Opinion

The finding of individual, 1- to 4-mm firm, red papules depicted in the image are consistent with facial angiofibromas, which are most commonly seen in pediatric patients as a manifestation of tuberous sclerosis (TSC). Angiofibromas, previously called adenoma sebaceum, a misnomer, are seen in TSC as smooth papules, nodules, and occasionally plaques that typically involve the malar region of the face. These lesions usually develop in childhood and adolescence and can be misdiagnosed as lesions of acne. The number of lesions tend to increase with age, though there is no significant risk of malignant transformation. Ultraviolet-induced DNA damage is thought to play a role in the development of facial angiofibromas, so sun protection is called for.¹ Patients may seek treatment to minimize deformity and the stigma of angiofibromas. Recently, the mammalian target of rapamycin inhibitor sirolimus (rapamycin) topical gel received Food and Drug Administration approval for the treatment of facial angiofibromas associated with TSC in patients age at least 6 years.²

The presence of angiofibromas should prompt consideration of TSC and as such, a thorough family history, medical history, and full-body skin examination. TSC is a rare autosomal-dominant genetic disorder, caused by a pathogenic variant in either the TSC1 or TSC2 gene. This neurocutaneous disorder is characterized by the development of multiple benign hamartomas across many organ systems including the brain, eyes, heart, lung, liver, kidney, and skin. The phenotypic expression of TSC is highly variable. Besides angiofibromas, some other characteristic dermatological findings in TSC include periungual fibromas, hypopigmented macules usually elliptical in shape (known as ash-leaf spots), and irregularly shaped elevated flesh-colored fibrous tissue most often found over the lower back (known as shagreen patches).³

What is on the differential?

Agminated spitz nevi refers to multiple spitz nevi in a localized area. Spitz nevi present as a well-circumscribed, dome-shaped, pink-red or brown papules, most commonly located on the face or lower extremities.⁴ The finding of agminated spitz nevi is very rare and less likely for this patient given the concomitant skin findings of dental pitting, renal cysts, and cortical tubers.

Juvenile xanthogranulomas are benign,proliferations of histiocytic cells that present as reddish or yellowish-to-brown papules, plaques, or nodules that typically develop in young children around the age of 1. With time, juvenile xanthogranulomas may flatten and become more yellow.

Basal cell carcinomas present as dome-shaped lesions with centralized erosions on sun-exposed areas of the skin. They are remarkably uncommon in children but are occasionally seen in basal cell nevus syndrome (also known as nevoid basal cell carcinoma syndrome or Gorlin syndrome). Affected patients may have other findings such as developmental anomalies, bifid ribs, palmar and plantar pitting, odontogenic keratocysts, and/or medulloblastomas.⁵

Flat warts commonly occur in children and occur by direct skin contact with human papillomavirus. Of the various types of warts, flat warts are smaller and tend to be smooth on top. The diagnosis of cutaneous warts is based on clinical appearance, showing thrombosed capillaries underneath the overlying hyperkeratotic debris. Our patient’s history of having a common wart on her hands raises suspicion for inoculation onto her face, but the morphology, distribution, and lack of response to tretinoin makes this diagnosis much less likely.

Disease workup and course

Our patient’s physical exam revealed dental pits but no evidence of hypopigmented macules, shagreen patches, or periungual lesions. Ultrasound of the kidney displayed renal cortical cysts and brain MRI showed cortical tubers, confirming extracutaneous TSC involvement. Over time, our patient developed angiofibromas on the forehead and was ultimately started on topical sirolimus, which led to marked improvement within months.

Ms. Kleinman is a pediatric dermatology research associate, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, also in San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. They have no relevant financial disclosures.

References

1. Tyburczy ME et al. Hum Molec Genet. 2014;23(8):2023-9.

2. Food & Drug Administration. New drug application (NDA) approval for Hyftor (sirolimus topical gel). https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/213478Orig1s000ltr.pdf.

3. Webb DW et al. Br J Dermatol. 1996;135(1):1-5.

4. Ricci F et al. Eur J Dermatol. 2017;27(1):59-62.

5. Evans DG and Farndon PA. Nevoid basal cell carcinoma syndrome, in “GeneReviews®.” Seattle: University of Washington, 2002.

The finding of individual, 1- to 4-mm firm, red papules depicted in the image are consistent with facial angiofibromas, which are most commonly seen in pediatric patients as a manifestation of tuberous sclerosis (TSC). Angiofibromas, previously called adenoma sebaceum, a misnomer, are seen in TSC as smooth papules, nodules, and occasionally plaques that typically involve the malar region of the face. These lesions usually develop in childhood and adolescence and can be misdiagnosed as lesions of acne. The number of lesions tend to increase with age, though there is no significant risk of malignant transformation. Ultraviolet-induced DNA damage is thought to play a role in the development of facial angiofibromas, so sun protection is called for.¹ Patients may seek treatment to minimize deformity and the stigma of angiofibromas. Recently, the mammalian target of rapamycin inhibitor sirolimus (rapamycin) topical gel received Food and Drug Administration approval for the treatment of facial angiofibromas associated with TSC in patients age at least 6 years.²

The presence of angiofibromas should prompt consideration of TSC and as such, a thorough family history, medical history, and full-body skin examination. TSC is a rare autosomal-dominant genetic disorder, caused by a pathogenic variant in either the TSC1 or TSC2 gene. This neurocutaneous disorder is characterized by the development of multiple benign hamartomas across many organ systems including the brain, eyes, heart, lung, liver, kidney, and skin. The phenotypic expression of TSC is highly variable. Besides angiofibromas, some other characteristic dermatological findings in TSC include periungual fibromas, hypopigmented macules usually elliptical in shape (known as ash-leaf spots), and irregularly shaped elevated flesh-colored fibrous tissue most often found over the lower back (known as shagreen patches).³

What is on the differential?

Agminated spitz nevi refers to multiple spitz nevi in a localized area. Spitz nevi present as a well-circumscribed, dome-shaped, pink-red or brown papules, most commonly located on the face or lower extremities.⁴ The finding of agminated spitz nevi is very rare and less likely for this patient given the concomitant skin findings of dental pitting, renal cysts, and cortical tubers.

Juvenile xanthogranulomas are benign,proliferations of histiocytic cells that present as reddish or yellowish-to-brown papules, plaques, or nodules that typically develop in young children around the age of 1. With time, juvenile xanthogranulomas may flatten and become more yellow.

Basal cell carcinomas present as dome-shaped lesions with centralized erosions on sun-exposed areas of the skin. They are remarkably uncommon in children but are occasionally seen in basal cell nevus syndrome (also known as nevoid basal cell carcinoma syndrome or Gorlin syndrome). Affected patients may have other findings such as developmental anomalies, bifid ribs, palmar and plantar pitting, odontogenic keratocysts, and/or medulloblastomas.⁵

Flat warts commonly occur in children and occur by direct skin contact with human papillomavirus. Of the various types of warts, flat warts are smaller and tend to be smooth on top. The diagnosis of cutaneous warts is based on clinical appearance, showing thrombosed capillaries underneath the overlying hyperkeratotic debris. Our patient’s history of having a common wart on her hands raises suspicion for inoculation onto her face, but the morphology, distribution, and lack of response to tretinoin makes this diagnosis much less likely.

Disease workup and course

Our patient’s physical exam revealed dental pits but no evidence of hypopigmented macules, shagreen patches, or periungual lesions. Ultrasound of the kidney displayed renal cortical cysts and brain MRI showed cortical tubers, confirming extracutaneous TSC involvement. Over time, our patient developed angiofibromas on the forehead and was ultimately started on topical sirolimus, which led to marked improvement within months.

Ms. Kleinman is a pediatric dermatology research associate, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, also in San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. They have no relevant financial disclosures.

References

1. Tyburczy ME et al. Hum Molec Genet. 2014;23(8):2023-9.

2. Food & Drug Administration. New drug application (NDA) approval for Hyftor (sirolimus topical gel). https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/213478Orig1s000ltr.pdf.

3. Webb DW et al. Br J Dermatol. 1996;135(1):1-5.

4. Ricci F et al. Eur J Dermatol. 2017;27(1):59-62.

5. Evans DG and Farndon PA. Nevoid basal cell carcinoma syndrome, in “GeneReviews®.” Seattle: University of Washington, 2002.

The finding of individual, 1- to 4-mm firm, red papules depicted in the image are consistent with facial angiofibromas, which are most commonly seen in pediatric patients as a manifestation of tuberous sclerosis (TSC). Angiofibromas, previously called adenoma sebaceum, a misnomer, are seen in TSC as smooth papules, nodules, and occasionally plaques that typically involve the malar region of the face. These lesions usually develop in childhood and adolescence and can be misdiagnosed as lesions of acne. The number of lesions tend to increase with age, though there is no significant risk of malignant transformation. Ultraviolet-induced DNA damage is thought to play a role in the development of facial angiofibromas, so sun protection is called for.¹ Patients may seek treatment to minimize deformity and the stigma of angiofibromas. Recently, the mammalian target of rapamycin inhibitor sirolimus (rapamycin) topical gel received Food and Drug Administration approval for the treatment of facial angiofibromas associated with TSC in patients age at least 6 years.²

The presence of angiofibromas should prompt consideration of TSC and as such, a thorough family history, medical history, and full-body skin examination. TSC is a rare autosomal-dominant genetic disorder, caused by a pathogenic variant in either the TSC1 or TSC2 gene. This neurocutaneous disorder is characterized by the development of multiple benign hamartomas across many organ systems including the brain, eyes, heart, lung, liver, kidney, and skin. The phenotypic expression of TSC is highly variable. Besides angiofibromas, some other characteristic dermatological findings in TSC include periungual fibromas, hypopigmented macules usually elliptical in shape (known as ash-leaf spots), and irregularly shaped elevated flesh-colored fibrous tissue most often found over the lower back (known as shagreen patches).³

What is on the differential?

