s only 702 cases – a drop of just 1.1% – the smallest by far since weekly cases peaked in mid-January, the AAP and CHA said in their weekly COVID-19 report. Since that peak, the last 7 weeks of declines have looked like this: 21.7%, 15.3%, 16.2%, 15.7%, 28.7%, 9.0%, and 1.1%.

Meanwhile, children’s share of the COVID-19 burden increased to its highest point ever: 18.0% of all new cases occurred in children during the week ending March 4, climbing from 15.7% the week before and eclipsing the previous high of 16.9%. Cumulatively, the 3.23 million cases in children represent 13.2% of all COVID-19 cases reported in 49 states (excluding New York), the District of Columbia, New York City, Puerto Rico, and Guam.

At the state level, the new leader in cumulative share of cases is Vermont at 19.4%, which just edged past Wyoming’s 19.3% as of the week ending March 4. The other states above 18% are Alaska (19.2%) and South Carolina (18.2%). The lowest rates can be found in Florida (8.1%), New Jersey (10.2%), Iowa (10.4%), and Utah (10.5%), the AAP and CHA said.

The overall rate of COVID-19 cases nationwide was 4,294 cases per 100,000 children as of March 4, up from 4,209 per 100,000 the week before. That measure had doubled between Dec. 3 (1,941 per 100,000) and Feb. 4 (3,899) but has only risen about 10% in the last month, the AAP/CHA data show.

Perhaps the most surprising news of the week involves the number of COVID-19 deaths in children, which went from 256 the previous week to 253 after Ohio made a downward revision of its mortality data. So far, children represent just 0.06% of all coronavirus-related deaths, a figure that has held steady since last summer in the 43 states (along with New York City and Guam) that are reporting mortality data by age, the AAP and CHA said.

rfranki@mdedge.com

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.

“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.

Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
 

TB and CLHIV

Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.

Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
 

Pediatric TB diagnosis

Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.

However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.

In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.

“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
 

Pediatric TB treatment

Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.

Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.

In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.

Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.

“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.

Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.

Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.

Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.

“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.

Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.

“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.

He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
 

Current TB preventive therapies

Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.

While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
 

LAI drugs

LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.

The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.

Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.

“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.

Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.

Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.

Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
 

Considerations for development and implementation

“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.

Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.

Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.

“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).

“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.

“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.

While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.

Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

A version of this article first appeared on Medscape.com.

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

A version of this article first appeared on Medscape.com.

A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.

That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.

“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”

Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”

Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.

“That’s a phase 3 objective we’ll need to prove,” she said in an interview.

Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.

In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.

In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.

Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.

Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.

“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.

Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.

By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.

Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.

In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.

“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”

Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.

The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.

“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”

A version of this article first appeared on Medscape.com.

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

There has been a rise in the prevalence of perniolike lesions—erythematous to violaceous, edematous papules or nodules on the fingers or toes—during the coronavirus disease 2019 (COVID-19) pandemic. These lesions are referred to as “COVID toes.” Although several studies have suggested an association with these lesions and COVID-19, and coronavirus particles have been identified in endothelial cells of biopsies of pernio lesions, questions remain on the management, pathophysiology, and implications of these lesions.¹ We provide a practical review for primary care clinicians and dermatologists on the current management, recommendations, and remaining questions, with particular attention to the distinctions for children vs adults presenting with pernio lesions.

Hypothetical Case of a Child Presenting With Acral Lesions

A 7-year-old boy presents with acute-onset, violaceous, mildly painful and pruritic macules on the distal toes that began 3 days earlier and have progressed to involve more toes and appear more purpuric. A review of symptoms reveals no fever, cough, fatigue, or viral symptoms. He has been staying at home for the last few weeks with his brother, mother, and father. His father is working in delivery services and is social distancing at work but not at home. His mother is concerned about the lesions, if they could be COVID toes, and if testing is needed for the patient or family. In your assessment and management of this patient, you consider the following questions.

What Is the Relationship Between These Clinical Findings and COVID-19?
Despite negative polymerase chain reaction (PCR) tests reported in cases of chilblains during the COVID-19 pandemic as well as the possibility that these lesions are an indirect result of environmental factors or behavioral changes during quarantine, the majority of studies favor an association between these chilblains lesions and COVID-19 infection.^2,3 Most compellingly, COVID-19 viral particles have been identified by immunohistochemistry and electron microscopy in the endothelial cells of biopsies of these lesions.¹ Additionally, there is evidence for possible associations of other viruses, including Epstein-Barr virus and parvovirus B19, with chilblains lesions.^4,5 In sum, with the lack of any large prospective study, the weight of current evidence suggests that these perniolike skin lesions are not specific markers of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).⁶

Published studies differ in reporting the coincidence of perniolike lesions with typical COVID-19 symptoms, including fever, dyspnea, cough, fatigue, myalgia, headache, and anosmia, among others. Some studies have reported that up to 63% of patients with reported perniolike lesions developed typical COVID-19 symptoms, but other studies found that no patients with these lesions developed symptoms.^6-11 Studies with younger cohorts tended to report lower prevalence of COVID-19 symptoms, and within cohorts, younger patients tended to have less severe symptoms. For example, 78.8% of patients in a cohort (n=58) with an average age of 14 years did not experience COVID-19–related symptoms.⁶ Based on these data, it has been hypothesized that patients with chilblainslike lesions may represent a subpopulation who will have a robust interferon response that is protective from more symptomatic and severe COVID-19.^12-14

Current evidence suggests that these lesions are most likely to occur between 9 days and 2 months after the onset of COVID-19 symptoms.^4,9,10 Most cases have been only mildly symptomatic, with an overall favorable prognosis of both lesions and any viral symptoms.^8,10 The lesions typically resolve without treatment within a few days of initial onset.^15,16

What Should Be the Workup and Management of These Lesions?
Given the currently available information and favorable prognosis, usually no further workup specific to the perniolike lesions is required in the case of an asymptomatic child presenting with acral lesions, and the majority of management will center around patient and parent/guardian education and reassurance. When asked by the patient’s parent, “What does it mean that my child has these lesions?”, clinicians can provide information on the possible association with COVID-19 and the excellent, self-resolving prognosis. An example of honest and reasonable phrasing with current understanding might be, “We are currently not certain if COVID-19 causes these lesions, although there are data to suggest that they are associated. There are a lot of data showing that children with these lesions either do not have any symptoms or have very mild symptoms that resolve without treatment.”

For management, important considerations include how painful the lesions are to the individual patient and how they affect quality of life. If less severe, clinicians can reassure patients and parents/guardians that the lesions will likely self-resolve without treatment. If worsening or symptomatic, clinicians can try typical treatments for chilblains, such as topical steroids, whole-body warming, and nifedipine.^17-19 Obtaining a review of symptoms, including COVID-19 symptoms and general viral symptoms, is important given the rare cases of children with severe COVID-19.^20,21

The question of COVID-19 testing as related to these lesions remains controversial, and currently there are still differing perspectives on the need for biopsy, PCR for COVID-19, or serologies for COVID-19 in patients presenting with these lesions. Some experts report that additional testing is not needed in the pediatric population because of the high frequency of negative testing reported to date.^22,23 However, these children may be silent carriers, and until more is known about their potential to transmit the virus, testing may be considered if resources allow, particularly if the patient has a known exposure.^10,12,16,24 The ultimate decision to pursue biopsy or serologic workup for COVID-19 remains up to clinical discretion with consideration of symptoms, severity, and immunocompromised household contacts. If lesions developed after infection, PCR likely will result negative, whereas serologic testing may reveal antibodies.

Hypothetical Case of an Adult Presenting With Acral Lesions and COVID-19 Symptoms

A 50-year-old man presents with acute-onset, violaceous, painful, edematous plaques on the distal toes that began 3 days earlier and have progressed to include the soles. A review of symptoms reveals fever (temperature, 38.4 °C [101 °F]), cough, dyspnea, diarrhea, and severe asthenia. He has had interactions with a coworker who recently tested positive for COVID-19.

