Article

To reach early diagnoses and improve outcomes in cases of mucosal and esophageal lichen planus (ELP), patient education along with a multidisciplinary approach centered on collaboration among dermatologists, gastroenterologists, gynecologists, and dental practitioners should be a priority. Tofacitinib therapy should be considered in the treatment of patients presenting with cutaneous lichen planus (CLP), mucosal lichen planus, and ELP.

Lichen planus is a papulosquamous disease of the skin and mucous membranes that is most common on the skin and oral mucosa. Typical lesions of CLP present as purple, pruritic, polygonal papules and plaques on the flexural surfaces of the wrists and ankles as well as areas of friction or trauma due to scratching such as the shins and lower back. Various subtypes of lichen planus can present simultaneously, resulting in extensive involvement that worsens through koebnerization and affects the oral cavity, esophagus, larynx, sclera, genitalia, scalp, and nails.^1,2

Esophageal lichen planus can develop with or without the presence of CLP, oral lichen planus (OLP), or genital lichen planus.³ It typically affects women older than 50 years and is linked to OLP and vulvar lichen planus, with 1 study reporting that 87% (63/72) of ELP patients were women with a median age of 61.9 years at the time of diagnosis (range, 22–85 years). Almost all ELP patients in the study had lichen planus symptoms in other locations; 89% (64/72) had OLP, and 42% (30/72) had vulvar lichen planus.⁴ Consequently, a diagnosis of ELP should be followed by a thorough full-body examination to check for lichen planus at other sites. Studies that examined lichen planus patients for ELP found that 25% to 50% of patients diagnosed with orocutaneous lichen planus also had ELP, with ELP frequently presenting without symptoms.^3,5 These findings indicate that ELP likely is underdiagnosed and often misdiagnosed, resulting in an underestimation of its prevalence.

Our case highlights a frequently misdiagnosed condition and underscores the importance of close examination of patients presenting with CLP and OLP for signs and symptoms of ELP. Furthermore, we discuss the importance of patient education and collaboration among different specialties in attaining an early diagnosis to improve patient outcomes. Finally, we review the clinical presentation, diagnosis, and treatment of CLP, OLP, and ELP, as well as the utility of tofacitinib for ELP.

Case Report

An emaciated 89-year-old woman with an 11-year history of CLP, OLP, and genital lichen planus that had been successfully treated with topicals presented with an OLP recurrence alongside difficulties eating and swallowing. Her symptoms lasted 1 year and would recur when treatment was paused. Her medical history included rheumatoid arthritis, hypothyroidism, and hypertension, and she was taking levothyroxine, olmesartan, and vitamin D supplements. Dentures and olmesartan previously were ruled out as potential triggers following a 2-month elimination. None of her remaining natural teeth had fillings. She also reported that neither she nor her partner had ever smoked or chewed tobacco.

The patient’s lichen planus involvement first manifested as red, itchy, polygonal, lichenoid papules on the superior and inferior mid back 11 years prior to the current presentation (Figure 1). Further examination noted erosions on the genitalia, and a subsequent biopsy of the vulva confirmed a diagnosis of lichen planus (Figure 2). Treatment with halobetasol propionate ointment and tacrolimus ointment 0.1% twice daily (BID) resulted in remission of the CLP and vulvar lichen planus. She presented a year later with oral involvement revealing Wickham striae on the buccal mucosa and erosions on the upper palate that resolved after 2 months of treatment with cyclosporine oral solution mixed with a 5-times-daily nystatin swish-and-spit (Figure 3). The CLP did not recur but OLP was punctuated by remissions and recurrences on a yearly basis, often related to the cessation of mouthwash and topical creams. The OLP and vulvar lichen planus were successfully treated with as-needed use of a cyclosporine mouthwash swish-and-spit 3 times daily as well as halobetasol ointment 0.05% 3 times daily, respectively. Six years later, the patient was hospitalized for unrelated causes and was lost to follow-up for 2 years.