Agminated spitz nevi refers to multiple spitz nevi in a localized area. Spitz nevi present as a well-circumscribed, dome-shaped, pink-red or brown papules, most commonly located on the face or lower extremities.⁴ The finding of agminated spitz nevi is very rare and less likely for this patient given the concomitant skin findings of dental pitting, renal cysts, and cortical tubers.

Juvenile xanthogranulomas are benign,proliferations of histiocytic cells that present as reddish or yellowish-to-brown papules, plaques, or nodules that typically develop in young children around the age of 1. With time, juvenile xanthogranulomas may flatten and become more yellow.

Basal cell carcinomas present as dome-shaped lesions with centralized erosions on sun-exposed areas of the skin. They are remarkably uncommon in children but are occasionally seen in basal cell nevus syndrome (also known as nevoid basal cell carcinoma syndrome or Gorlin syndrome). Affected patients may have other findings such as developmental anomalies, bifid ribs, palmar and plantar pitting, odontogenic keratocysts, and/or medulloblastomas.⁵

Flat warts commonly occur in children and occur by direct skin contact with human papillomavirus. Of the various types of warts, flat warts are smaller and tend to be smooth on top. The diagnosis of cutaneous warts is based on clinical appearance, showing thrombosed capillaries underneath the overlying hyperkeratotic debris. Our patient’s history of having a common wart on her hands raises suspicion for inoculation onto her face, but the morphology, distribution, and lack of response to tretinoin makes this diagnosis much less likely.

Disease workup and course

Our patient’s physical exam revealed dental pits but no evidence of hypopigmented macules, shagreen patches, or periungual lesions. Ultrasound of the kidney displayed renal cortical cysts and brain MRI showed cortical tubers, confirming extracutaneous TSC involvement. Over time, our patient developed angiofibromas on the forehead and was ultimately started on topical sirolimus, which led to marked improvement within months.

Ms. Kleinman is a pediatric dermatology research associate, division of pediatric and adolescent dermatology, University of California, San Diego, and Rady Children’s Hospital, also in San Diego. Dr. Eichenfield is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego, and Rady Children’s Hospital. They have no relevant financial disclosures.

References

1. Tyburczy ME et al. Hum Molec Genet. 2014;23(8):2023-9.

2. Food & Drug Administration. New drug application (NDA) approval for Hyftor (sirolimus topical gel). https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/213478Orig1s000ltr.pdf.

3. Webb DW et al. Br J Dermatol. 1996;135(1):1-5.

4. Ricci F et al. Eur J Dermatol. 2017;27(1):59-62.

5. Evans DG and Farndon PA. Nevoid basal cell carcinoma syndrome, in “GeneReviews®.” Seattle: University of Washington, 2002.

There is little I enjoy more than an opportunity to get together with old friends.

I write this missive on the return trip from a week of CHEST leadership meetings held last month, and I find myself filled with joy, awe, and great appreciation for the hard work our volunteers contribute to making the American College of Chest Physicians an extraordinarily productive and successful organization. This year’s meetings meant more than any I can ever recall from the past, in the context of a return to in-person gatherings that let our members share laughs, stories, and even a game or two of laser tag in the context of celebrating good times and friendship. And while some great works were accomplished by our committees, some of which I will enumerate below, the highlight of the week was definitely the esprit de corps that was on broad display.

Courtesy ACCP

Our Membership Committee meeting was led by Vice-Chair Marie Budev, DO, FCCP. While this committee is tasked with the critical duty of reviewing applications for the prestigious FCCP designation, they are just as importantly tasked with promoting membership, to our domestic and international colleagues. This is a challenging task, because different members prioritize the variety of benefits from CHEST differently; some focus on access to our educational offerings, both throughout the year and at our annual meeting, while others find greater value in the chance to network with colleagues from around the world and to participate in leadership in an international society. Making sure that we are helping our members realize these benefits, while also identifying (and potentially enhancing) those opportunities in which members are most interested is a challenging task, and I very much enjoyed watching these folks brainstorm ways that we could further increase the value of joining CHEST for current and potential future members.

The Guidelines Oversight Committee, chaired by Lisa Moores, MD, FCCP, is responsible for the oversight of CHEST’s evidence-based guidelines. As our clinical guidelines are among the most highly regarded of all of the things we publish, the members of this committee take special care to ensure that the subjects selected for review as part of the guideline process meet strict criteria. They receive dozens of proposals for new guidelines each year and carefully examine each one to identify the potential public health impact, to ensure the availability of literature in the space worthy of review, and to provide the opportunity to illuminate areas where there are significant clinical uncertainties, often due to new treatments or diagnostic tests. Watching committee members meticulously debate the merits of the many good ideas received to finalize a short list of topics for guideline development in the coming year was incredibly informative and validated my longstanding perception that our members are some of the best clinical minds in the pulmonary, critical care, and sleep fields in the world.

The Professional Standards Committee (PSC), chaired by Scott Manaker, MD, PhD, FCCP, has the important duty of developing CHEST’s conflict of interest (COI) policy, as well as reviewing all potential COI among CHEST leaders and members of our guideline panels. While this may sound a little dry, the fascinating part of this meeting was the ongoing discussion of what constitutes a meaningful COI. As one would expect, many of the best medical experts in the world have relationships with pharmaceutical and medical device companies, who often seek the counsel and participation of high-performing, high-volume clinicians for research trials. CHEST has extremely strict rules with regard to COI among its many levels of leadership, but the question of what constitutes a potentially problematic COI for the large number of folks who volunteer their time and energy to teach at one of our many courses is an interesting (albeit possibly philosophical) question. Since PSC members cannot observe every CHEST faculty interaction, we rely on our members to let us know if they perceive any potential bias in faculty teaching (and we so very much appreciate those of you who bring the extremely rare concerns to our attention!), but this is an area that we continue to watch very closely, as we continue to ensure that all CHEST education is accurate, unbiased, and the best available throughout the world.

The reformulated Council of Networks met under the leadership of Angel Coz Yataco, MD, FCCP, and Cassie Kennedy, MD, FCCP, to discuss how to best engage our members in the new structure, which comprises seven Networks and 22 component Sections. The Council’s primary charges are to develop educational content, to review project applications from Sections, and to serve as expert consultants to the President in their specific clinical domains. While the new configuration provides a significant increase in leadership positions for our members, as well as more formal opportunities to cultivate relationships across different Sections, I have received a few emails from colleagues who were concerned about elimination of certain former Networks, or the placement of a specific Section under a specific Network. Some of these concerns were discussed at the April meeting. While there will be some growing pains, listening to the thoughtful discussion that ensued validated my belief that Drs. Coz and Kennedy are the right folks to be leading the Council as it matures into this new and stronger structure.

While I also had the opportunity to hear reports from the Training and Transitions Committee, the Education Committee, and the Council of Global Governors, I wanted to briefly mention the Scientific Program Committee and its Innovations Group. While we are looking forward to seeing everyone in Nashville this October, I cannot tell you how excited I am about some of the new things we have in store for our first in-person annual meeting in 3 years. (Literally ... I am absolutely sworn to secrecy!) But under the leadership of Program Chair Subani Chandra, MD, FCCP, and my two other “Chief Fun Officers” Aneesa Das, MD, FCCP, and William Kelly, MD, FCCP, I can say that attendees are going to be in for a heck of a lot of fun. Oh, and there’s going to be some education there, also.

In closing, I want to reiterate how much of a pleasure and privilege it has been to sit in the President’s chair over the first few months of 2022. If any of the committees I’ve described above sound interesting to you, please strongly consider throwing your hat into the ring when nominations open up in the coming months. Getting involved at CHEST has been one of the best experiences of my career, and I expect you’ll feel the same way after you join in the fun. As always, I remain available to you, either by emailing me at [email protected] or messaging me on Twitter @ChestPrez. And, please come find me in Nashville in October, either to say hello, or to challenge me to a game of laser tag. ... I’m not very hard to beat.

Until next time,

David

There is little I enjoy more than an opportunity to get together with old friends.

I write this missive on the return trip from a week of CHEST leadership meetings held last month, and I find myself filled with joy, awe, and great appreciation for the hard work our volunteers contribute to making the American College of Chest Physicians an extraordinarily productive and successful organization. This year’s meetings meant more than any I can ever recall from the past, in the context of a return to in-person gatherings that let our members share laughs, stories, and even a game or two of laser tag in the context of celebrating good times and friendship. And while some great works were accomplished by our committees, some of which I will enumerate below, the highlight of the week was definitely the esprit de corps that was on broad display.

Courtesy ACCP

Our Membership Committee meeting was led by Vice-Chair Marie Budev, DO, FCCP. While this committee is tasked with the critical duty of reviewing applications for the prestigious FCCP designation, they are just as importantly tasked with promoting membership, to our domestic and international colleagues. This is a challenging task, because different members prioritize the variety of benefits from CHEST differently; some focus on access to our educational offerings, both throughout the year and at our annual meeting, while others find greater value in the chance to network with colleagues from around the world and to participate in leadership in an international society. Making sure that we are helping our members realize these benefits, while also identifying (and potentially enhancing) those opportunities in which members are most interested is a challenging task, and I very much enjoyed watching these folks brainstorm ways that we could further increase the value of joining CHEST for current and potential future members.