How Should You Consider These Lesions in the Context of the Other Symptoms Concerning for COVID-19?
In contrast to the asymptomatic child above, this adult has chilblainslike lesions and viral symptoms. In adults, chilblainslike lesions have been associated with relatively mild COVID-19, and patients with these lesions who are otherwise asymptomatic have largely tested negative for COVID-19 by PCR and serologic antibody testing.^11,25,26

True acral ischemia, which is more severe and should be differentiated from chilblains, has been reported in critically ill patients.⁹ Additionally, studies have found that retiform purpura is the most common cutaneous finding in patients with severe COVID-19.²⁷ For this patient, who has an examination consistent with progressive and severe chilblainslike lesions and suspicion for COVID-19 infection, it is important to observe and monitor these lesions, as clinical progression suggestive of acral ischemia or retiform purpura should be taken seriously and may indicate worsening of the underlying disease. Early intervention with anticoagulation might be considered, though there currently is no evidence of successful treatment.²⁸

What Causes These Lesions in a Patient With COVID-19?
The underlying pathophysiology has been proposed to be a monocytic-macrophage–induced hyperinflammatory systemic state that damages the lungs, as well as the gastrointestinal, renal, and endothelial systems. The activation of the innate immune system triggers a cytokine storm that creates a hypercoagulable state that ultimately can manifest as superficial thromboses, leading to gangrene of the extremities. Additionally, interferon response and resulting hypercytokinemia may cause direct cytopathic damage to the endothelium of arterioles and capillaries, causing the development of papulovesicular lesions that resemble the chilblainslike lesions observed in children.²⁹ In contrast to children, who typically have no or mild COVID-19 symptoms, adults may have a delayed interferon response, which has been proposed to allow for more severe manifestations of infection.^12,30

How Should an Adult With Perniolike Lesions Be Managed?
Adults with chilblainslike lesions and no other signs or symptoms of COVID-19 infection do not necessarily need be tested for COVID-19, given the reports demonstrating most patients in this clinical situation will have negative PCRs and serologies for antibodies. However, there have been several reports of adults with acro-ischemic skin findings who also had severe COVID-19, with an observed incidence of 23% in intensive care unit patients with COVID-19.^27,28,31,32 If there is suspicion of infection with COVID-19, it is advisable to first obtain workup for COVID-19 and other viruses that can cause acral lesions, including Epstein-Barr virus and parvovirus. Other pertinent laboratory tests may include D-dimer, fibrinogen, prothrombin time, activated partial thromboplastin time, antithrombin activity, platelet count, neutrophil count, procalcitonin, triglycerides, ferritin, C-reactive protein, and hemoglobin. For patients with evidence of worsening acro-ischemia, regular monitoring of these values up to several times per week can allow for initiation of vascular intervention, including angiontensin-converting enzyme inhibitors, statins, or antiplatelet drugs.³² The presence of antiphospholipid antibodies also has been associated with critically ill patients who develop digit ischemia as part of the sequelae of COVID-19 infection and therefore may act as an important marker for the potential to develop disseminated intravascular coagulation in this patient.³³ Even if COVID-19 infection is not suspected, a thorough review of systems is important to look for an underlying connective tissue disease, such as systemic lupus erythematosus, which is associated with pernio. Associated symptoms may warrant workup with antinuclear antibodies and other appropriate autoimmune serologies.

If there is any doubt of the diagnosis, the patient is experiencing symptoms from the lesion, or the patient is experiencing other viral symptoms, it is appropriate to biopsy immediately to confirm the diagnosis. Prior studies have identified fibrin clots, angiocentric and eccrinotropic lymphocytic infiltrates, lymphocytic vasculopathy, and papillary dermal edema as the most common features in chilblainslike lesions during the COVID-19 pandemic.⁹

For COVID-19 testing, many studies have revealed adult patients with an acute hypercoagulable state testing positive by SARS-CoV-2 PCR. These same patients also experienced thromboembolic events shortly after testing positive for COVID-19, which suggests that patients with elevated D-dimer and fibrinogen likely will have a viral load that is sufficient to test positive for COVID-19.^32,34-36 It is appropriate to test all patients with suspected COVID-19, especially adults who are more likely to experience adverse complications secondary to infection.

This patient experiencing COVID-19 symptoms with signs of acral ischemia is likely to test positive by PCR, and additional testing for serologic antibodies is unlikely to be clinically meaningful in this patient’s state. Furthermore, there is little evidence that serology is reliable because of the markedly high levels of both false-negative and false-positive results when using the available antibody testing kits.³⁷ The latter evidence makes serology testing of little value for the general population, but particularly for patients with acute COVID-19.

Conclusion and Outstanding Questions

There is evidence suggesting an association between chilblainslike lesions and COVID-19.^11,22,38,39 Children presenting with these lesions have an excellent prognosis and only need a workup or treatment if there are other symptoms, as the lesions self-resolve in the majority of reported cases.^7-9 Adults presenting with these lesions and without symptoms likewise are unlikely to test positive for COVID-19, and the lesions typically resolve spontaneously or with first-line treatment. However, adults presenting with these lesions and COVID-19 symptoms should raise clinical concern for evolving skin manifestations of acro-ischemia. If the diagnosis is uncertain or systemic symptoms are concerning, biopsy, COVID-19 PCR, and other appropriate laboratory workup should be obtained.

There remains controversy and uncertainty over the relationship between these skin findings and SARS-CoV-2 infection, with clinical evidence to support both a direct relationship representing convalescent-phase cutaneous reaction as well as an indirect epiphenomenon. If there was a direct relationship, we would have expected to see a rise in the incidence of acral lesions proportionate to the rising caseload of COVID-19 after the reopening of many states in the summer of 2020. Similarly, because young adults represent the largest demographic of increasing cases and as some schools have remained open for in-person instruction during the current academic year, we also would have expected the incidence of chilblains-like lesions presenting to dermatologists and pediatricians to increase alongside these cases. Continued evaluation of emerging literature and ongoing efforts to understand the cause of this observed phenomenon will hopefully help us arrive at a future understanding of the pathophysiology of this puzzling skin manifestation.⁴⁰

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

A version of this article first appeared on Medscape.com.

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

A version of this article first appeared on Medscape.com.

On the advice of its independent data monitoring committee (DMC), the RECOVERY trial has stopped recruitment to the colchicine arm for lack of efficacy in patients hospitalized with COVID-19.

“The DMC saw no convincing evidence that further recruitment would provide conclusive proof of worthwhile mortality benefit either overall or in any prespecified subgroup,” the British investigators announced on March 5.

“The RECOVERY trial has already identified two anti-inflammatory drugs – dexamethasone and tocilizumab – that improve the chances of survival for patients with severe COVID-19. So, it is disappointing that colchicine, which is widely used to treat gout and other inflammatory conditions, has no effect in these patients,” cochief investigator Martin Landray, MBChB, PhD, said in a statement.

“We do large, randomized trials to establish whether a drug that seems promising in theory has real benefits for patients in practice. Unfortunately, colchicine is not one of those,” said Dr. Landry, University of Oxford (England).

The RECOVERY trial is evaluating a range of potential treatments for COVID-19 at 180 hospitals in the United Kingdom, Indonesia, and Nepal, and was designed with the expectation that drugs would be added or dropped as the evidence changes. Since November 2020, the trial has included an arm comparing colchicine with usual care alone.

As part of a routine meeting March 4, the DMC reviewed data from a preliminary analysis based on 2,178 deaths among 11,162 patients, 94% of whom were being treated with a corticosteroid such as dexamethasone.

The results showed no significant difference in the primary endpoint of 28-day mortality in patients randomized to colchicine versus usual care alone (20% vs. 19%; risk ratio, 1.02; 95% confidence interval, 0.94-1.11; P = .63).

Follow-up is ongoing and final results will be published as soon as possible, the investigators said. Thus far, there has been no convincing evidence of an effect of colchicine on clinical outcomes in hospitalized COVID-19 patients.

Recruitment will continue to all other treatment arms – aspirin, baricitinib, Regeneron’s antibody cocktail, and, in select hospitals, dimethyl fumarate – the investigators said.

Cochief investigator Peter Hornby, MD, PhD, also from the University of Oxford, noted that this has been the largest trial ever of colchicine. “Whilst we are disappointed that the overall result is negative, it is still important information for the future care of patients in the U.K. and worldwide.”

A version of this article first appeared on Medscape.com.

The discovery of any novel disease or condition means a steep learning curve as physicians must develop protocols for diagnosis, management, and follow-up on the fly in the midst of admitting and treating patients. Medical society task forces and committees often release interim guidance during the learning process, but each institution ultimately has to determine what works for them based on their resources, clinical experience, and patient population.

Geber86/Getty Images

But when the novel condition demands the involvement of multiple different specialties, the challenge of management grows even more complex – as does follow-up after patients are discharged. Such has been the story with multisystem inflammatory syndrome in children (MIS-C), a complication of COVID-19 that shares some features with Kawasaki disease.

The similarities to Kawasaki provided physicians a place to start in developing appropriate treatment regimens and involved a similar interdisciplinary team from, at the least, cardiology and rheumatology, plus infectious disease since MIS-C results from COVID-19.