The patient experienced worsening dysphagia and odynophagia over a period of 2 years (mild dysphagia was first recorded 7 years prior to the initial presentation) and reported an unintentional weight loss of 20 pounds. An endoscopy was performed 3 years after the initial report of dysphagia and noted esophageal erosions (Figure 4A) and a stricture (Figure 4B), but all abnormal involvement was attributed to active gastroesophageal reflux disease. She underwent 8 esophageal dilations to treat the stricture but noted that the duration of symptomatic relief decreased with every subsequent dilation. An esophageal stent was placed 4 years after the initial concern of dysphagia, but it was not well tolerated and had to be removed soon thereafter. A year later, the patient underwent an esophageal bypass with a substernal gastric conduit that provided relief for 2 months but failed to permanently resolve the condition. In fact, her condition worsened over the next 1.5 years when she presented with extreme emaciation attributed to a low appetite and pain while eating. A review of the slides from a prior hospital esophageal biopsy revealed lichen planus (Figure 5). She was prescribed tofacitinib 5 mg BID as a dual-purpose treatment for the rheumatoid arthritis and OLP/ELP. At 1-month follow-up she noted that she had only taken one 5-mg pill daily without notable improvement, and after the visit she started the initial recommendation of 5 mg BID. Over the next several months, her condition continued to consistently improve; the odynophagia resolved, and she regained the majority of her lost weight. Tofacitinib was well tolerated across the course of treatment, and no adverse side effects were noted. Furthermore, the patient regained a full range of motion in the previously immobile arthritic right shoulder. She has experienced no recurrence of the genital lichen planus, OLP, or CLP since starting tofacitinib. To date, the patient is still taking only tofacitinib 5 mg BID with no recurrence of the cutaneous, mucosal, or esophageal lichen planus and has experienced no adverse events from the medication.

Clinical Presentation—Lichen planus—CLP and OLP—most frequently presents between the ages of 40 and 60 years, with a slight female predilection.^1,2 The lesions typically present with the 5 P’s—purple, pruritic, polygonal papules and plaques—with some lesions revealing white lacy lines overlying them called Wickham striae.⁶ The lesions may be red at first before turning purple. They often present on the flexural surfaces of the wrists and ankles as well as the shins and back but rarely affect the face, perhaps because of increased chronic sun exposure.^2,6 Less common locations include the scalp, nails, and mucosal areas (eg, oral, vulvar, conjunctival, laryngeal, esophageal, anal).¹

If CLP is diagnosed, the patient likely will also have oral lesions, which occur in 50% of patients.² Once any form of lichen planus is found, it is important to examine all of the most frequently involved locations—mucocutaneous and cutaneous as well as the nails and scalp. Special care should be taken when examining OLP and genital lichen planus, as long-standing lesions have a 2% to 5% chance of transforming into squamous cell carcinoma.²

Although cases of traditional OLP and CLP are ubiquitous in the literature, ELP rarely is documented because of frequent misdiagnoses. Esophageal lichen planus has a closer histopathologic resemblance to OLP compared to CLP, and its highly variable presentation often results in an inconclusive diagnosis.³ A review of 27 patients with lichen planus highlighted the difficult nature of diagnosing ELP; ELP manifested up to 20 years after initial lichen planus diagnosis, and patients underwent an average of 2.5 dilations prior to the successful diagnosis of ELP. Interestingly, 2 patients in the study presented with ELP in isolation, which emphasizes the importance of secondary examination for lichen planus in the presence of esophageal strictures.⁷ The eTable provides common patient demographics and symptoms to more effectively identify ELP.Differential Diagnosis—Because lichen planus can present anywhere on the body, it may be difficult to differentiate it from other skin conditions. Clinical appearance alone often is insufficient for diagnosing lichen planus, and a punch biopsy often is needed.^2,20 Cutaneous lichen planus may resemble eczema, lichen simplex chronicus, pityriasis rosea, prurigo nodularis, and psoriasis, while OLP may resemble bite trauma, leukoplakia, pemphigus, and thrush.²⁰ Dermoscopy of the tissue makes Wickham striae easier to visualize and assists in the diagnosis of lichen planus. Furthermore, thickening of the stratum granulosum, a prevalence of lymphocytes in the dermoepidermal junction, and vacuolar alteration of the stratum basale help to distinguish between lichen planus and other inflammatory dermatoses.²⁰ A diagnosis of lichen planus merits a full-body skin examination—hair, nails, eyes, oral mucosa, and genitalia—to rule out additional involvement.