The Guidelines Oversight Committee, chaired by Lisa Moores, MD, FCCP, is responsible for the oversight of CHEST’s evidence-based guidelines. As our clinical guidelines are among the most highly regarded of all of the things we publish, the members of this committee take special care to ensure that the subjects selected for review as part of the guideline process meet strict criteria. They receive dozens of proposals for new guidelines each year and carefully examine each one to identify the potential public health impact, to ensure the availability of literature in the space worthy of review, and to provide the opportunity to illuminate areas where there are significant clinical uncertainties, often due to new treatments or diagnostic tests. Watching committee members meticulously debate the merits of the many good ideas received to finalize a short list of topics for guideline development in the coming year was incredibly informative and validated my longstanding perception that our members are some of the best clinical minds in the pulmonary, critical care, and sleep fields in the world.

The Professional Standards Committee (PSC), chaired by Scott Manaker, MD, PhD, FCCP, has the important duty of developing CHEST’s conflict of interest (COI) policy, as well as reviewing all potential COI among CHEST leaders and members of our guideline panels. While this may sound a little dry, the fascinating part of this meeting was the ongoing discussion of what constitutes a meaningful COI. As one would expect, many of the best medical experts in the world have relationships with pharmaceutical and medical device companies, who often seek the counsel and participation of high-performing, high-volume clinicians for research trials. CHEST has extremely strict rules with regard to COI among its many levels of leadership, but the question of what constitutes a potentially problematic COI for the large number of folks who volunteer their time and energy to teach at one of our many courses is an interesting (albeit possibly philosophical) question. Since PSC members cannot observe every CHEST faculty interaction, we rely on our members to let us know if they perceive any potential bias in faculty teaching (and we so very much appreciate those of you who bring the extremely rare concerns to our attention!), but this is an area that we continue to watch very closely, as we continue to ensure that all CHEST education is accurate, unbiased, and the best available throughout the world.

The reformulated Council of Networks met under the leadership of Angel Coz Yataco, MD, FCCP, and Cassie Kennedy, MD, FCCP, to discuss how to best engage our members in the new structure, which comprises seven Networks and 22 component Sections. The Council’s primary charges are to develop educational content, to review project applications from Sections, and to serve as expert consultants to the President in their specific clinical domains. While the new configuration provides a significant increase in leadership positions for our members, as well as more formal opportunities to cultivate relationships across different Sections, I have received a few emails from colleagues who were concerned about elimination of certain former Networks, or the placement of a specific Section under a specific Network. Some of these concerns were discussed at the April meeting. While there will be some growing pains, listening to the thoughtful discussion that ensued validated my belief that Drs. Coz and Kennedy are the right folks to be leading the Council as it matures into this new and stronger structure.

While I also had the opportunity to hear reports from the Training and Transitions Committee, the Education Committee, and the Council of Global Governors, I wanted to briefly mention the Scientific Program Committee and its Innovations Group. While we are looking forward to seeing everyone in Nashville this October, I cannot tell you how excited I am about some of the new things we have in store for our first in-person annual meeting in 3 years. (Literally ... I am absolutely sworn to secrecy!) But under the leadership of Program Chair Subani Chandra, MD, FCCP, and my two other “Chief Fun Officers” Aneesa Das, MD, FCCP, and William Kelly, MD, FCCP, I can say that attendees are going to be in for a heck of a lot of fun. Oh, and there’s going to be some education there, also.

In closing, I want to reiterate how much of a pleasure and privilege it has been to sit in the President’s chair over the first few months of 2022. If any of the committees I’ve described above sound interesting to you, please strongly consider throwing your hat into the ring when nominations open up in the coming months. Getting involved at CHEST has been one of the best experiences of my career, and I expect you’ll feel the same way after you join in the fun. As always, I remain available to you, either by emailing me at [email protected] or messaging me on Twitter @ChestPrez. And, please come find me in Nashville in October, either to say hello, or to challenge me to a game of laser tag. ... I’m not very hard to beat.

Until next time,

David

There is little I enjoy more than an opportunity to get together with old friends.

I write this missive on the return trip from a week of CHEST leadership meetings held last month, and I find myself filled with joy, awe, and great appreciation for the hard work our volunteers contribute to making the American College of Chest Physicians an extraordinarily productive and successful organization. This year’s meetings meant more than any I can ever recall from the past, in the context of a return to in-person gatherings that let our members share laughs, stories, and even a game or two of laser tag in the context of celebrating good times and friendship. And while some great works were accomplished by our committees, some of which I will enumerate below, the highlight of the week was definitely the esprit de corps that was on broad display.

Courtesy ACCP

Our Membership Committee meeting was led by Vice-Chair Marie Budev, DO, FCCP. While this committee is tasked with the critical duty of reviewing applications for the prestigious FCCP designation, they are just as importantly tasked with promoting membership, to our domestic and international colleagues. This is a challenging task, because different members prioritize the variety of benefits from CHEST differently; some focus on access to our educational offerings, both throughout the year and at our annual meeting, while others find greater value in the chance to network with colleagues from around the world and to participate in leadership in an international society. Making sure that we are helping our members realize these benefits, while also identifying (and potentially enhancing) those opportunities in which members are most interested is a challenging task, and I very much enjoyed watching these folks brainstorm ways that we could further increase the value of joining CHEST for current and potential future members.

The Guidelines Oversight Committee, chaired by Lisa Moores, MD, FCCP, is responsible for the oversight of CHEST’s evidence-based guidelines. As our clinical guidelines are among the most highly regarded of all of the things we publish, the members of this committee take special care to ensure that the subjects selected for review as part of the guideline process meet strict criteria. They receive dozens of proposals for new guidelines each year and carefully examine each one to identify the potential public health impact, to ensure the availability of literature in the space worthy of review, and to provide the opportunity to illuminate areas where there are significant clinical uncertainties, often due to new treatments or diagnostic tests. Watching committee members meticulously debate the merits of the many good ideas received to finalize a short list of topics for guideline development in the coming year was incredibly informative and validated my longstanding perception that our members are some of the best clinical minds in the pulmonary, critical care, and sleep fields in the world.

The Professional Standards Committee (PSC), chaired by Scott Manaker, MD, PhD, FCCP, has the important duty of developing CHEST’s conflict of interest (COI) policy, as well as reviewing all potential COI among CHEST leaders and members of our guideline panels. While this may sound a little dry, the fascinating part of this meeting was the ongoing discussion of what constitutes a meaningful COI. As one would expect, many of the best medical experts in the world have relationships with pharmaceutical and medical device companies, who often seek the counsel and participation of high-performing, high-volume clinicians for research trials. CHEST has extremely strict rules with regard to COI among its many levels of leadership, but the question of what constitutes a potentially problematic COI for the large number of folks who volunteer their time and energy to teach at one of our many courses is an interesting (albeit possibly philosophical) question. Since PSC members cannot observe every CHEST faculty interaction, we rely on our members to let us know if they perceive any potential bias in faculty teaching (and we so very much appreciate those of you who bring the extremely rare concerns to our attention!), but this is an area that we continue to watch very closely, as we continue to ensure that all CHEST education is accurate, unbiased, and the best available throughout the world.

The reformulated Council of Networks met under the leadership of Angel Coz Yataco, MD, FCCP, and Cassie Kennedy, MD, FCCP, to discuss how to best engage our members in the new structure, which comprises seven Networks and 22 component Sections. The Council’s primary charges are to develop educational content, to review project applications from Sections, and to serve as expert consultants to the President in their specific clinical domains. While the new configuration provides a significant increase in leadership positions for our members, as well as more formal opportunities to cultivate relationships across different Sections, I have received a few emails from colleagues who were concerned about elimination of certain former Networks, or the placement of a specific Section under a specific Network. Some of these concerns were discussed at the April meeting. While there will be some growing pains, listening to the thoughtful discussion that ensued validated my belief that Drs. Coz and Kennedy are the right folks to be leading the Council as it matures into this new and stronger structure.

While I also had the opportunity to hear reports from the Training and Transitions Committee, the Education Committee, and the Council of Global Governors, I wanted to briefly mention the Scientific Program Committee and its Innovations Group. While we are looking forward to seeing everyone in Nashville this October, I cannot tell you how excited I am about some of the new things we have in store for our first in-person annual meeting in 3 years. (Literally ... I am absolutely sworn to secrecy!) But under the leadership of Program Chair Subani Chandra, MD, FCCP, and my two other “Chief Fun Officers” Aneesa Das, MD, FCCP, and William Kelly, MD, FCCP, I can say that attendees are going to be in for a heck of a lot of fun. Oh, and there’s going to be some education there, also.

In closing, I want to reiterate how much of a pleasure and privilege it has been to sit in the President’s chair over the first few months of 2022. If any of the committees I’ve described above sound interesting to you, please strongly consider throwing your hat into the ring when nominations open up in the coming months. Getting involved at CHEST has been one of the best experiences of my career, and I expect you’ll feel the same way after you join in the fun. As always, I remain available to you, either by emailing me at [email protected] or messaging me on Twitter @ChestPrez. And, please come find me in Nashville in October, either to say hello, or to challenge me to a game of laser tag. ... I’m not very hard to beat.

Until next time,

David

I want to talk about a new continuous glucose monitoring (CGM) metric known as glycemic risk index, or GRI. You may ask why we need another metric. We currently have multiple CGM metrics, including time in range, time below range, time above range, mean glucose, glucose management indicator (GMI), and coefficient of variation, and it seems like an overwhelming number of ways to look at the same data.

The problem is that no single metric tells you exactly what is happening with the patient. For instance, a patient could be at a target time in range of 70%, but that could mean that 30% of that patient’s time is spent too low or even very low, which is a very serious problem, versus if 30% of their time was spent in a somewhat but not very high range, which requires less immediate attention.