“It literally has it in the name – multisystem essentially hints that there are multiple specialties involved, multiple hands in the pot trying to manage the kids, and so each specialty has their own kind of unique role in the patient’s care even on the outpatient side,” said Samina S. Bhumbra, MD, an infectious disease pediatrician at Riley Hospital for Children and assistant professor of clinical pediatrics at Indiana University in Indianapolis. “This isn’t a disease that falls under one specialty.”

Determining a follow-up regimen

Even before determining how to coordinate appointments, hospitals had to decide what follow-up itself should be.

“How long do we follow these patients and how often do we follow them?” said Melissa S. Oliver, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University.

“We’re seeing that a lot of our patients rapidly respond when they get appropriate therapy, but we don’t know about long-term outcomes yet. We’re all still learning.”

At Children’s Hospital of Philadelphia, infectious disease follows up 4-6 weeks post discharge. The cardiology division came up with a follow-up plan that has evolved over time, said Matthew Elias, MD, an attending cardiologist at CHOP’s Cardiac Center and clinical assistant professor of pediatrics at the University of Pennsylvania, Philadelphia.

The dedicated clinic model

The two challenges Riley needed to address were the lack of a clear consensus on what MIS-C follow-up should look like and the need for continuity of care, Dr. Serrano said.

Regular discussion in departmental meetings at Riley “progressed from how do we take care of them and what treatments do we give them to how do we follow them and manage them in outpatient,” Dr. Oliver said. In the inpatient setting, they had an interdisciplinary team, but how could they maintain that for outpatients without overwhelming the families?

“I think the main challenge is for the families to identify who is leading the care for them,” said Martha M. Rodriguez, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University. That sometimes led to families picking which follow-up appointments they would attend and which they would skip if they could not make them all – and sometimes they skipped the more important ones. “They would go to the appointment with me and then miss the cardiology appointments and the echocardiogram, which was more important to follow any abnormalities in the heart,” Dr. Rodriguez said.

After trying to coordinate separate follow-up appointments for months, Riley ultimately decided to form a dedicated clinic for MIS-C follow-up – a “one-stop shop” single appointment at each follow-up, Dr. Bhumbra said, that covers labs, EKG, echocardiogram, and any other necessary tests.

“Our goal with the clinic is to make life easier for the families and to be able to coordinate the appointments,” Dr. Rodriguez said. “They will be able to see the three of us, and it would be easier for us to communicate with each other about their plan.”

The clinic began Feb. 11 and occurs twice a month. Though it’s just begun, Dr. Oliver said the first clinic went well, and it’s helping them figure out the role each specialty needs to play in follow-up care.

“For us with rheumatology, after lab values have returned to normal and they’re off steroids, sometimes we think there isn’t much more we can contribute to,” she said. And then there are the patients who didn’t see any rheumatologists while inpatients.

“That’s what we’re trying to figure out as well,” Dr. Oliver said. “Should we be seeing every single kid regardless of whether we were involved in their inpatient [stay] or only seeing the ones we’ve seen?” She expects the coming months will help them work that out.

Texas Children’s Hospital in Houston also uses a dedicated clinic, but they set it up before the first MIS-C patient came through the doors, said Sara Kristen Sexson Tejtel, MD, a pediatric cardiologist at Texas Children’s. The hospital already has other types of multidisciplinary clinics, and they anticipated the challenge of getting families to come to too many appointments in a short period of time.

Separate but coordinated appointments

A dedicated clinic isn’t the answer for all institutions, however. At Children’s Hospital of Philadelphia, the size of the networks and all its satellites made a one-stop shop impractical.

“We talked about a consolidated clinic early on, when MIS-C was first emerging and all our groups were collaborating and coming up with our inpatient and outpatient care pathways,” said Sanjeev K. Swami, MD, an infectious disease pediatrician at CHOP and associate professor of clinical pediatrics at the University of Pennsylvania. But timing varies on when each specialist wants to see the families return, and existing clinic schedules and locations varied too much.

Looking ahead

The biggest question that still looms is what happens to these children, if anything, down the line.

“What was unique about this was this was a new disease we were all learning about together with no baseline,” Dr. Swami said. “None of us had ever seen this condition before.”

So far, the prognosis for the vast majority of children is good. “Most of these kids survive, most of them are doing well, and they almost all recover,” Dr. Serrano said. Labs tend to normalize by 6 weeks post discharge, if not much earlier, and not much cardiac involvement is showing up at later follow-ups. But not even a year has passed, so there’s plenty to learn. “We don’t know if there’s long-term risk. I would not be surprised if 20 years down the road we’re finding out things about this that we had no idea” about, Dr. Serrano said. “Everybody wants answers, and nobody has any, and the answers we have may end up being wrong. That’s how it goes when you’re dealing with something you’ve never seen.”

Research underway will ideally begin providing those answers soon. CHOP is a participating site in an NIH-NHLBI–sponsored study, called COVID MUSIC, that is tracking long-term outcomes for MIS-C at 30 centers across the United States and Canada for 5 years.

“That will really definitely be helpful in answering some of the questions about long-term outcomes,” Dr. Elias said. “We hope this is going to be a transient issue and that patients won’t have any long-term manifestations, but we don’t know that yet.”

Meanwhile, one benefit that has come out of the pandemic is strong collaboration, Dr. Bhumbra said.

“The biggest thing we’re all eagerly waiting and hoping for is standard guidelines on how best to follow-up on these kids, but I know that’s a ways away,” Dr. Bhumbra said. So for now, each institution is doing what it can to develop protocols that they feel best serve the patients’ needs, such as Riley’s new dedicated MIS-C clinic. “It takes a village to take care of these kids, and MIS-C has proven that having a clinic with all three specialties at one clinic is going to be great for the families.”

Dr. Fox serves on a committee for Pfizer unrelated to MIS-C. No other doctors interviewed for this story had relevant conflicts of interest to disclose.

The discovery of any novel disease or condition means a steep learning curve as physicians must develop protocols for diagnosis, management, and follow-up on the fly in the midst of admitting and treating patients. Medical society task forces and committees often release interim guidance during the learning process, but each institution ultimately has to determine what works for them based on their resources, clinical experience, and patient population.

Geber86/Getty Images

But when the novel condition demands the involvement of multiple different specialties, the challenge of management grows even more complex – as does follow-up after patients are discharged. Such has been the story with multisystem inflammatory syndrome in children (MIS-C), a complication of COVID-19 that shares some features with Kawasaki disease.

The similarities to Kawasaki provided physicians a place to start in developing appropriate treatment regimens and involved a similar interdisciplinary team from, at the least, cardiology and rheumatology, plus infectious disease since MIS-C results from COVID-19.

“It literally has it in the name – multisystem essentially hints that there are multiple specialties involved, multiple hands in the pot trying to manage the kids, and so each specialty has their own kind of unique role in the patient’s care even on the outpatient side,” said Samina S. Bhumbra, MD, an infectious disease pediatrician at Riley Hospital for Children and assistant professor of clinical pediatrics at Indiana University in Indianapolis. “This isn’t a disease that falls under one specialty.”

Determining a follow-up regimen

Even before determining how to coordinate appointments, hospitals had to decide what follow-up itself should be.

“How long do we follow these patients and how often do we follow them?” said Melissa S. Oliver, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University.

“We’re seeing that a lot of our patients rapidly respond when they get appropriate therapy, but we don’t know about long-term outcomes yet. We’re all still learning.”

At Children’s Hospital of Philadelphia, infectious disease follows up 4-6 weeks post discharge. The cardiology division came up with a follow-up plan that has evolved over time, said Matthew Elias, MD, an attending cardiologist at CHOP’s Cardiac Center and clinical assistant professor of pediatrics at the University of Pennsylvania, Philadelphia.

The dedicated clinic model

The two challenges Riley needed to address were the lack of a clear consensus on what MIS-C follow-up should look like and the need for continuity of care, Dr. Serrano said.

Regular discussion in departmental meetings at Riley “progressed from how do we take care of them and what treatments do we give them to how do we follow them and manage them in outpatient,” Dr. Oliver said. In the inpatient setting, they had an interdisciplinary team, but how could they maintain that for outpatients without overwhelming the families?

“I think the main challenge is for the families to identify who is leading the care for them,” said Martha M. Rodriguez, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University. That sometimes led to families picking which follow-up appointments they would attend and which they would skip if they could not make them all – and sometimes they skipped the more important ones. “They would go to the appointment with me and then miss the cardiology appointments and the echocardiogram, which was more important to follow any abnormalities in the heart,” Dr. Rodriguez said.