Esophageal lichen planus most frequently presents as dysphagia, odynophagia, and weight loss, but other symptoms including heartburn, hoarseness, choking, and epigastric pain may suggest esophageal involvement.⁴ Typically, ELP presents in the proximal and/or central esophagus, assisting in the differentiation between ELP and other esophageal conditions.³ Special consideration should be taken when both ELP and gastroesophageal reflux disease are considered in a differential diagnosis, and it is recommended to pair an upper endoscopy with pH monitoring to avoid misdiagnosis.⁸ Screening endoscopies also are helpful, as they assist in identifying the characteristic white webs, skin peeling, skin surface erosion, and strictures of ELP.⁴ Taken together, dermatologists should encourage patients with cutaneous or mucocutaneous lichen planus to undergo an esophagogastroduodenoscopy, especially in the presence of any of ELP’s common symptoms (eTable).

Etiology—Although the exact etiology of lichen planus is not well established, there are several known correlative factors, including hepatitis C; increased stress; dental materials; oral medications, most frequently antihypertensives and nonsteroidal anti-inflammatory drugs; systemic diseases; and tobacco usage.^6,21

Dental materials used in oral treatments such as silver amalgam, gold, cobalt, palladium, chromium, epoxy resins, and dentures can trigger or exacerbate OLP, and patch testing of a patient’s dental materials can help determine if the reaction was caused by the materials.^6,22 The removal of material contributing to lesions often will cause OLP to resolve.²²

It also has been suggested that the presence of thyroid disorders, autoimmune disease, various cancers, hypertension, type 2 diabetes mellitus, hyperlipidemia, oral sedative usage, and/or vitamin D deficiency may be associated with OLP.^21,23 Although OLP patients who were initially deficient in vitamin D demonstrated marked improvement with supplementation, it is unlikely that vitamin D supplements impacted our patient’s presentation of OLP, as she had been consistently taking them for more than 5 years with no change in OLP presentation.²⁴

Pathogenesis—Lichen planus is thought to be a cytotoxic CD8⁺ T cell–mediated autoimmune disease to a virally modified epidermal self-antigen on keratinocytes. The cytotoxic T cells target the modified self-antigens on basal keratinocytes and induce apoptosis.²⁵ The cytokine-mediated lymphocyte homing mechanism is human leukocyte antigen dependent and involves tumor necrosis factor α as well as IFN-γ and IL-1. The latter cytokines lead to upregulation of vascular adhesion molecules on endothelial vessels of subepithelial vascular plexus as well as a cascade of nonspecific mechanisms such as mast cell degranulation and matrix metalloproteinase activation, resulting in increased basement membrane disruption.⁶

Shao et al¹⁹ underscored the role of IFN-γ in CD8⁺ T cell–mediated cytotoxic cellular responses, noting that the Janus kinase (JAK)–signal transducer and activator of transcription pathway may play a key role in the pathogenesis of lichen planus. They proposed using JAK inhibitors for the treatment of lichen planus, specifically tofacitinib, a JAK1/JAK3 inhibitor, and baricitinib, a JAK1/JAK2 inhibitor, as top therapeutic agents for lichen planus (eTable).¹⁹ Tofacitinib has been reported to successfully treat conditions such as psoriasis, psoriatic arthritis, alopecia areata, vitiligo, atopic dermatitis, sarcoidosis, pyoderma gangrenosum, and lichen planopilaris.²⁶ Additionally, the efficacy of tofacitinib has been established in patients with erosive lichen planus; tofacitinib resulted in marked improvement while prednisone, acitretin, methotrexate, mycophenolate mofetil, and cyclosporine treatment failed.²⁷ Although more studies on tofacitinib’s long-term efficacy, cost, and safety are necessary, tofacitinib may soon play an integral role in the battle against inflammatory dermatoses.