Dr. David Klonoff and colleagues, including me, decided to see if one number could be used to identify which patients needed more immediate attention and which needed less. He asked 330 clinicians to evaluate 225 CGM tracings and rank their clinical status in terms of these metrics: very low glucose and low glucose hypoglycemia, very high glucose and high glucose hyperglycemia, time in range, mean glucose, and coefficient of variation.

Then he took all the data and analyzed it in complex ways that I barely understood and came up with one number, the GRI, that captures what the clinicians considered important. The analysis showed that the clinician rankings depended primarily on two components: One related to hypoglycemia, which gives more weight to very low glucose than to low glucose hypoglycemia; and the other related to hyperglycemia, which gives greater weight to very high glucose than to high glucose.

These two components were combined into a single glycemic risk index, the GRI, that corresponds closely to the clinician rankings of the overall quality of glycemia. In terms of numbers, the best GRI is in the zero to 20th percentile and the worst in the 81st to 100th percentile. The GRI grid that is provided in the paper enables users to track sequential changes within an individual over time and compare groups of individuals.

As I said initially, at first I wasn’t sure of the utility of adding yet another number to the mix, but I realized that for triaging what I hope will be increasing amounts of CGM data in a health care system, this could help identify those patients who need the most urgent assistance. It can also help providers have an overall sense of how a patient is doing and whether or not they are improving.

The GRI is not yet in general use and needs to be studied to see if it is actually helpful in clinical practice; however, I like the concept. Given the need to increase provider understanding of CGM metrics overall, I think it is a good way for providers to identify which patients need further analysis of their CGM data for potential treatment modifications.

Thank you.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies.

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

I want to talk about a new continuous glucose monitoring (CGM) metric known as glycemic risk index, or GRI. You may ask why we need another metric. We currently have multiple CGM metrics, including time in range, time below range, time above range, mean glucose, glucose management indicator (GMI), and coefficient of variation, and it seems like an overwhelming number of ways to look at the same data.

The problem is that no single metric tells you exactly what is happening with the patient. For instance, a patient could be at a target time in range of 70%, but that could mean that 30% of that patient’s time is spent too low or even very low, which is a very serious problem, versus if 30% of their time was spent in a somewhat but not very high range, which requires less immediate attention.

Dr. David Klonoff and colleagues, including me, decided to see if one number could be used to identify which patients needed more immediate attention and which needed less. He asked 330 clinicians to evaluate 225 CGM tracings and rank their clinical status in terms of these metrics: very low glucose and low glucose hypoglycemia, very high glucose and high glucose hyperglycemia, time in range, mean glucose, and coefficient of variation.

Then he took all the data and analyzed it in complex ways that I barely understood and came up with one number, the GRI, that captures what the clinicians considered important. The analysis showed that the clinician rankings depended primarily on two components: One related to hypoglycemia, which gives more weight to very low glucose than to low glucose hypoglycemia; and the other related to hyperglycemia, which gives greater weight to very high glucose than to high glucose.

These two components were combined into a single glycemic risk index, the GRI, that corresponds closely to the clinician rankings of the overall quality of glycemia. In terms of numbers, the best GRI is in the zero to 20th percentile and the worst in the 81st to 100th percentile. The GRI grid that is provided in the paper enables users to track sequential changes within an individual over time and compare groups of individuals.

As I said initially, at first I wasn’t sure of the utility of adding yet another number to the mix, but I realized that for triaging what I hope will be increasing amounts of CGM data in a health care system, this could help identify those patients who need the most urgent assistance. It can also help providers have an overall sense of how a patient is doing and whether or not they are improving.

The GRI is not yet in general use and needs to be studied to see if it is actually helpful in clinical practice; however, I like the concept. Given the need to increase provider understanding of CGM metrics overall, I think it is a good way for providers to identify which patients need further analysis of their CGM data for potential treatment modifications.

Thank you.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies.

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

I want to talk about a new continuous glucose monitoring (CGM) metric known as glycemic risk index, or GRI. You may ask why we need another metric. We currently have multiple CGM metrics, including time in range, time below range, time above range, mean glucose, glucose management indicator (GMI), and coefficient of variation, and it seems like an overwhelming number of ways to look at the same data.

The problem is that no single metric tells you exactly what is happening with the patient. For instance, a patient could be at a target time in range of 70%, but that could mean that 30% of that patient’s time is spent too low or even very low, which is a very serious problem, versus if 30% of their time was spent in a somewhat but not very high range, which requires less immediate attention.

Dr. David Klonoff and colleagues, including me, decided to see if one number could be used to identify which patients needed more immediate attention and which needed less. He asked 330 clinicians to evaluate 225 CGM tracings and rank their clinical status in terms of these metrics: very low glucose and low glucose hypoglycemia, very high glucose and high glucose hyperglycemia, time in range, mean glucose, and coefficient of variation.

Then he took all the data and analyzed it in complex ways that I barely understood and came up with one number, the GRI, that captures what the clinicians considered important. The analysis showed that the clinician rankings depended primarily on two components: One related to hypoglycemia, which gives more weight to very low glucose than to low glucose hypoglycemia; and the other related to hyperglycemia, which gives greater weight to very high glucose than to high glucose.

These two components were combined into a single glycemic risk index, the GRI, that corresponds closely to the clinician rankings of the overall quality of glycemia. In terms of numbers, the best GRI is in the zero to 20th percentile and the worst in the 81st to 100th percentile. The GRI grid that is provided in the paper enables users to track sequential changes within an individual over time and compare groups of individuals.

As I said initially, at first I wasn’t sure of the utility of adding yet another number to the mix, but I realized that for triaging what I hope will be increasing amounts of CGM data in a health care system, this could help identify those patients who need the most urgent assistance. It can also help providers have an overall sense of how a patient is doing and whether or not they are improving.

The GRI is not yet in general use and needs to be studied to see if it is actually helpful in clinical practice; however, I like the concept. Given the need to increase provider understanding of CGM metrics overall, I think it is a good way for providers to identify which patients need further analysis of their CGM data for potential treatment modifications.

Thank you.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies.

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

Eating disorders are among the most prevalent, disabling, and potentially fatal psychiatric illnesses, and the COVID-19 pandemic has exacerbated their burden, with a 15.3% increase in incidence in 2020 compared with previous years.¹ This increase was almost solely among adolescent girls with anorexia nervosa (AN), which is often insidious in onset and more difficult to treat as it advances. Adolescents with AN are most likely to present to their pediatricians, so awareness and early recognition of the symptoms is critical. Pediatricians are also an integral part of the treatment team in AN and can offer monitoring for serious complications, alongside valuable guidance to parents, who are central to treatment and the reestablishment of healthy eating habits in their children. Here we will review the epidemiology, diagnosis, and treatment of anorexia, with an emphasis on what pediatricians need to know to screen and to facilitate treatment.

Epidemiology

AN is marked by a fear of gaining weight or behaviors that interfere with weight gain and a self-evaluation unduly influenced by weight and body shape. Youth with AN often deny the seriousness of their malnutrition, although that is not required for diagnosis. AN can be of a restrictive or binge-purge subtype, and amenorrhea is no longer a requirement for diagnosis. There is not a specific weight or body mass index cutoff for the diagnosis, but the severity of AN is determined by the BMI percentile normed to age and sex. The average age of onset is 18, and the prepandemic prevalence of AN was about 1% of the population. It affects about 10 times as many females as males. It is quite rare prior to puberty, affecting about 0.01% of that age group. There is a heritable component, with a fivefold relative risk in youth with a parent with AN, and twin studies suggest heritability rates as high as 75%. Youth with rigid cognitive styles appear more vulnerable, as do those who participate in activities such as ballet, gymnastics, modeling, and wrestling because of the role of appearance and weight in performance. More than half of patients with AN will have another psychiatric illness, most commonly anxiety disorders, depression, or obsessive-compulsive disorder. AN becomes chronic in up to 15% of sufferers and the mortality rate is close to 10%, with approximately half dying from medical complications and half dying by suicide.

Screening

Parents and pediatricians are usually the first to notice that a child has started to lose weight or is falling off the growth curve. But weight changes usually emerge after feelings of preoccupation with weight, body shape, and body satisfaction. If parents report escalating pickiness around food, increased or compulsive exercise, persistent self-consciousness and self-criticism around weight and body shape, it is worth starting with screening questions.

If you notice preoccupation or anxiety around being weighed, even if the weight or growth curve are still normal, it is worthwhile to screen. Screening questions, such as the SCOFF questionnaire with five simple questions, can be very sensitive for both AN and bulimia nervosa.² There are also many validated screening instruments, such as the Eating Disorder Inventory or Eating Attitudes Test (for adolescents) and the Kids Eating Disorder Survey and the Child Eating Attitudes Test (for younger children), that are short self-reports that you can have your patients fill out when you have a higher index of suspicion. Weight loss or growth failure without a preoccupation around weight or appearance needs a thorough a medical workup, and could be a function of other psychiatric problems, such as depression.

If a child screens positive for an eating disorder, your full physical examination, growth curves, and longitudinal growth charts are critical for diagnosis. Percentile BMIs must be used, given the inaccuracy of standard BMI calculations in this age group. (Centers for Disease Control and Prevention age and sex growth charts include methods for this calculation). Laboratory assessment, including metabolic, kidney, pancreatic, and thyroid function, and an EKG can illuminate if there are consequences of restricting or purging. Of course, you want to evaluate for significant medical symptoms, including bradycardia, orthostasis, and hypokalemia. These medical symptoms are not limited to the severely underweight and merit referral to an emergency department and possible medical admission.