After trying to coordinate separate follow-up appointments for months, Riley ultimately decided to form a dedicated clinic for MIS-C follow-up – a “one-stop shop” single appointment at each follow-up, Dr. Bhumbra said, that covers labs, EKG, echocardiogram, and any other necessary tests.

“Our goal with the clinic is to make life easier for the families and to be able to coordinate the appointments,” Dr. Rodriguez said. “They will be able to see the three of us, and it would be easier for us to communicate with each other about their plan.”

The clinic began Feb. 11 and occurs twice a month. Though it’s just begun, Dr. Oliver said the first clinic went well, and it’s helping them figure out the role each specialty needs to play in follow-up care.

“For us with rheumatology, after lab values have returned to normal and they’re off steroids, sometimes we think there isn’t much more we can contribute to,” she said. And then there are the patients who didn’t see any rheumatologists while inpatients.

“That’s what we’re trying to figure out as well,” Dr. Oliver said. “Should we be seeing every single kid regardless of whether we were involved in their inpatient [stay] or only seeing the ones we’ve seen?” She expects the coming months will help them work that out.

Texas Children’s Hospital in Houston also uses a dedicated clinic, but they set it up before the first MIS-C patient came through the doors, said Sara Kristen Sexson Tejtel, MD, a pediatric cardiologist at Texas Children’s. The hospital already has other types of multidisciplinary clinics, and they anticipated the challenge of getting families to come to too many appointments in a short period of time.

Separate but coordinated appointments

A dedicated clinic isn’t the answer for all institutions, however. At Children’s Hospital of Philadelphia, the size of the networks and all its satellites made a one-stop shop impractical.

“We talked about a consolidated clinic early on, when MIS-C was first emerging and all our groups were collaborating and coming up with our inpatient and outpatient care pathways,” said Sanjeev K. Swami, MD, an infectious disease pediatrician at CHOP and associate professor of clinical pediatrics at the University of Pennsylvania. But timing varies on when each specialist wants to see the families return, and existing clinic schedules and locations varied too much.

Looking ahead

The biggest question that still looms is what happens to these children, if anything, down the line.

“What was unique about this was this was a new disease we were all learning about together with no baseline,” Dr. Swami said. “None of us had ever seen this condition before.”

So far, the prognosis for the vast majority of children is good. “Most of these kids survive, most of them are doing well, and they almost all recover,” Dr. Serrano said. Labs tend to normalize by 6 weeks post discharge, if not much earlier, and not much cardiac involvement is showing up at later follow-ups. But not even a year has passed, so there’s plenty to learn. “We don’t know if there’s long-term risk. I would not be surprised if 20 years down the road we’re finding out things about this that we had no idea” about, Dr. Serrano said. “Everybody wants answers, and nobody has any, and the answers we have may end up being wrong. That’s how it goes when you’re dealing with something you’ve never seen.”

Research underway will ideally begin providing those answers soon. CHOP is a participating site in an NIH-NHLBI–sponsored study, called COVID MUSIC, that is tracking long-term outcomes for MIS-C at 30 centers across the United States and Canada for 5 years.

“That will really definitely be helpful in answering some of the questions about long-term outcomes,” Dr. Elias said. “We hope this is going to be a transient issue and that patients won’t have any long-term manifestations, but we don’t know that yet.”

Meanwhile, one benefit that has come out of the pandemic is strong collaboration, Dr. Bhumbra said.

“The biggest thing we’re all eagerly waiting and hoping for is standard guidelines on how best to follow-up on these kids, but I know that’s a ways away,” Dr. Bhumbra said. So for now, each institution is doing what it can to develop protocols that they feel best serve the patients’ needs, such as Riley’s new dedicated MIS-C clinic. “It takes a village to take care of these kids, and MIS-C has proven that having a clinic with all three specialties at one clinic is going to be great for the families.”

Dr. Fox serves on a committee for Pfizer unrelated to MIS-C. No other doctors interviewed for this story had relevant conflicts of interest to disclose.

The discovery of any novel disease or condition means a steep learning curve as physicians must develop protocols for diagnosis, management, and follow-up on the fly in the midst of admitting and treating patients. Medical society task forces and committees often release interim guidance during the learning process, but each institution ultimately has to determine what works for them based on their resources, clinical experience, and patient population.

Geber86/Getty Images

But when the novel condition demands the involvement of multiple different specialties, the challenge of management grows even more complex – as does follow-up after patients are discharged. Such has been the story with multisystem inflammatory syndrome in children (MIS-C), a complication of COVID-19 that shares some features with Kawasaki disease.

The similarities to Kawasaki provided physicians a place to start in developing appropriate treatment regimens and involved a similar interdisciplinary team from, at the least, cardiology and rheumatology, plus infectious disease since MIS-C results from COVID-19.

“It literally has it in the name – multisystem essentially hints that there are multiple specialties involved, multiple hands in the pot trying to manage the kids, and so each specialty has their own kind of unique role in the patient’s care even on the outpatient side,” said Samina S. Bhumbra, MD, an infectious disease pediatrician at Riley Hospital for Children and assistant professor of clinical pediatrics at Indiana University in Indianapolis. “This isn’t a disease that falls under one specialty.”

Determining a follow-up regimen

Even before determining how to coordinate appointments, hospitals had to decide what follow-up itself should be.

“How long do we follow these patients and how often do we follow them?” said Melissa S. Oliver, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University.

“We’re seeing that a lot of our patients rapidly respond when they get appropriate therapy, but we don’t know about long-term outcomes yet. We’re all still learning.”

At Children’s Hospital of Philadelphia, infectious disease follows up 4-6 weeks post discharge. The cardiology division came up with a follow-up plan that has evolved over time, said Matthew Elias, MD, an attending cardiologist at CHOP’s Cardiac Center and clinical assistant professor of pediatrics at the University of Pennsylvania, Philadelphia.

The dedicated clinic model

The two challenges Riley needed to address were the lack of a clear consensus on what MIS-C follow-up should look like and the need for continuity of care, Dr. Serrano said.

Regular discussion in departmental meetings at Riley “progressed from how do we take care of them and what treatments do we give them to how do we follow them and manage them in outpatient,” Dr. Oliver said. In the inpatient setting, they had an interdisciplinary team, but how could they maintain that for outpatients without overwhelming the families?

“I think the main challenge is for the families to identify who is leading the care for them,” said Martha M. Rodriguez, MD, a rheumatologist at Riley and assistant professor of clinical pediatrics at Indiana University. That sometimes led to families picking which follow-up appointments they would attend and which they would skip if they could not make them all – and sometimes they skipped the more important ones. “They would go to the appointment with me and then miss the cardiology appointments and the echocardiogram, which was more important to follow any abnormalities in the heart,” Dr. Rodriguez said.

After trying to coordinate separate follow-up appointments for months, Riley ultimately decided to form a dedicated clinic for MIS-C follow-up – a “one-stop shop” single appointment at each follow-up, Dr. Bhumbra said, that covers labs, EKG, echocardiogram, and any other necessary tests.

“Our goal with the clinic is to make life easier for the families and to be able to coordinate the appointments,” Dr. Rodriguez said. “They will be able to see the three of us, and it would be easier for us to communicate with each other about their plan.”

The clinic began Feb. 11 and occurs twice a month. Though it’s just begun, Dr. Oliver said the first clinic went well, and it’s helping them figure out the role each specialty needs to play in follow-up care.

“For us with rheumatology, after lab values have returned to normal and they’re off steroids, sometimes we think there isn’t much more we can contribute to,” she said. And then there are the patients who didn’t see any rheumatologists while inpatients.

“That’s what we’re trying to figure out as well,” Dr. Oliver said. “Should we be seeing every single kid regardless of whether we were involved in their inpatient [stay] or only seeing the ones we’ve seen?” She expects the coming months will help them work that out.

Texas Children’s Hospital in Houston also uses a dedicated clinic, but they set it up before the first MIS-C patient came through the doors, said Sara Kristen Sexson Tejtel, MD, a pediatric cardiologist at Texas Children’s. The hospital already has other types of multidisciplinary clinics, and they anticipated the challenge of getting families to come to too many appointments in a short period of time.

Separate but coordinated appointments

A dedicated clinic isn’t the answer for all institutions, however. At Children’s Hospital of Philadelphia, the size of the networks and all its satellites made a one-stop shop impractical.