Conclusion

Esophageal lichen planus is an underreported form of lichen planus that often is misdiagnosed. It frequently causes dysphagia and odynophagia, resulting in a major decrease in a patient’s quality of life. We present the case of an 89-year-old woman who underwent procedures to dilate her esophagus that worsened her condition. We emphasize the importance of considering ELP in the differential diagnosis of patients presenting with lichen planus in another region. In our patient, tofacitinib 5 mg BID resolved her condition without any adverse effects.

To reach early diagnoses and improve outcomes in cases of mucosal and esophageal lichen planus (ELP), patient education along with a multidisciplinary approach centered on collaboration among dermatologists, gastroenterologists, gynecologists, and dental practitioners should be a priority. Tofacitinib therapy should be considered in the treatment of patients presenting with cutaneous lichen planus (CLP), mucosal lichen planus, and ELP.

Lichen planus is a papulosquamous disease of the skin and mucous membranes that is most common on the skin and oral mucosa. Typical lesions of CLP present as purple, pruritic, polygonal papules and plaques on the flexural surfaces of the wrists and ankles as well as areas of friction or trauma due to scratching such as the shins and lower back. Various subtypes of lichen planus can present simultaneously, resulting in extensive involvement that worsens through koebnerization and affects the oral cavity, esophagus, larynx, sclera, genitalia, scalp, and nails.^1,2

Esophageal lichen planus can develop with or without the presence of CLP, oral lichen planus (OLP), or genital lichen planus.³ It typically affects women older than 50 years and is linked to OLP and vulvar lichen planus, with 1 study reporting that 87% (63/72) of ELP patients were women with a median age of 61.9 years at the time of diagnosis (range, 22–85 years). Almost all ELP patients in the study had lichen planus symptoms in other locations; 89% (64/72) had OLP, and 42% (30/72) had vulvar lichen planus.⁴ Consequently, a diagnosis of ELP should be followed by a thorough full-body examination to check for lichen planus at other sites. Studies that examined lichen planus patients for ELP found that 25% to 50% of patients diagnosed with orocutaneous lichen planus also had ELP, with ELP frequently presenting without symptoms.^3,5 These findings indicate that ELP likely is underdiagnosed and often misdiagnosed, resulting in an underestimation of its prevalence.

Our case highlights a frequently misdiagnosed condition and underscores the importance of close examination of patients presenting with CLP and OLP for signs and symptoms of ELP. Furthermore, we discuss the importance of patient education and collaboration among different specialties in attaining an early diagnosis to improve patient outcomes. Finally, we review the clinical presentation, diagnosis, and treatment of CLP, OLP, and ELP, as well as the utility of tofacitinib for ELP.

Case Report

An emaciated 89-year-old woman with an 11-year history of CLP, OLP, and genital lichen planus that had been successfully treated with topicals presented with an OLP recurrence alongside difficulties eating and swallowing. Her symptoms lasted 1 year and would recur when treatment was paused. Her medical history included rheumatoid arthritis, hypothyroidism, and hypertension, and she was taking levothyroxine, olmesartan, and vitamin D supplements. Dentures and olmesartan previously were ruled out as potential triggers following a 2-month elimination. None of her remaining natural teeth had fillings. She also reported that neither she nor her partner had ever smoked or chewed tobacco.

The patient’s lichen planus involvement first manifested as red, itchy, polygonal, lichenoid papules on the superior and inferior mid back 11 years prior to the current presentation (Figure 1). Further examination noted erosions on the genitalia, and a subsequent biopsy of the vulva confirmed a diagnosis of lichen planus (Figure 2). Treatment with halobetasol propionate ointment and tacrolimus ointment 0.1% twice daily (BID) resulted in remission of the CLP and vulvar lichen planus. She presented a year later with oral involvement revealing Wickham striae on the buccal mucosa and erosions on the upper palate that resolved after 2 months of treatment with cyclosporine oral solution mixed with a 5-times-daily nystatin swish-and-spit (Figure 3). The CLP did not recur but OLP was punctuated by remissions and recurrences on a yearly basis, often related to the cessation of mouthwash and topical creams. The OLP and vulvar lichen planus were successfully treated with as-needed use of a cyclosporine mouthwash swish-and-spit 3 times daily as well as halobetasol ointment 0.05% 3 times daily, respectively. Six years later, the patient was hospitalized for unrelated causes and was lost to follow-up for 2 years.