Then, a referral to a clinician who is expert in the assessment and treatment of eating disorders is needed. This may be a child psychiatrist, psychologist, or a colleague pediatrician with this specialization. It is also very important to begin the conversation with the family to introduce your concerns, describe what you have noticed, and discuss the need for further assessment and possibly treatment.

Treatment

Family-based therapy (FBT) is the first-line treatment of shorter-duration AN in children and adolescents. It focuses on the parents, helping them to calmly and effectively manage their child’s eating behaviors until their weight and behaviors have normalized. As a patient’s nutritional status improves, so does cognitive function, emotional flexibility, and mood. Individual therapy and psychopharmacologic treatment can be very effective for comorbid anxiety, mood, attentional, and thought disorders. Family-based work does include the child and is often done in group-based settings with clinicians from multiple disciplines. Dietitians provide education and guidance about healthy nutrition to the child and parents. Therapists may work with the child, parents, or full family to focus on behavior modification and managing distress. Most academic medical centers provide access to FBT, but there are many regions with no providers of this evidence-based treatment. One of the silver linings of the COVID-19 pandemic is that several online services have emerged offering FBT, working with families to manage mealtimes and treatment entirely at home.³ Pediatricians provide regular medical checks to measure progress and help with decisions about when it is safe to permit exercise or advance privileges and independence around eating. Some pediatricians have discovered a deep interest in this area of pediatrics and built their practices on it. Given the surge in prevalence of AN and the needs for adolescent mental health services, we hope more will do so.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

References

1. Taquet M et al. Br J Psychiatry. 2022;220:262-4.

2. Morgan JF et al. West J Med. 2000 Mar;172(3):164-5.

3. Matheson BE et al. Int J Eat Disord. 2020 Jul;53(7):1142-54.

Eating disorders are among the most prevalent, disabling, and potentially fatal psychiatric illnesses, and the COVID-19 pandemic has exacerbated their burden, with a 15.3% increase in incidence in 2020 compared with previous years.¹ This increase was almost solely among adolescent girls with anorexia nervosa (AN), which is often insidious in onset and more difficult to treat as it advances. Adolescents with AN are most likely to present to their pediatricians, so awareness and early recognition of the symptoms is critical. Pediatricians are also an integral part of the treatment team in AN and can offer monitoring for serious complications, alongside valuable guidance to parents, who are central to treatment and the reestablishment of healthy eating habits in their children. Here we will review the epidemiology, diagnosis, and treatment of anorexia, with an emphasis on what pediatricians need to know to screen and to facilitate treatment.

Epidemiology

AN is marked by a fear of gaining weight or behaviors that interfere with weight gain and a self-evaluation unduly influenced by weight and body shape. Youth with AN often deny the seriousness of their malnutrition, although that is not required for diagnosis. AN can be of a restrictive or binge-purge subtype, and amenorrhea is no longer a requirement for diagnosis. There is not a specific weight or body mass index cutoff for the diagnosis, but the severity of AN is determined by the BMI percentile normed to age and sex. The average age of onset is 18, and the prepandemic prevalence of AN was about 1% of the population. It affects about 10 times as many females as males. It is quite rare prior to puberty, affecting about 0.01% of that age group. There is a heritable component, with a fivefold relative risk in youth with a parent with AN, and twin studies suggest heritability rates as high as 75%. Youth with rigid cognitive styles appear more vulnerable, as do those who participate in activities such as ballet, gymnastics, modeling, and wrestling because of the role of appearance and weight in performance. More than half of patients with AN will have another psychiatric illness, most commonly anxiety disorders, depression, or obsessive-compulsive disorder. AN becomes chronic in up to 15% of sufferers and the mortality rate is close to 10%, with approximately half dying from medical complications and half dying by suicide.

Screening

Parents and pediatricians are usually the first to notice that a child has started to lose weight or is falling off the growth curve. But weight changes usually emerge after feelings of preoccupation with weight, body shape, and body satisfaction. If parents report escalating pickiness around food, increased or compulsive exercise, persistent self-consciousness and self-criticism around weight and body shape, it is worth starting with screening questions.

If you notice preoccupation or anxiety around being weighed, even if the weight or growth curve are still normal, it is worthwhile to screen. Screening questions, such as the SCOFF questionnaire with five simple questions, can be very sensitive for both AN and bulimia nervosa.² There are also many validated screening instruments, such as the Eating Disorder Inventory or Eating Attitudes Test (for adolescents) and the Kids Eating Disorder Survey and the Child Eating Attitudes Test (for younger children), that are short self-reports that you can have your patients fill out when you have a higher index of suspicion. Weight loss or growth failure without a preoccupation around weight or appearance needs a thorough a medical workup, and could be a function of other psychiatric problems, such as depression.

If a child screens positive for an eating disorder, your full physical examination, growth curves, and longitudinal growth charts are critical for diagnosis. Percentile BMIs must be used, given the inaccuracy of standard BMI calculations in this age group. (Centers for Disease Control and Prevention age and sex growth charts include methods for this calculation). Laboratory assessment, including metabolic, kidney, pancreatic, and thyroid function, and an EKG can illuminate if there are consequences of restricting or purging. Of course, you want to evaluate for significant medical symptoms, including bradycardia, orthostasis, and hypokalemia. These medical symptoms are not limited to the severely underweight and merit referral to an emergency department and possible medical admission.

Then, a referral to a clinician who is expert in the assessment and treatment of eating disorders is needed. This may be a child psychiatrist, psychologist, or a colleague pediatrician with this specialization. It is also very important to begin the conversation with the family to introduce your concerns, describe what you have noticed, and discuss the need for further assessment and possibly treatment.

Treatment

Family-based therapy (FBT) is the first-line treatment of shorter-duration AN in children and adolescents. It focuses on the parents, helping them to calmly and effectively manage their child’s eating behaviors until their weight and behaviors have normalized. As a patient’s nutritional status improves, so does cognitive function, emotional flexibility, and mood. Individual therapy and psychopharmacologic treatment can be very effective for comorbid anxiety, mood, attentional, and thought disorders. Family-based work does include the child and is often done in group-based settings with clinicians from multiple disciplines. Dietitians provide education and guidance about healthy nutrition to the child and parents. Therapists may work with the child, parents, or full family to focus on behavior modification and managing distress. Most academic medical centers provide access to FBT, but there are many regions with no providers of this evidence-based treatment. One of the silver linings of the COVID-19 pandemic is that several online services have emerged offering FBT, working with families to manage mealtimes and treatment entirely at home.³ Pediatricians provide regular medical checks to measure progress and help with decisions about when it is safe to permit exercise or advance privileges and independence around eating. Some pediatricians have discovered a deep interest in this area of pediatrics and built their practices on it. Given the surge in prevalence of AN and the needs for adolescent mental health services, we hope more will do so.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

References

1. Taquet M et al. Br J Psychiatry. 2022;220:262-4.

2. Morgan JF et al. West J Med. 2000 Mar;172(3):164-5.

3. Matheson BE et al. Int J Eat Disord. 2020 Jul;53(7):1142-54.

Eating disorders are among the most prevalent, disabling, and potentially fatal psychiatric illnesses, and the COVID-19 pandemic has exacerbated their burden, with a 15.3% increase in incidence in 2020 compared with previous years.¹ This increase was almost solely among adolescent girls with anorexia nervosa (AN), which is often insidious in onset and more difficult to treat as it advances. Adolescents with AN are most likely to present to their pediatricians, so awareness and early recognition of the symptoms is critical. Pediatricians are also an integral part of the treatment team in AN and can offer monitoring for serious complications, alongside valuable guidance to parents, who are central to treatment and the reestablishment of healthy eating habits in their children. Here we will review the epidemiology, diagnosis, and treatment of anorexia, with an emphasis on what pediatricians need to know to screen and to facilitate treatment.

Epidemiology

AN is marked by a fear of gaining weight or behaviors that interfere with weight gain and a self-evaluation unduly influenced by weight and body shape. Youth with AN often deny the seriousness of their malnutrition, although that is not required for diagnosis. AN can be of a restrictive or binge-purge subtype, and amenorrhea is no longer a requirement for diagnosis. There is not a specific weight or body mass index cutoff for the diagnosis, but the severity of AN is determined by the BMI percentile normed to age and sex. The average age of onset is 18, and the prepandemic prevalence of AN was about 1% of the population. It affects about 10 times as many females as males. It is quite rare prior to puberty, affecting about 0.01% of that age group. There is a heritable component, with a fivefold relative risk in youth with a parent with AN, and twin studies suggest heritability rates as high as 75%. Youth with rigid cognitive styles appear more vulnerable, as do those who participate in activities such as ballet, gymnastics, modeling, and wrestling because of the role of appearance and weight in performance. More than half of patients with AN will have another psychiatric illness, most commonly anxiety disorders, depression, or obsessive-compulsive disorder. AN becomes chronic in up to 15% of sufferers and the mortality rate is close to 10%, with approximately half dying from medical complications and half dying by suicide.

Screening

Parents and pediatricians are usually the first to notice that a child has started to lose weight or is falling off the growth curve. But weight changes usually emerge after feelings of preoccupation with weight, body shape, and body satisfaction. If parents report escalating pickiness around food, increased or compulsive exercise, persistent self-consciousness and self-criticism around weight and body shape, it is worth starting with screening questions.