“We talked about a consolidated clinic early on, when MIS-C was first emerging and all our groups were collaborating and coming up with our inpatient and outpatient care pathways,” said Sanjeev K. Swami, MD, an infectious disease pediatrician at CHOP and associate professor of clinical pediatrics at the University of Pennsylvania. But timing varies on when each specialist wants to see the families return, and existing clinic schedules and locations varied too much.

Looking ahead

The biggest question that still looms is what happens to these children, if anything, down the line.

“What was unique about this was this was a new disease we were all learning about together with no baseline,” Dr. Swami said. “None of us had ever seen this condition before.”

So far, the prognosis for the vast majority of children is good. “Most of these kids survive, most of them are doing well, and they almost all recover,” Dr. Serrano said. Labs tend to normalize by 6 weeks post discharge, if not much earlier, and not much cardiac involvement is showing up at later follow-ups. But not even a year has passed, so there’s plenty to learn. “We don’t know if there’s long-term risk. I would not be surprised if 20 years down the road we’re finding out things about this that we had no idea” about, Dr. Serrano said. “Everybody wants answers, and nobody has any, and the answers we have may end up being wrong. That’s how it goes when you’re dealing with something you’ve never seen.”

Research underway will ideally begin providing those answers soon. CHOP is a participating site in an NIH-NHLBI–sponsored study, called COVID MUSIC, that is tracking long-term outcomes for MIS-C at 30 centers across the United States and Canada for 5 years.

“That will really definitely be helpful in answering some of the questions about long-term outcomes,” Dr. Elias said. “We hope this is going to be a transient issue and that patients won’t have any long-term manifestations, but we don’t know that yet.”

Meanwhile, one benefit that has come out of the pandemic is strong collaboration, Dr. Bhumbra said.

“The biggest thing we’re all eagerly waiting and hoping for is standard guidelines on how best to follow-up on these kids, but I know that’s a ways away,” Dr. Bhumbra said. So for now, each institution is doing what it can to develop protocols that they feel best serve the patients’ needs, such as Riley’s new dedicated MIS-C clinic. “It takes a village to take care of these kids, and MIS-C has proven that having a clinic with all three specialties at one clinic is going to be great for the families.”

Dr. Fox serves on a committee for Pfizer unrelated to MIS-C. No other doctors interviewed for this story had relevant conflicts of interest to disclose.

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

 

 

Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

 

 

Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; mstephens3@pennstatehealth.psu.edu.

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

 

 

Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

 

 

Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; mstephens3@pennstatehealth.psu.edu.

Adolescents are an increasingly diverse population reflecting changes in the racial, ethnic, and geopolitical milieus of the United States. The World Health Organization classifies adolescence as ages 10 to 19 years.¹ However, given the complexity of adolescent development physically, behaviorally, emotionally, and socially, others propose that adolescence may extend to age 24.²

Recognizing the specific challenges adolescents face is key to providing comprehensive longitudinal health care. Moreover, creating an environment of trust helps to ensure open 2-way communication that can facilitate anticipatory guidance.

Our review focuses on common adolescent issues, including injury from vehicles and firearms, tobacco and substance misuse, obesity, behavioral health, sexual health, and social media use. We discuss current trends and recommend strategies to maximize health and wellness.

Start by framing the visit

Confidentiality

Laws governing confidentiality in adolescent health care vary by state. Be aware of the laws pertaining to your practice setting. In addition, health care facilities may have their own policies regarding consent and confidentiality in adolescent care. Discuss confidentiality with both an adolescent and the parent/guardian at the initial visit. And, to help avoid potential misunderstandings, let them know in advance what will (and will not) be divulged.

The American Academy of Pediatrics has developed a useful tip sheet regarding confidentiality laws (www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/healthy-foster-care-america/Documents/Confidentiality_Laws.pdf). Examples of required (conditional) disclosure include abuse and suicidal or homicidal ideations. Patients should understand that sexually transmitted infections (STIs) are reportable to public health authorities and that potentially injurious behaviors to self or others (eg, excessive drinking prior to driving) may also warrant disclosure(TABLE 1³).

Privacy and general visit structure

Create a safe atmosphere where adolescents can discuss personal issues without fear of repercussion or judgment. While parents may prefer to be present during the visit, allowing for time to visit independently with an adolescent offers the opportunity to reinforce issues of privacy and confidentiality. Also discuss your office policies regarding electronic communication, phone communication, and relaying test results.

A useful paradigm for organizing a visit for routine adolescent care is to use an expanded version of the HEADSS mnemonic (TABLE 2^4,5), which includes questions about an adolescent’s Home, Education, Activities, Drug and alcohol use, Sexual behavior, Suicidality and depression, and other topics. Other validated screening tools include RAAPS (Rapid Adolescent Prevention Screening)⁶ (www.possibilitiesforchange.com/raaps/); the Guidelines for Adolescent Preventive Services⁷; and the Bright Futures recommendations for preventive care from the American Academy of Pediatrics.⁸ Below, we consider important topics addressed with the HEADSS approach.

Continue to: Injury from vehicles and firearms

 

 

Injury from vehicles and firearms

Motor vehicle accidents and firearm wounds are the 2 leading causes of adolescent injury. In 2016, of the more than 20,000 deaths in children and adolescents (ages 1-19 years), 20% were due to motor vehicle accidents (4074) and 15% were a result of firearm-­related injuries (3143). Among firearm-­related deaths, 60% were homicides, 35% were suicides, and 4% were due to accidental discharge.⁹ The rate of firearm-related deaths among American teens is 36 times greater than that of any other developed nation.⁹ Currently, 1 of every 3 US households with children younger than 18 has a firearm. Data suggest that in 43% of these households, the firearm is loaded and kept in an unlocked location.¹⁰

To aid anticipatory guidance, ask adolescents about firearm and seat belt use, drinking and driving, and suicidal thoughts (TABLE 2^4,5). Advise them to always wear seat belts whether driving or riding as a passenger. They should never drink and drive (or get in a car with someone who has been drinking). Advise parents that if firearms are present in the household, they should be kept in a secure, locked location. Weapons should be separated from ammunition and safety mechanisms should be engaged on all devices.

Tobacco and substance misuse

Tobacco use, the leading preventable cause of death in the United States,¹¹ is responsible for more deaths than alcohol, motor vehicle accidents, suicides, homicides, and HIV disease combined.¹² Most tobacco-associated mortality occurs in individuals who began smoking before the age of 18.¹² Individuals who start smoking early are also more likely to continue smoking through adulthood.

Encouragingly, tobacco use has declined significantly among adolescents over the past several decades. Roughly 1 in 25 high school seniors reports daily tobacco use.¹³ Adolescent smoking behaviors are also changing dramatically with the increasing popularity of electronic cigarettes (“vaping”). Currently, more adolescents vape than smoke cigarettes.¹³ Vaping has additional health risks including toxic lung injury.

Multiple resources can help combat tobacco and nicotine use in adolescents. The US Preventive Services Task Force recommends that primary care clinicians intervene through education or brief counselling to prevent initiation of tobacco use in school-aged children and adolescents.¹⁴ Ask teens about tobacco and electronic cigarette use and encourage them to quit when use is acknowledged. Other helpful office-based tools are the “Quit Line” 800-QUIT-NOW and texting “Quit” to 47848. Smokefree teen (https://teen.smokefree.gov/) is a website that reviews the risks of tobacco and nicotine use and provides age-appropriate cessation tools and tips (including a smartphone app and a live-chat feature). Other useful information is available in a report from the Surgeon General on preventing tobacco use among young adults.¹⁵

Continue to: Alcohol use

Alcohol use. Three in 5 high school students report ever having used alcohol.¹³ As with tobacco, adolescent alcohol use has declined over the past decade. However, binge drinking (≥ 5 drinks on 1 occasion for males; ≥ 4 drinks on 1 occasion for females) remains a common high-risk behavior among adolescents (particularly college students). Based on the Monitoring the Future Survey, 1 in 6 high school seniors reported binge drinking in the past 2 weeks.¹³ While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.¹³

While historically more common among males, rates of binge drinking are now basically similar between male and female adolescents.

The National Institute on Alcohol Abuse and Alcoholism has a screening and intervention guide specifically for adolescents.¹⁶A 2-question screening tool asking about personal use of alcohol and use of alcohol by friends is followed by a risk assessment with recommendations to advise young patients not to drink and to assist them with appropriate intervention and follow-up (https://pubs.niaaa.nih.gov/publications/Practitioner/YouthGuide/YouthGuidePocket.pdf).