The patient experienced worsening dysphagia and odynophagia over a period of 2 years (mild dysphagia was first recorded 7 years prior to the initial presentation) and reported an unintentional weight loss of 20 pounds. An endoscopy was performed 3 years after the initial report of dysphagia and noted esophageal erosions (Figure 4A) and a stricture (Figure 4B), but all abnormal involvement was attributed to active gastroesophageal reflux disease. She underwent 8 esophageal dilations to treat the stricture but noted that the duration of symptomatic relief decreased with every subsequent dilation. An esophageal stent was placed 4 years after the initial concern of dysphagia, but it was not well tolerated and had to be removed soon thereafter. A year later, the patient underwent an esophageal bypass with a substernal gastric conduit that provided relief for 2 months but failed to permanently resolve the condition. In fact, her condition worsened over the next 1.5 years when she presented with extreme emaciation attributed to a low appetite and pain while eating. A review of the slides from a prior hospital esophageal biopsy revealed lichen planus (Figure 5). She was prescribed tofacitinib 5 mg BID as a dual-purpose treatment for the rheumatoid arthritis and OLP/ELP. At 1-month follow-up she noted that she had only taken one 5-mg pill daily without notable improvement, and after the visit she started the initial recommendation of 5 mg BID. Over the next several months, her condition continued to consistently improve; the odynophagia resolved, and she regained the majority of her lost weight. Tofacitinib was well tolerated across the course of treatment, and no adverse side effects were noted. Furthermore, the patient regained a full range of motion in the previously immobile arthritic right shoulder. She has experienced no recurrence of the genital lichen planus, OLP, or CLP since starting tofacitinib. To date, the patient is still taking only tofacitinib 5 mg BID with no recurrence of the cutaneous, mucosal, or esophageal lichen planus and has experienced no adverse events from the medication.

Clinical Presentation—Lichen planus—CLP and OLP—most frequently presents between the ages of 40 and 60 years, with a slight female predilection.^1,2 The lesions typically present with the 5 P’s—purple, pruritic, polygonal papules and plaques—with some lesions revealing white lacy lines overlying them called Wickham striae.⁶ The lesions may be red at first before turning purple. They often present on the flexural surfaces of the wrists and ankles as well as the shins and back but rarely affect the face, perhaps because of increased chronic sun exposure.^2,6 Less common locations include the scalp, nails, and mucosal areas (eg, oral, vulvar, conjunctival, laryngeal, esophageal, anal).¹

If CLP is diagnosed, the patient likely will also have oral lesions, which occur in 50% of patients.² Once any form of lichen planus is found, it is important to examine all of the most frequently involved locations—mucocutaneous and cutaneous as well as the nails and scalp. Special care should be taken when examining OLP and genital lichen planus, as long-standing lesions have a 2% to 5% chance of transforming into squamous cell carcinoma.²

Although cases of traditional OLP and CLP are ubiquitous in the literature, ELP rarely is documented because of frequent misdiagnoses. Esophageal lichen planus has a closer histopathologic resemblance to OLP compared to CLP, and its highly variable presentation often results in an inconclusive diagnosis.³ A review of 27 patients with lichen planus highlighted the difficult nature of diagnosing ELP; ELP manifested up to 20 years after initial lichen planus diagnosis, and patients underwent an average of 2.5 dilations prior to the successful diagnosis of ELP. Interestingly, 2 patients in the study presented with ELP in isolation, which emphasizes the importance of secondary examination for lichen planus in the presence of esophageal strictures.⁷ The eTable provides common patient demographics and symptoms to more effectively identify ELP.Differential Diagnosis—Because lichen planus can present anywhere on the body, it may be difficult to differentiate it from other skin conditions. Clinical appearance alone often is insufficient for diagnosing lichen planus, and a punch biopsy often is needed.^2,20 Cutaneous lichen planus may resemble eczema, lichen simplex chronicus, pityriasis rosea, prurigo nodularis, and psoriasis, while OLP may resemble bite trauma, leukoplakia, pemphigus, and thrush.²⁰ Dermoscopy of the tissue makes Wickham striae easier to visualize and assists in the diagnosis of lichen planus. Furthermore, thickening of the stratum granulosum, a prevalence of lymphocytes in the dermoepidermal junction, and vacuolar alteration of the stratum basale help to distinguish between lichen planus and other inflammatory dermatoses.²⁰ A diagnosis of lichen planus merits a full-body skin examination—hair, nails, eyes, oral mucosa, and genitalia—to rule out additional involvement.