If you notice preoccupation or anxiety around being weighed, even if the weight or growth curve are still normal, it is worthwhile to screen. Screening questions, such as the SCOFF questionnaire with five simple questions, can be very sensitive for both AN and bulimia nervosa.² There are also many validated screening instruments, such as the Eating Disorder Inventory or Eating Attitudes Test (for adolescents) and the Kids Eating Disorder Survey and the Child Eating Attitudes Test (for younger children), that are short self-reports that you can have your patients fill out when you have a higher index of suspicion. Weight loss or growth failure without a preoccupation around weight or appearance needs a thorough a medical workup, and could be a function of other psychiatric problems, such as depression.

If a child screens positive for an eating disorder, your full physical examination, growth curves, and longitudinal growth charts are critical for diagnosis. Percentile BMIs must be used, given the inaccuracy of standard BMI calculations in this age group. (Centers for Disease Control and Prevention age and sex growth charts include methods for this calculation). Laboratory assessment, including metabolic, kidney, pancreatic, and thyroid function, and an EKG can illuminate if there are consequences of restricting or purging. Of course, you want to evaluate for significant medical symptoms, including bradycardia, orthostasis, and hypokalemia. These medical symptoms are not limited to the severely underweight and merit referral to an emergency department and possible medical admission.

Then, a referral to a clinician who is expert in the assessment and treatment of eating disorders is needed. This may be a child psychiatrist, psychologist, or a colleague pediatrician with this specialization. It is also very important to begin the conversation with the family to introduce your concerns, describe what you have noticed, and discuss the need for further assessment and possibly treatment.

Treatment

Family-based therapy (FBT) is the first-line treatment of shorter-duration AN in children and adolescents. It focuses on the parents, helping them to calmly and effectively manage their child’s eating behaviors until their weight and behaviors have normalized. As a patient’s nutritional status improves, so does cognitive function, emotional flexibility, and mood. Individual therapy and psychopharmacologic treatment can be very effective for comorbid anxiety, mood, attentional, and thought disorders. Family-based work does include the child and is often done in group-based settings with clinicians from multiple disciplines. Dietitians provide education and guidance about healthy nutrition to the child and parents. Therapists may work with the child, parents, or full family to focus on behavior modification and managing distress. Most academic medical centers provide access to FBT, but there are many regions with no providers of this evidence-based treatment. One of the silver linings of the COVID-19 pandemic is that several online services have emerged offering FBT, working with families to manage mealtimes and treatment entirely at home.³ Pediatricians provide regular medical checks to measure progress and help with decisions about when it is safe to permit exercise or advance privileges and independence around eating. Some pediatricians have discovered a deep interest in this area of pediatrics and built their practices on it. Given the surge in prevalence of AN and the needs for adolescent mental health services, we hope more will do so.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

References

1. Taquet M et al. Br J Psychiatry. 2022;220:262-4.

2. Morgan JF et al. West J Med. 2000 Mar;172(3):164-5.

3. Matheson BE et al. Int J Eat Disord. 2020 Jul;53(7):1142-54.

You have an appointment with a 14-year-old youth you last saw for an annual camp physical. He had screened positive for depression, and you had referred him to a local therapist. He did not have an appointment until after camp, and you have only met a few times, but since you had spoken with him about his depression, he set up an appointment with you to ask about medications. When you meet him you ask about what he had been doing in therapy and he says, “I’m learning ‘coping skills,’ but they don’t work.”

From breathing exercises and sticker charts to mindfulness and grounding exercise, coping skills can be crucial for learning how to manage distress, regulate emotions, become more effective interpersonally, and function better. Similarly, parenting interventions, which change the way parents and youth interact, are a central family intervention for behavioral problems in youth.

It is very common, however, to hear that they “don’t work” or have a parent say, “We tried that, it doesn’t work.”

When kids and parents reject coping skills and behavioral interventions by saying they do not work, the consequences can be substantial. It can mean the rejection of coping skills and strategies that actually would have helped, given time and support; that kids and families bounce between services with increasing frustration; that they search for a magic bullet (which also won’t work); and, particularly concerning for physicians, a belief that the youth have not received the right medication, resulting in potentially unhelpful concoctions of medication.

One of the biggest challenges in helping youth and parents overcome their difficulties – whether these difficulties are depression and anxiety or being better parents to struggling kids – is helping them understand that despite the fact that coping skills and behavioral interventions do not seem to work, they work.

We just have to do a better job explaining what that “work” is.

There are five points you can make.

• First, the coping skill or behavioral intervention is not supposed to work if that means solving the underlying problem. Coping skills and behavioral interventions do not immediately cure anxiety, mend broken hearts, correct disruptive behaviors, disentangle power struggles, or alleviate depression. That is not what their job is. Coping skills and behavioral interventions are there to help us get better at handling complex situations and feelings. In particular, they are good at helping us manage our thoughts (“I can’t do it,” “He should behave better”) and our affect (anger, frustration, rage, anxiety, sadness), so that over time we get better at solving the problems, and break out of the patterns that perpetuate these problems.
• Second, kids and parents do not give skills credit for when they do work. That time you were spiraling out of control and told your mom you needed a break and watched some YouTube videos and then joined the family for dinner? Your coping skills worked, but nobody noticed because they worked. We need to help our young patients and families identify those times that coping skills and behavioral interventions worked.
• Third, let’s face it: Nothing works all the time. It is no wonder kids and families are disappointed by coping skills and behavioral interventions if they think they magically work once and forever. We need to manage expectations.
• Fourth, we know they are supposed to fail, and we should discuss this openly up front. This may sound surprising, but challenging behaviors often get worse when we begin to work on them. “Extinction bursts” is probably the easiest explanation, but for psychodynamically oriented youth and families we could talk about “resistance.” No matter what, things tend to get worse before they get better. We should let people know this ahead of time.
• Fifth, and this is the one that forces youth and parents to ask how hard they actually tried, these skills need to be practiced. You can’t be in the middle of a panic attack and for the first time start trying to pace your breathing with a technique a therapist told you about 3 weeks ago. This makes about as much sense as not training for a marathon. You need to practice and build up the skills, recognizing that as you become more familiar with them, they will help you manage during stressful situations. Every skill should be practiced, preferably several times or more in sessions, maybe every session, and definitely outside of sessions when not in distress.

We cannot blame children and parents for thinking that coping skills and behavioral interventions do not work. They are struggling, suffering, fighting, frightened, angry, anxious, frustrated, and often desperate for something to make everything better. Helping them recognize this desire for things to be better while managing expectations is an essential complement to supporting the use of coping skills and behavioral interventions, and a fairly easy conversation to have with youth.

So when you are talking about coping skills and parental behavioral interventions, it is important to be prepared for the “it didn’t work” conversation, and even to address these issues up front. After all, these strategies may not solve all the problems in the world, but can be lifelong ways of coping with life’s challenges.
 

Dr. Henderson is associate professor of clinical psychiatry at New York University and deputy director of child and adolescent psychiatry at Bellevue Hospital, New York.

You have an appointment with a 14-year-old youth you last saw for an annual camp physical. He had screened positive for depression, and you had referred him to a local therapist. He did not have an appointment until after camp, and you have only met a few times, but since you had spoken with him about his depression, he set up an appointment with you to ask about medications. When you meet him you ask about what he had been doing in therapy and he says, “I’m learning ‘coping skills,’ but they don’t work.”

From breathing exercises and sticker charts to mindfulness and grounding exercise, coping skills can be crucial for learning how to manage distress, regulate emotions, become more effective interpersonally, and function better. Similarly, parenting interventions, which change the way parents and youth interact, are a central family intervention for behavioral problems in youth.

It is very common, however, to hear that they “don’t work” or have a parent say, “We tried that, it doesn’t work.”

When kids and parents reject coping skills and behavioral interventions by saying they do not work, the consequences can be substantial. It can mean the rejection of coping skills and strategies that actually would have helped, given time and support; that kids and families bounce between services with increasing frustration; that they search for a magic bullet (which also won’t work); and, particularly concerning for physicians, a belief that the youth have not received the right medication, resulting in potentially unhelpful concoctions of medication.

One of the biggest challenges in helping youth and parents overcome their difficulties – whether these difficulties are depression and anxiety or being better parents to struggling kids – is helping them understand that despite the fact that coping skills and behavioral interventions do not seem to work, they work.

We just have to do a better job explaining what that “work” is.

There are five points you can make.

• First, the coping skill or behavioral intervention is not supposed to work if that means solving the underlying problem. Coping skills and behavioral interventions do not immediately cure anxiety, mend broken hearts, correct disruptive behaviors, disentangle power struggles, or alleviate depression. That is not what their job is. Coping skills and behavioral interventions are there to help us get better at handling complex situations and feelings. In particular, they are good at helping us manage our thoughts (“I can’t do it,” “He should behave better”) and our affect (anger, frustration, rage, anxiety, sadness), so that over time we get better at solving the problems, and break out of the patterns that perpetuate these problems.
• Second, kids and parents do not give skills credit for when they do work. That time you were spiraling out of control and told your mom you needed a break and watched some YouTube videos and then joined the family for dinner? Your coping skills worked, but nobody noticed because they worked. We need to help our young patients and families identify those times that coping skills and behavioral interventions worked.
• Third, let’s face it: Nothing works all the time. It is no wonder kids and families are disappointed by coping skills and behavioral interventions if they think they magically work once and forever. We need to manage expectations.
• Fourth, we know they are supposed to fail, and we should discuss this openly up front. This may sound surprising, but challenging behaviors often get worse when we begin to work on them. “Extinction bursts” is probably the easiest explanation, but for psychodynamically oriented youth and families we could talk about “resistance.” No matter what, things tend to get worse before they get better. We should let people know this ahead of time.
• Fifth, and this is the one that forces youth and parents to ask how hard they actually tried, these skills need to be practiced. You can’t be in the middle of a panic attack and for the first time start trying to pace your breathing with a technique a therapist told you about 3 weeks ago. This makes about as much sense as not training for a marathon. You need to practice and build up the skills, recognizing that as you become more familiar with them, they will help you manage during stressful situations. Every skill should be practiced, preferably several times or more in sessions, maybe every session, and definitely outside of sessions when not in distress.