Illicit drug use. Half of adolescents report using an illicit drug by their senior year in high school.¹³ Marijuana is the most commonly used substance, and laws governing its use are rapidly changing across the United States. Marijuana is illegal in 10 states and legal in 10 states (and the District of Columbia). The remaining states have varying policies on the medical use of marijuana and the decriminalization of marijuana. In addition, cannabinoid (CBD) products are increasingly available. Frequent cannabis use in adolescence has an adverse impact on general executive function (compared with adult users) and learning.¹⁷ Marijuana may serve as a gateway drug in the abuse of other substances,¹⁸ and its use should be strongly discouraged in adolescents.

Of note, there has been a sharp rise in the illicit use of prescription drugs, particularly opioids, creating a public health emergency across the United States.¹⁹ In 2015, more than 4000 young people, ages 15 to 24, died from a drug-related overdose (> 50% of these attributable to opioids).²⁰ Adolescents with a history of substance abuse and behavioral illness are at particular risk. Many adolescents who misuse opioids and other prescription drugs obtain them from friends and relatives.²¹

The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends universal screening of adolescents for substance abuse. This screening should be accompanied by a brief intervention to prevent, mitigate, or eliminate substance use, or a referral to appropriate treatment sources. This process of screening, brief intervention, and referral to treatment (SBIRT) is recommended as part of routine health care.²²

Continue to: Obesity and physical activity

Obesity and physical activity

The percentage of overweight and obese adolescents in the United States has more than tripled over the past 40 years,²³ and 1 in 5 US adolescents is obese.²³ Obese teens are at higher risk for multiple chronic diseases, including type 2 diabetes, sleep apnea, and heart disease.²⁴ They are also more likely to be bullied and to have poor self-esteem.²⁵ Only 1 in 5 American high school students engages in 60 or more minutes of moderate-to-­vigorous physical activity on 5 or more days per week.²⁶

Regular physical activity is, of course, beneficial for cardiorespiratory fitness, bone health, weight control, and improved indices of behavioral health.²⁶ Adolescents who are physically active consistently demonstrate better school attendance and grades.¹⁷ Higher levels of physical fitness are also associated with improved overall cognitive performance.²⁴

General recommendations. The Department of Health and Human Services recommends that adolescents get at least 60 minutes of mostly moderate physical activity every day.²⁶ Encourage adolescents to engage in vigorous physical activity (heavy breathing, sweating) at least 3 days a week. As part of their physical activity patterns, adolescents should also engage in muscle-­strengthening and bone-strengthening activities on at least 3 days per week.

Behavioral health

As young people develop their sense of personal identity, they also strive for independence. It can be difficult, at times, to differentiate normal adolescent rebellion from true mental illness. An estimated 17% to 19% of adolescents meet criteria for mental illness, and about 7% have a severe psychiatric disorder.²⁷ Only one-third of adolescents with mental illness receive any mental health services.²⁸

Depression. The 1-year incidence of major depression in adolescents is 3% to 4%, and the lifetime prevalence of depressive symptoms is 25% in all high school students.²⁷ Risk factors include ethnic minority status, poor self-esteem, poor health, recent personal crisis, insomnia, and alcohol/­substance abuse. Depression in adolescent girls is correlated with becoming sexually active at a younger age, failure to use contraception, having an STI, and suicide attempts. Depressed boys are more likely to have unprotected intercourse and participate in physical fights.²⁹ Depressed teens have a 2- to 3-fold greater risk for behavioral disorders, anxiety, and attention-deficit/hyperactivity disorder (ADHD).³⁰

Continue to: Suicide

Suicide. Among individuals 15 to 29 years of age, suicide is the second leading cause of death globally, with an annual incidence of 11 to 15 per 100,000.³¹ Suicide attempts are 10 to 20 times more common than completed suicide.³¹ Males are more likely than females to die by suicide,³² and boys with a history of attempted suicide have a 30-fold increased risk of subsequent successful suicide.³¹ Hanging, drug poisoning, and firearms (particularly for males) are the most common means of suicide in adolescents. More than half of adolescents dying by suicide have coexisting depression.³¹

Adolescents prefer that providers address sexual health and are more likely to respond if asked directly about sexual behaviors.

Characteristics associated with suicidal behaviors in adolescents include impulsivity, poor problem-solving skills, and dichotomous thinking.³¹ There may be a genetic component as well. In 1 of 5 teenage suicides, a precipitating life event such as the break-up of a relationship, cyber-bullying, or peer rejection is felt to contribute.³¹

ADHD. The prevalence of ADHD is 7% to 9% in US school-aged children.³³ Boys more commonly exhibit hyperactive behaviors, while girls have more inattention. Hyperactivity often diminishes in teens, but inattention and impulsivity persist. Sequelae of ADHD include high-risk sexual behaviors, motor vehicle accidents, incarceration, and substance abuse.³⁴ Poor self-esteem, suicidal ideation, smoking, and obesity are also increased.³⁴ ADHD often persists into adulthood, with implications for social relationships and job performance.³⁴

Eating disorders. The distribution of eating disorders is now known to increasingly include more minorities and males, the latter representing 5% to 10% of cases.³⁵ Eating disorders show a strong genetic tendency and appear to be accelerated by puberty. The most common eating disorder (diagnosed in 0.8%-14% of teens) is eating disorder not otherwise specified (NOS).³⁵ Anorexia nervosa is diagnosed in 0.5% of adolescent girls, and bulimia nervosa in 1% to 2%—particularly among athletes and performers.³⁵ Unanticipated loss of weight, amenorrhea, excessive concern about weight, and deceleration in height/weight curves are potential indicators of an eating disorder. When identified, eating disorders are best managed by a trusted family physician, acting as a coordinator of a multidisciplinary team.

Sexual health

Girls begin to menstruate at an average age of 12, and it takes about 4 years for them to reach reproductive maturity.³⁶ Puberty has been documented to start at younger ages over the past 30 years, likely due to an increase in average body mass index and a decrease in levels of physical activity.³⁷ Girls with early maturation are often insecure and self-conscious, with higher levels of psychological distress.³⁸ In boys, the average age for spermarche (first ejaculation) is 13.³⁹ Boys who mature early tend to be taller, be more confident, and express a good body image.⁴⁰ Those who have early puberty are more likely to be sexually active or participate in high-risk behaviors.⁴¹

Continue to: Pregnancy and contraception

 

 

Pregnancy and contraception

Over the past several decades, more US teens have been abstaining from sexual intercourse or have been using effective forms of birth control, particularly condoms and long-acting reversible contraceptives (LARCs).⁴² Teenage birth rates in girls ages 15 to 19 have declined significantly since the 1980s.⁴² Despite this, the teenage birth rate in the United States remains higher than in other industrialized nations, and most teen pregnancies are unintended.⁴³ Disparities in teenage birth rates also persist across racial and socioeconomic lines.⁴⁴

Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.

There are numerous interventions to reduce teen pregnancy, including sex education, contraceptive counseling, the use of mobile apps that track a user’s monthly fertility cycle or issue reminders to take oral contraceptives,⁴⁵ and the liberal distribution of contraceptives and condoms. The Contraceptive CHOICE Project shows that providing free (or low-cost) LARCs influences young women to choose these as their preferred contraceptive method.⁴⁶ Other programs specifically empower girls to convince partners to use condoms and to resist unwanted sexual advances or intimate partner violence.

Adolescents prefer to have their health care providers address the topic of sexual health. Teens are more likely to share information with providers if asked directly about sexual behaviors.⁴⁷TABLE 2^4,5 offers tips for anticipatory guidance and potential ways to frame questions with adolescents in this context. State laws vary with regard to the ability of minors to seek contraception, pregnancy testing, or care/screening for STIs without parental consent. Contraceptive counseling combined with effective screening decrease the incidence of STIs and pelvic inflammatory disease for sexually active teens.⁴⁸

Sexually transmitted infections

Young adolescents often have a limited ability to imagine consequences related to specific actions. In general, there is also an increased desire to engage in experimental behaviors as an expression of developing autonomy, which may expose them to STIs. About half of all STIs contracted in the United States occur in individuals 15 to 24 years of age.⁴⁹ Girls are at particular risk for the sequelae of these infections, including cervical dysplasia and infertility. Many teens erroneously believe that sexual activities other than intercourse decrease their risk of contracting an STI.⁵⁰

Human papillomavirus (HPV) infection is the most common STI in adolescence.⁵¹ In most cases, HPV is transient and asymptomatic. Oncogenic strains may cause cervical cancer or cancers of the anogenital or oropharyngeal systems. Due to viral latency, it is not recommended to perform HPV typing in men or in women younger than 30 years of age; however, Pap tests are recommended every 3 years for women ages 21 to 29. Primary care providers are pivotal in the public health struggle to prevent HPV infection.