Esophageal lichen planus most frequently presents as dysphagia, odynophagia, and weight loss, but other symptoms including heartburn, hoarseness, choking, and epigastric pain may suggest esophageal involvement.⁴ Typically, ELP presents in the proximal and/or central esophagus, assisting in the differentiation between ELP and other esophageal conditions.³ Special consideration should be taken when both ELP and gastroesophageal reflux disease are considered in a differential diagnosis, and it is recommended to pair an upper endoscopy with pH monitoring to avoid misdiagnosis.⁸ Screening endoscopies also are helpful, as they assist in identifying the characteristic white webs, skin peeling, skin surface erosion, and strictures of ELP.⁴ Taken together, dermatologists should encourage patients with cutaneous or mucocutaneous lichen planus to undergo an esophagogastroduodenoscopy, especially in the presence of any of ELP’s common symptoms (eTable).

Etiology—Although the exact etiology of lichen planus is not well established, there are several known correlative factors, including hepatitis C; increased stress; dental materials; oral medications, most frequently antihypertensives and nonsteroidal anti-inflammatory drugs; systemic diseases; and tobacco usage.^6,21

Dental materials used in oral treatments such as silver amalgam, gold, cobalt, palladium, chromium, epoxy resins, and dentures can trigger or exacerbate OLP, and patch testing of a patient’s dental materials can help determine if the reaction was caused by the materials.^6,22 The removal of material contributing to lesions often will cause OLP to resolve.²²

It also has been suggested that the presence of thyroid disorders, autoimmune disease, various cancers, hypertension, type 2 diabetes mellitus, hyperlipidemia, oral sedative usage, and/or vitamin D deficiency may be associated with OLP.^21,23 Although OLP patients who were initially deficient in vitamin D demonstrated marked improvement with supplementation, it is unlikely that vitamin D supplements impacted our patient’s presentation of OLP, as she had been consistently taking them for more than 5 years with no change in OLP presentation.²⁴

Pathogenesis—Lichen planus is thought to be a cytotoxic CD8⁺ T cell–mediated autoimmune disease to a virally modified epidermal self-antigen on keratinocytes. The cytotoxic T cells target the modified self-antigens on basal keratinocytes and induce apoptosis.²⁵ The cytokine-mediated lymphocyte homing mechanism is human leukocyte antigen dependent and involves tumor necrosis factor α as well as IFN-γ and IL-1. The latter cytokines lead to upregulation of vascular adhesion molecules on endothelial vessels of subepithelial vascular plexus as well as a cascade of nonspecific mechanisms such as mast cell degranulation and matrix metalloproteinase activation, resulting in increased basement membrane disruption.⁶

Shao et al¹⁹ underscored the role of IFN-γ in CD8⁺ T cell–mediated cytotoxic cellular responses, noting that the Janus kinase (JAK)–signal transducer and activator of transcription pathway may play a key role in the pathogenesis of lichen planus. They proposed using JAK inhibitors for the treatment of lichen planus, specifically tofacitinib, a JAK1/JAK3 inhibitor, and baricitinib, a JAK1/JAK2 inhibitor, as top therapeutic agents for lichen planus (eTable).¹⁹ Tofacitinib has been reported to successfully treat conditions such as psoriasis, psoriatic arthritis, alopecia areata, vitiligo, atopic dermatitis, sarcoidosis, pyoderma gangrenosum, and lichen planopilaris.²⁶ Additionally, the efficacy of tofacitinib has been established in patients with erosive lichen planus; tofacitinib resulted in marked improvement while prednisone, acitretin, methotrexate, mycophenolate mofetil, and cyclosporine treatment failed.²⁷ Although more studies on tofacitinib’s long-term efficacy, cost, and safety are necessary, tofacitinib may soon play an integral role in the battle against inflammatory dermatoses.