We cannot blame children and parents for thinking that coping skills and behavioral interventions do not work. They are struggling, suffering, fighting, frightened, angry, anxious, frustrated, and often desperate for something to make everything better. Helping them recognize this desire for things to be better while managing expectations is an essential complement to supporting the use of coping skills and behavioral interventions, and a fairly easy conversation to have with youth.

So when you are talking about coping skills and parental behavioral interventions, it is important to be prepared for the “it didn’t work” conversation, and even to address these issues up front. After all, these strategies may not solve all the problems in the world, but can be lifelong ways of coping with life’s challenges.
 

Dr. Henderson is associate professor of clinical psychiatry at New York University and deputy director of child and adolescent psychiatry at Bellevue Hospital, New York.

You have an appointment with a 14-year-old youth you last saw for an annual camp physical. He had screened positive for depression, and you had referred him to a local therapist. He did not have an appointment until after camp, and you have only met a few times, but since you had spoken with him about his depression, he set up an appointment with you to ask about medications. When you meet him you ask about what he had been doing in therapy and he says, “I’m learning ‘coping skills,’ but they don’t work.”

From breathing exercises and sticker charts to mindfulness and grounding exercise, coping skills can be crucial for learning how to manage distress, regulate emotions, become more effective interpersonally, and function better. Similarly, parenting interventions, which change the way parents and youth interact, are a central family intervention for behavioral problems in youth.

It is very common, however, to hear that they “don’t work” or have a parent say, “We tried that, it doesn’t work.”

When kids and parents reject coping skills and behavioral interventions by saying they do not work, the consequences can be substantial. It can mean the rejection of coping skills and strategies that actually would have helped, given time and support; that kids and families bounce between services with increasing frustration; that they search for a magic bullet (which also won’t work); and, particularly concerning for physicians, a belief that the youth have not received the right medication, resulting in potentially unhelpful concoctions of medication.

One of the biggest challenges in helping youth and parents overcome their difficulties – whether these difficulties are depression and anxiety or being better parents to struggling kids – is helping them understand that despite the fact that coping skills and behavioral interventions do not seem to work, they work.

We just have to do a better job explaining what that “work” is.

There are five points you can make.

• First, the coping skill or behavioral intervention is not supposed to work if that means solving the underlying problem. Coping skills and behavioral interventions do not immediately cure anxiety, mend broken hearts, correct disruptive behaviors, disentangle power struggles, or alleviate depression. That is not what their job is. Coping skills and behavioral interventions are there to help us get better at handling complex situations and feelings. In particular, they are good at helping us manage our thoughts (“I can’t do it,” “He should behave better”) and our affect (anger, frustration, rage, anxiety, sadness), so that over time we get better at solving the problems, and break out of the patterns that perpetuate these problems.
• Second, kids and parents do not give skills credit for when they do work. That time you were spiraling out of control and told your mom you needed a break and watched some YouTube videos and then joined the family for dinner? Your coping skills worked, but nobody noticed because they worked. We need to help our young patients and families identify those times that coping skills and behavioral interventions worked.
• Third, let’s face it: Nothing works all the time. It is no wonder kids and families are disappointed by coping skills and behavioral interventions if they think they magically work once and forever. We need to manage expectations.
• Fourth, we know they are supposed to fail, and we should discuss this openly up front. This may sound surprising, but challenging behaviors often get worse when we begin to work on them. “Extinction bursts” is probably the easiest explanation, but for psychodynamically oriented youth and families we could talk about “resistance.” No matter what, things tend to get worse before they get better. We should let people know this ahead of time.
• Fifth, and this is the one that forces youth and parents to ask how hard they actually tried, these skills need to be practiced. You can’t be in the middle of a panic attack and for the first time start trying to pace your breathing with a technique a therapist told you about 3 weeks ago. This makes about as much sense as not training for a marathon. You need to practice and build up the skills, recognizing that as you become more familiar with them, they will help you manage during stressful situations. Every skill should be practiced, preferably several times or more in sessions, maybe every session, and definitely outside of sessions when not in distress.

We cannot blame children and parents for thinking that coping skills and behavioral interventions do not work. They are struggling, suffering, fighting, frightened, angry, anxious, frustrated, and often desperate for something to make everything better. Helping them recognize this desire for things to be better while managing expectations is an essential complement to supporting the use of coping skills and behavioral interventions, and a fairly easy conversation to have with youth.

So when you are talking about coping skills and parental behavioral interventions, it is important to be prepared for the “it didn’t work” conversation, and even to address these issues up front. After all, these strategies may not solve all the problems in the world, but can be lifelong ways of coping with life’s challenges.
 

Dr. Henderson is associate professor of clinical psychiatry at New York University and deputy director of child and adolescent psychiatry at Bellevue Hospital, New York.

Recently, I encountered a study in Pediatrics that hoped to answer the question of whether there was any benefit to tactile stimulation in those nerve-rattling moments when a newborn didn’t seem to take much interest in breathing: “Tactile stimulation in newborn infants with inadequate respiration at birth: A systematic review.” Now there is a title that grabs the attention of every frontline pediatrician who has sweated through those minutes that seemed like hours in the delivery room when some little rascal has decided that breathing isn’t a priority.

Of course, your great grandmother and everyone else knew what needed to be done – the obstetrician hung the baby by his or her ankles and slapped it on the bottom a couple of times. But you went to medical school and learned that was barbaric. Instead, you modeled the behavior of the residents and delivery room nurses who had more refined techniques such as heel flicking and vigorous spine rubbing. You never thought to ask if there was any science behind those activities because everyone did them.

Well, the authors of the article in Pediatrics, writing on behalf of the International Liaison Committee on Resuscitation and Neonatal Life Support Task Force, thought the time had come to turn over a few stones and see if tactile stimulation was a benefit in resuscitation. Beginning with 2,455 possibly relevant articles, they quickly (I suspect they would quibble with the “quickly” part) winnowed these down to two observational studies, one of which was rejected because of “critical risk of bias.” The surviving study showed a reduction in tracheal intubation in infants who had received tactile stimulation. However, the authors felt that the “certainty of evidence was very low.”

So, there you have it. Aren’t you glad you didn’t invest 15 or 20 minutes discovering what you probably had guessed already? You can thank me later.

You already suspected that it may not help. However, like any good physician, what you really wanted to know is whether were you doing any harm by heel flicking and spine rubbing. And I bet you already had an opinion about the answer to that question. During your training, you may have seen delivery room personnel who were clearly too vigorous in their tactile stimulation and/or too persistent in their heel flicking and spine rubbing when the next steps in resuscitation needed to be taken. That’s the next study that needs to be done. I hope that study finds that tactile stimulation may not help but as long as it is done using specific techniques and within certain temporal parameters it does no harm.

I was never much for heel flicking. My favorite tactile stimulation was encircling the pokey infant’s chest in my hand, gently compressing and then quickly releasing a couple of times. My hope was that by mimicking the birth process the sensors in the infant’s chest wall would remind him it was time to breathe. That, and a silent plea to Mother Nature, worked most of the time.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Recently, I encountered a study in Pediatrics that hoped to answer the question of whether there was any benefit to tactile stimulation in those nerve-rattling moments when a newborn didn’t seem to take much interest in breathing: “Tactile stimulation in newborn infants with inadequate respiration at birth: A systematic review.” Now there is a title that grabs the attention of every frontline pediatrician who has sweated through those minutes that seemed like hours in the delivery room when some little rascal has decided that breathing isn’t a priority.

Of course, your great grandmother and everyone else knew what needed to be done – the obstetrician hung the baby by his or her ankles and slapped it on the bottom a couple of times. But you went to medical school and learned that was barbaric. Instead, you modeled the behavior of the residents and delivery room nurses who had more refined techniques such as heel flicking and vigorous spine rubbing. You never thought to ask if there was any science behind those activities because everyone did them.

Well, the authors of the article in Pediatrics, writing on behalf of the International Liaison Committee on Resuscitation and Neonatal Life Support Task Force, thought the time had come to turn over a few stones and see if tactile stimulation was a benefit in resuscitation. Beginning with 2,455 possibly relevant articles, they quickly (I suspect they would quibble with the “quickly” part) winnowed these down to two observational studies, one of which was rejected because of “critical risk of bias.” The surviving study showed a reduction in tracheal intubation in infants who had received tactile stimulation. However, the authors felt that the “certainty of evidence was very low.”

So, there you have it. Aren’t you glad you didn’t invest 15 or 20 minutes discovering what you probably had guessed already? You can thank me later.

You already suspected that it may not help. However, like any good physician, what you really wanted to know is whether were you doing any harm by heel flicking and spine rubbing. And I bet you already had an opinion about the answer to that question. During your training, you may have seen delivery room personnel who were clearly too vigorous in their tactile stimulation and/or too persistent in their heel flicking and spine rubbing when the next steps in resuscitation needed to be taken. That’s the next study that needs to be done. I hope that study finds that tactile stimulation may not help but as long as it is done using specific techniques and within certain temporal parameters it does no harm.