Continue to: Universal immunization of all children...

Universal immunization of all children older than 11 years of age against HPV is strongly advised as part of routine well-child care. Emphasize the proven role of HPV vaccination in preventing cervical⁵² and oropharyngeal⁵³ cancers. And be prepared to address concerns raised by parents in the context of vaccine safety and the initiation of sexual behaviors (www.cdc.gov/hpv/hcp/answering-questions.html).

Chlamydia is the second most common STI in the United States, usually occurring in individuals younger than 24.⁵⁴ The CDC estimates that more than 3 million new chlamydial infections occur yearly. These infections are often asymptomatic, particularly in females, but may cause urethritis, cervicitis, epididymitis, proctitis, or pelvic inflammatory disease. Indolent chlamydial infection is the leading cause of tubal infertility in women.⁵⁴ Routine annual screening for chlamydia is recommended for all sexually active females ≤ 25 years (and for older women with specific risks).⁵⁵ Annual screening is also recommended for men who have sex with men (MSM).⁵⁵

Chlamydial infection may be diagnosed with first-catch urine sampling (men or women), urethral swab (men), endocervical swab (women), or self-collected vaginal swab. Nucleic acid amplification testing is the most sensitive test that is widely available.⁵⁶ First-line treatment includes either azithromycin (1 g orally, single dose) or doxycycline (100 mg orally, twice daily for 7 days).⁵⁶

Gonorrhea. In 2018, there were more than 500,000 annual cases of gonorrhea, with the majority occurring in those between 15 and 24 years of age.⁵⁷ Gonorrhea may increase rates of HIV infection transmission up to 5-fold.⁵⁷ As more adolescents practice oral sex, cases of pharyngeal gonorrhea (and oropharyngeal HPV) have increased. Symptoms of urethritis occur more frequently in men. Screening is recommended for all sexually active women younger than 25.⁵⁶ Importantly, the organism Neisseria gonorrhoeae has developed significant antibiotic resistance over the past decade. The CDC currently recommends dual therapy for the treatment of gonorrhea using 250 mg of intramuscular ceftriaxone and 1 g of oral azithromycin.⁵⁶

Syphilis. Rates of syphilis are increasing among individuals ages 15 to 24.⁵¹ Screening is particularly recommended for MSM and individuals infected with HIV. Benzathine penicillin G, 50,000 U/kg IM, remains the treatment of choice.⁵⁶

Continue to: HIV

HIV. Globally, HIV impacts young people disproportionately. HIV infection also facilitates infection with other STIs. In the United States, the highest burden of HIV infection is borne by young MSM, with prevalence among those 18 to 24 years old varying between 26% to 30% (black) and 3% to 5.5% (non-Hispanic white).⁵¹ The use of emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis (PrEP) has recently been approved for the prevention of HIV. PrEP reduces risk by up to 92% for MSM and transgender women.⁵⁸

Sexual identity

One in 10 high school students self-identifies as “nonheterosexual,” and 1 in 15 reports same-sex sexual contact.⁵⁹ The term LGBTQ+ includes the communities of lesbian, gay, bisexual, transgender, transsexual, queer, questioning, intersex, and asexual individuals. Developing a safe sense of sexual identity is fundamental to adolescent psychological development, and many adolescents struggle to develop a positive sexual identity. Suicide rates and self-harm behaviors among ­LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.⁶⁰ Rates of mood disorders, substance abuse, and high-risk sexual behaviors are also increased in the LGBTQ+ population.⁶¹

Suicide rates and self-harm behaviors among LGBTQ+ adolescents can be 4 times higher than among their heterosexual peers.

The LGBTQ+ community often seeks health care advice and affirmation from primary care providers. Resources to enhance this care are available at www.lgbthealtheducation.org.

Social media

Adolescents today have more media exposure than any prior generation, with smartphone and computer use increasing exponentially. Most (95%) teens have access to a smartphone,⁶² 45% describe themselves as constantly connected to the Internet, and 14% feel that social media is “addictive.”⁶² Most manage their social media portfolio on multiple sites. Patterns of adolescents' online activities show that boys prefer online gaming, while girls tend to spend more time on social networking.⁶²

Whether extensive media use is psychologically beneficial or deleterious has been widely debated. Increased time online correlates with decreased levels of physical activity.⁶³ And sleep disturbances have been associated with excessive screen time and the presence of mobile devices in the bedroom.⁶⁴ The use of social media prior to bedtime also has an adverse impact on academic performance—particularly for girls. This adverse impact on academics persists after correcting for daytime sleepiness, body mass index, and number of hours spent on homework.⁶⁴

Continue to: Due to growing concerns...

Due to growing concerns about the risks of social media in children and adolescents, the American Academy of Pediatrics has developed the Family Media Plan (www.healthychildren.org/English/media/Pages/default.aspx). Some specific questions that providers may ask are outlined in TABLE 3.⁶⁴ The Family Media Plan can provide age-specific guidelines to assist parents or caregivers in answering these questions.

Cyber-bullying. One in 3 adolescents (primarily female) has been a victim of cyber-bullying.⁶⁵ Sadly, 1 in 5 teens has received some form of electronic sexual solicitation.⁶⁶ The likelihood of unsolicited stranger contact correlates with teens’ online habits and the amount of information disclosed. Predictors include female sex, visiting chat rooms, posting photos, and disclosing personal information. Restricting computer use to an area with parental supervision or installing monitoring programs does not seem to exert any protective influence on cyber-bullying or unsolicited stranger contact.⁶⁵ While 63% of cyber-bullying victims feel upset, embarrassed, or stressed by these contacts,⁶⁶ few events are actually reported. To address this, some states have adopted laws adding cyber-bullying to school disciplinary codes.

Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.

Negative health impacts associated with cyber-bullying include anxiety, sadness, and greater difficulty in concentrating on school work.⁶⁵ Victims of bullying are more likely to have school disciplinary actions and depression and to be truant or to carry weapons to school.⁶⁶ Cyber-bullying is uniquely destructive due to its ubiquitous presence. A sense of relative anonymity online may encourage perpetrators to act more cruelly, with less concern for punishment.

Young people are also more likely to share passwords as a sign of friendship. This may result in others assuming their identity online. Adolescents rarely disclose bullying to parents or other adults, fearing restriction of Internet access, and many of them think that adults may downplay the seriousness of the events.⁶⁶

CORRESPONDENCE
Mark B. Stephens, MD, Penn State Health Medical Group, 1850 East Park Avenue, State College, PA 16803; mstephens3@pennstatehealth.psu.edu.

Physicians are going to have to play catch-up when it comes to getting older patients their routine, but important, vaccinations missed during the pandemic.

©Sean Warren/iStockphoto.com

Weekly general vaccination among Medicare beneficiaries aged ≥ 65 year fell by around 80% soon after the national COVID-19 emergency declaration and have recovered only partially and gradually, according to a report by Kai Hong, PhD, and colleagues at the Centers for Disease Control and Prevention, published in the Morbidity and Mortality Weekly Report. “As the pandemic continues,” the investigators stated, “vaccination providers should continue efforts to resolve disruptions in routine adult vaccination.”

The CDC issued guidance recommending postponement of routine adult vaccination in response to the March 13, 2020, COVID-19 national emergency declaration by the U.S. government and also to state and local shelter-in-place orders. Health care facility operations were restricted because of safety concerns around exposure to the SARS-CoV-2 virus. The result was a significant drop in routine medical care including adult vaccinations.

The investigators examined Medicare enrollment and claims data to assess the change in weekly receipt of four routine adult vaccines by Medicare beneficiaries aged ≥65 during the pandemic: (13-valent pneu­mococcal conjugate vaccine [PCV13], 23-valent pneumococ­cal polysaccharide vaccine [PPSV23], tetanus-diphtheria or tetanus-diphtheria-acellular pertussis vaccine [Td/Tdap], and recombinant zoster vaccine [RZV]). The comparison periods were Jan. 6–July 20, 2019, and Jan. 5–July 18, 2020.

Of the Medicare enrollees in the study sample, 85% were White, 7% Black, 2% Asian, 2% Hispanic, and 4% other racial and ethnic groups. For each of the four vaccines overall, weekly rates of vaccination declined sharply after the emergency declaration, compared with corresponding weeks in 2019. In the period prior to the emergency declaration (Jan. 5–March 14, 2020), weekly percentages of Medicare beneficiaries vaccinated with PPSV23, Td/Tdap, and RZV were consistently higher than rates during the same period in 2019.