I was never much for heel flicking. My favorite tactile stimulation was encircling the pokey infant’s chest in my hand, gently compressing and then quickly releasing a couple of times. My hope was that by mimicking the birth process the sensors in the infant’s chest wall would remind him it was time to breathe. That, and a silent plea to Mother Nature, worked most of the time.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

Recently, I encountered a study in Pediatrics that hoped to answer the question of whether there was any benefit to tactile stimulation in those nerve-rattling moments when a newborn didn’t seem to take much interest in breathing: “Tactile stimulation in newborn infants with inadequate respiration at birth: A systematic review.” Now there is a title that grabs the attention of every frontline pediatrician who has sweated through those minutes that seemed like hours in the delivery room when some little rascal has decided that breathing isn’t a priority.

Of course, your great grandmother and everyone else knew what needed to be done – the obstetrician hung the baby by his or her ankles and slapped it on the bottom a couple of times. But you went to medical school and learned that was barbaric. Instead, you modeled the behavior of the residents and delivery room nurses who had more refined techniques such as heel flicking and vigorous spine rubbing. You never thought to ask if there was any science behind those activities because everyone did them.

Well, the authors of the article in Pediatrics, writing on behalf of the International Liaison Committee on Resuscitation and Neonatal Life Support Task Force, thought the time had come to turn over a few stones and see if tactile stimulation was a benefit in resuscitation. Beginning with 2,455 possibly relevant articles, they quickly (I suspect they would quibble with the “quickly” part) winnowed these down to two observational studies, one of which was rejected because of “critical risk of bias.” The surviving study showed a reduction in tracheal intubation in infants who had received tactile stimulation. However, the authors felt that the “certainty of evidence was very low.”

So, there you have it. Aren’t you glad you didn’t invest 15 or 20 minutes discovering what you probably had guessed already? You can thank me later.

You already suspected that it may not help. However, like any good physician, what you really wanted to know is whether were you doing any harm by heel flicking and spine rubbing. And I bet you already had an opinion about the answer to that question. During your training, you may have seen delivery room personnel who were clearly too vigorous in their tactile stimulation and/or too persistent in their heel flicking and spine rubbing when the next steps in resuscitation needed to be taken. That’s the next study that needs to be done. I hope that study finds that tactile stimulation may not help but as long as it is done using specific techniques and within certain temporal parameters it does no harm.

I was never much for heel flicking. My favorite tactile stimulation was encircling the pokey infant’s chest in my hand, gently compressing and then quickly releasing a couple of times. My hope was that by mimicking the birth process the sensors in the infant’s chest wall would remind him it was time to breathe. That, and a silent plea to Mother Nature, worked most of the time.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

A few weeks ago I talked about my evening practice of doing jigsaw puzzles to relax, as a pleasant alternative to surfing the Internet.

Last week my daughter moved home from college for the summer. It’s been several years since she and I last did puzzles together, and I’d forgotten how much she likes them.

So now each night we sit there, either side by side or across the table from each other, each quietly working on some little portion of the same jigsaw. Very little is said, but it’s still the same bonding time I’ve always cherished.

But I notice things I’d never thought of.

I always start a puzzle like I thought most people do: Pick out the flat edge pieces to build the outside frame, then work inward from there.

But she doesn’t. Once the box is opened and pieces dumped out, she starts sorting them by patterns and colors, and begins there. The edges don’t get her attention at all as she begins. She assembles like-pieces and gradually expands from there.

Why?

I mean, I’m a neurologist. Brains are my business. So why are our thought patterns on the same task so different?

I have no clue.

This is part of the mystery of the brain. Why different ones, although anatomically similar, can function so differently in how they approach and solve the same problem.

I can’t blame this on who she learned from. We’ve been doing puzzles together since she was little. Think about it – do you even remember someone teaching you to do jigsaw puzzles at some point? Neither do I. I assume a family member or schoolteacher showed me a basic one at some point, and how the pieces fit together, but that’s a guess.

So I sit there working on my section and watch her doing hers, and the neurologist turns the whole thing over. Does she have more neurons and/or glia in whatever the “puzzle solving” portion of her brain (I assume part of visual memory and spatial relationships) is? Or do I? Like so much of neurology this should have a structural answer – I think.

It reminds me of how little we still know. And it bugs me.

Has anyone done PET scans while people work on jigsaw puzzles? I checked PubMed and couldn’t find anything. I doubt it due to the logistics of having someone do one inside a scanner. Searching Google with the same question only gets me ads for customized jigsaws of pets.

So I made the leap to doing a jigsaw puzzle on an iPad while in a PET machine. But even then, how do I know I’d be testing the same functions? The touchscreen is similar, but not the same, as doing a real jigsaw. (In my opinion real puzzles are preferable to iPad ones, except when traveling).

At the end of the day it’s a mystery I don’t know the answer to, probably never will, and realistically shouldn’t think too much about.

Because this summer the real meaning of the puzzle isn’t the jigsaw itself. It’s the young woman sitting next to me working on it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A few weeks ago I talked about my evening practice of doing jigsaw puzzles to relax, as a pleasant alternative to surfing the Internet.

Last week my daughter moved home from college for the summer. It’s been several years since she and I last did puzzles together, and I’d forgotten how much she likes them.

So now each night we sit there, either side by side or across the table from each other, each quietly working on some little portion of the same jigsaw. Very little is said, but it’s still the same bonding time I’ve always cherished.

But I notice things I’d never thought of.

I always start a puzzle like I thought most people do: Pick out the flat edge pieces to build the outside frame, then work inward from there.

But she doesn’t. Once the box is opened and pieces dumped out, she starts sorting them by patterns and colors, and begins there. The edges don’t get her attention at all as she begins. She assembles like-pieces and gradually expands from there.

Why?

I mean, I’m a neurologist. Brains are my business. So why are our thought patterns on the same task so different?

I have no clue.

This is part of the mystery of the brain. Why different ones, although anatomically similar, can function so differently in how they approach and solve the same problem.

I can’t blame this on who she learned from. We’ve been doing puzzles together since she was little. Think about it – do you even remember someone teaching you to do jigsaw puzzles at some point? Neither do I. I assume a family member or schoolteacher showed me a basic one at some point, and how the pieces fit together, but that’s a guess.

So I sit there working on my section and watch her doing hers, and the neurologist turns the whole thing over. Does she have more neurons and/or glia in whatever the “puzzle solving” portion of her brain (I assume part of visual memory and spatial relationships) is? Or do I? Like so much of neurology this should have a structural answer – I think.

It reminds me of how little we still know. And it bugs me.

Has anyone done PET scans while people work on jigsaw puzzles? I checked PubMed and couldn’t find anything. I doubt it due to the logistics of having someone do one inside a scanner. Searching Google with the same question only gets me ads for customized jigsaws of pets.

So I made the leap to doing a jigsaw puzzle on an iPad while in a PET machine. But even then, how do I know I’d be testing the same functions? The touchscreen is similar, but not the same, as doing a real jigsaw. (In my opinion real puzzles are preferable to iPad ones, except when traveling).

At the end of the day it’s a mystery I don’t know the answer to, probably never will, and realistically shouldn’t think too much about.

Because this summer the real meaning of the puzzle isn’t the jigsaw itself. It’s the young woman sitting next to me working on it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A few weeks ago I talked about my evening practice of doing jigsaw puzzles to relax, as a pleasant alternative to surfing the Internet.

Last week my daughter moved home from college for the summer. It’s been several years since she and I last did puzzles together, and I’d forgotten how much she likes them.

So now each night we sit there, either side by side or across the table from each other, each quietly working on some little portion of the same jigsaw. Very little is said, but it’s still the same bonding time I’ve always cherished.

But I notice things I’d never thought of.

I always start a puzzle like I thought most people do: Pick out the flat edge pieces to build the outside frame, then work inward from there.

But she doesn’t. Once the box is opened and pieces dumped out, she starts sorting them by patterns and colors, and begins there. The edges don’t get her attention at all as she begins. She assembles like-pieces and gradually expands from there.

Why?

I mean, I’m a neurologist. Brains are my business. So why are our thought patterns on the same task so different?

I have no clue.

This is part of the mystery of the brain. Why different ones, although anatomically similar, can function so differently in how they approach and solve the same problem.

I can’t blame this on who she learned from. We’ve been doing puzzles together since she was little. Think about it – do you even remember someone teaching you to do jigsaw puzzles at some point? Neither do I. I assume a family member or schoolteacher showed me a basic one at some point, and how the pieces fit together, but that’s a guess.

So I sit there working on my section and watch her doing hers, and the neurologist turns the whole thing over. Does she have more neurons and/or glia in whatever the “puzzle solving” portion of her brain (I assume part of visual memory and spatial relationships) is? Or do I? Like so much of neurology this should have a structural answer – I think.

It reminds me of how little we still know. And it bugs me.

Has anyone done PET scans while people work on jigsaw puzzles? I checked PubMed and couldn’t find anything. I doubt it due to the logistics of having someone do one inside a scanner. Searching Google with the same question only gets me ads for customized jigsaws of pets.

So I made the leap to doing a jigsaw puzzle on an iPad while in a PET machine. But even then, how do I know I’d be testing the same functions? The touchscreen is similar, but not the same, as doing a real jigsaw. (In my opinion real puzzles are preferable to iPad ones, except when traveling).

At the end of the day it’s a mystery I don’t know the answer to, probably never will, and realistically shouldn’t think too much about.

Because this summer the real meaning of the puzzle isn’t the jigsaw itself. It’s the young woman sitting next to me working on it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.

Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.

Transitioning from active therapy to symptom management

Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.

The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones. Hospice transitions seem to reside in an area of clinical practice that is overlooked or, in my experience they are considered an afterthought by many oncologists.

When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.

In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.

A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
 

‘Don’t just put in the hospice order and walk away’

Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.

First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.

Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.

If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.

These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.

As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.

Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.