After the March 13 declaration, while weekly vaccination rates plummeted 25% for PPSV23 and 62% for RZV in the first week, the greatest weekly declines were during April 5-11, 2020, for PCV13, PPSV23, and Td/Tdap, and during April 12-18, 2020, for RZV. The pandemic weekly vaccination rate nadirs revealed declines of 88% for PCV13, 80% for PPSV23, 70% for Td/Tdap, and 89% for RZV.
 

Routine vaccinations increased midyear

Vaccination rates recovered gradually. For the most recently assessed pandemic week (July 12-18, 2020), the rate for PPSV23 was 8% higher than in the corresponding period in 2019. Weekly corresponding rates for other examined vaccines, however, remained much lower than in 2019: 44% lower for RZV, 24% lower for Td/Tdap and 43% lower for PCV13. The CDC Advisory Committee on Immunization Practices voted in June 2019 to stop recommending PCV13 for adults aged ≥65 years and so vaccination with PCV13 among this population declined in 2020, compared with that in 2019.

Another significant drop in the rates of adult vaccinations may have occurred because of the surge in COVID-19 infections in the fall of 2020 and subsequent closures and renewal of lockdown in many localities.
 

Disparities in routine vaccination trends

Dr. Hong and colleagues noted that their findings are consistent with prior reports of declines in pediatric vaccine ordering, administration, and coverage during the pandemic. While the reductions were similar across all racial and ethnic groups, the magnitudes of recovery varied, with vaccination rates lower among racial and ethnic minority adults than among White adults.

Physicians are going to have to play catch-up when it comes to getting older patients their routine, but important, vaccinations missed during the pandemic.

©Sean Warren/iStockphoto.com

Weekly general vaccination among Medicare beneficiaries aged ≥ 65 year fell by around 80% soon after the national COVID-19 emergency declaration and have recovered only partially and gradually, according to a report by Kai Hong, PhD, and colleagues at the Centers for Disease Control and Prevention, published in the Morbidity and Mortality Weekly Report. “As the pandemic continues,” the investigators stated, “vaccination providers should continue efforts to resolve disruptions in routine adult vaccination.”

The CDC issued guidance recommending postponement of routine adult vaccination in response to the March 13, 2020, COVID-19 national emergency declaration by the U.S. government and also to state and local shelter-in-place orders. Health care facility operations were restricted because of safety concerns around exposure to the SARS-CoV-2 virus. The result was a significant drop in routine medical care including adult vaccinations.

The investigators examined Medicare enrollment and claims data to assess the change in weekly receipt of four routine adult vaccines by Medicare beneficiaries aged ≥65 during the pandemic: (13-valent pneu­mococcal conjugate vaccine [PCV13], 23-valent pneumococ­cal polysaccharide vaccine [PPSV23], tetanus-diphtheria or tetanus-diphtheria-acellular pertussis vaccine [Td/Tdap], and recombinant zoster vaccine [RZV]). The comparison periods were Jan. 6–July 20, 2019, and Jan. 5–July 18, 2020.

Of the Medicare enrollees in the study sample, 85% were White, 7% Black, 2% Asian, 2% Hispanic, and 4% other racial and ethnic groups. For each of the four vaccines overall, weekly rates of vaccination declined sharply after the emergency declaration, compared with corresponding weeks in 2019. In the period prior to the emergency declaration (Jan. 5–March 14, 2020), weekly percentages of Medicare beneficiaries vaccinated with PPSV23, Td/Tdap, and RZV were consistently higher than rates during the same period in 2019.

After the March 13 declaration, while weekly vaccination rates plummeted 25% for PPSV23 and 62% for RZV in the first week, the greatest weekly declines were during April 5-11, 2020, for PCV13, PPSV23, and Td/Tdap, and during April 12-18, 2020, for RZV. The pandemic weekly vaccination rate nadirs revealed declines of 88% for PCV13, 80% for PPSV23, 70% for Td/Tdap, and 89% for RZV.
 

Routine vaccinations increased midyear

Vaccination rates recovered gradually. For the most recently assessed pandemic week (July 12-18, 2020), the rate for PPSV23 was 8% higher than in the corresponding period in 2019. Weekly corresponding rates for other examined vaccines, however, remained much lower than in 2019: 44% lower for RZV, 24% lower for Td/Tdap and 43% lower for PCV13. The CDC Advisory Committee on Immunization Practices voted in June 2019 to stop recommending PCV13 for adults aged ≥65 years and so vaccination with PCV13 among this population declined in 2020, compared with that in 2019.

Another significant drop in the rates of adult vaccinations may have occurred because of the surge in COVID-19 infections in the fall of 2020 and subsequent closures and renewal of lockdown in many localities.
 

Disparities in routine vaccination trends

Dr. Hong and colleagues noted that their findings are consistent with prior reports of declines in pediatric vaccine ordering, administration, and coverage during the pandemic. While the reductions were similar across all racial and ethnic groups, the magnitudes of recovery varied, with vaccination rates lower among racial and ethnic minority adults than among White adults.

Physicians are going to have to play catch-up when it comes to getting older patients their routine, but important, vaccinations missed during the pandemic.

©Sean Warren/iStockphoto.com

Weekly general vaccination among Medicare beneficiaries aged ≥ 65 year fell by around 80% soon after the national COVID-19 emergency declaration and have recovered only partially and gradually, according to a report by Kai Hong, PhD, and colleagues at the Centers for Disease Control and Prevention, published in the Morbidity and Mortality Weekly Report. “As the pandemic continues,” the investigators stated, “vaccination providers should continue efforts to resolve disruptions in routine adult vaccination.”

The CDC issued guidance recommending postponement of routine adult vaccination in response to the March 13, 2020, COVID-19 national emergency declaration by the U.S. government and also to state and local shelter-in-place orders. Health care facility operations were restricted because of safety concerns around exposure to the SARS-CoV-2 virus. The result was a significant drop in routine medical care including adult vaccinations.

The investigators examined Medicare enrollment and claims data to assess the change in weekly receipt of four routine adult vaccines by Medicare beneficiaries aged ≥65 during the pandemic: (13-valent pneu­mococcal conjugate vaccine [PCV13], 23-valent pneumococ­cal polysaccharide vaccine [PPSV23], tetanus-diphtheria or tetanus-diphtheria-acellular pertussis vaccine [Td/Tdap], and recombinant zoster vaccine [RZV]). The comparison periods were Jan. 6–July 20, 2019, and Jan. 5–July 18, 2020.

Of the Medicare enrollees in the study sample, 85% were White, 7% Black, 2% Asian, 2% Hispanic, and 4% other racial and ethnic groups. For each of the four vaccines overall, weekly rates of vaccination declined sharply after the emergency declaration, compared with corresponding weeks in 2019. In the period prior to the emergency declaration (Jan. 5–March 14, 2020), weekly percentages of Medicare beneficiaries vaccinated with PPSV23, Td/Tdap, and RZV were consistently higher than rates during the same period in 2019.

After the March 13 declaration, while weekly vaccination rates plummeted 25% for PPSV23 and 62% for RZV in the first week, the greatest weekly declines were during April 5-11, 2020, for PCV13, PPSV23, and Td/Tdap, and during April 12-18, 2020, for RZV. The pandemic weekly vaccination rate nadirs revealed declines of 88% for PCV13, 80% for PPSV23, 70% for Td/Tdap, and 89% for RZV.
 

Routine vaccinations increased midyear

Vaccination rates recovered gradually. For the most recently assessed pandemic week (July 12-18, 2020), the rate for PPSV23 was 8% higher than in the corresponding period in 2019. Weekly corresponding rates for other examined vaccines, however, remained much lower than in 2019: 44% lower for RZV, 24% lower for Td/Tdap and 43% lower for PCV13. The CDC Advisory Committee on Immunization Practices voted in June 2019 to stop recommending PCV13 for adults aged ≥65 years and so vaccination with PCV13 among this population declined in 2020, compared with that in 2019.

Another significant drop in the rates of adult vaccinations may have occurred because of the surge in COVID-19 infections in the fall of 2020 and subsequent closures and renewal of lockdown in many localities.
 

Disparities in routine vaccination trends

Dr. Hong and colleagues noted that their findings are consistent with prior reports of declines in pediatric vaccine ordering, administration, and coverage during the pandemic. While the reductions were similar across all racial and ethnic groups, the magnitudes of recovery varied, with vaccination rates lower among racial and ethnic minority adults than among White adults.