Conclusion

Esophageal lichen planus is an underreported form of lichen planus that often is misdiagnosed. It frequently causes dysphagia and odynophagia, resulting in a major decrease in a patient’s quality of life. We present the case of an 89-year-old woman who underwent procedures to dilate her esophagus that worsened her condition. We emphasize the importance of considering ELP in the differential diagnosis of patients presenting with lichen planus in another region. In our patient, tofacitinib 5 mg BID resolved her condition without any adverse effects.

To reach early diagnoses and improve outcomes in cases of mucosal and esophageal lichen planus (ELP), patient education along with a multidisciplinary approach centered on collaboration among dermatologists, gastroenterologists, gynecologists, and dental practitioners should be a priority. Tofacitinib therapy should be considered in the treatment of patients presenting with cutaneous lichen planus (CLP), mucosal lichen planus, and ELP.

Lichen planus is a papulosquamous disease of the skin and mucous membranes that is most common on the skin and oral mucosa. Typical lesions of CLP present as purple, pruritic, polygonal papules and plaques on the flexural surfaces of the wrists and ankles as well as areas of friction or trauma due to scratching such as the shins and lower back. Various subtypes of lichen planus can present simultaneously, resulting in extensive involvement that worsens through koebnerization and affects the oral cavity, esophagus, larynx, sclera, genitalia, scalp, and nails.^1,2

Esophageal lichen planus can develop with or without the presence of CLP, oral lichen planus (OLP), or genital lichen planus.³ It typically affects women older than 50 years and is linked to OLP and vulvar lichen planus, with 1 study reporting that 87% (63/72) of ELP patients were women with a median age of 61.9 years at the time of diagnosis (range, 22–85 years). Almost all ELP patients in the study had lichen planus symptoms in other locations; 89% (64/72) had OLP, and 42% (30/72) had vulvar lichen planus.⁴ Consequently, a diagnosis of ELP should be followed by a thorough full-body examination to check for lichen planus at other sites. Studies that examined lichen planus patients for ELP found that 25% to 50% of patients diagnosed with orocutaneous lichen planus also had ELP, with ELP frequently presenting without symptoms.^3,5 These findings indicate that ELP likely is underdiagnosed and often misdiagnosed, resulting in an underestimation of its prevalence.

Our case highlights a frequently misdiagnosed condition and underscores the importance of close examination of patients presenting with CLP and OLP for signs and symptoms of ELP. Furthermore, we discuss the importance of patient education and collaboration among different specialties in attaining an early diagnosis to improve patient outcomes. Finally, we review the clinical presentation, diagnosis, and treatment of CLP, OLP, and ELP, as well as the utility of tofacitinib for ELP.

Case Report

An emaciated 89-year-old woman with an 11-year history of CLP, OLP, and genital lichen planus that had been successfully treated with topicals presented with an OLP recurrence alongside difficulties eating and swallowing. Her symptoms lasted 1 year and would recur when treatment was paused. Her medical history included rheumatoid arthritis, hypothyroidism, and hypertension, and she was taking levothyroxine, olmesartan, and vitamin D supplements. Dentures and olmesartan previously were ruled out as potential triggers following a 2-month elimination. None of her remaining natural teeth had fillings. She also reported that neither she nor her partner had ever smoked or chewed tobacco.

The patient’s lichen planus involvement first manifested as red, itchy, polygonal, lichenoid papules on the superior and inferior mid back 11 years prior to the current presentation (Figure 1). Further examination noted erosions on the genitalia, and a subsequent biopsy of the vulva confirmed a diagnosis of lichen planus (Figure 2). Treatment with halobetasol propionate ointment and tacrolimus ointment 0.1% twice daily (BID) resulted in remission of the CLP and vulvar lichen planus. She presented a year later with oral involvement revealing Wickham striae on the buccal mucosa and erosions on the upper palate that resolved after 2 months of treatment with cyclosporine oral solution mixed with a 5-times-daily nystatin swish-and-spit (Figure 3). The CLP did not recur but OLP was punctuated by remissions and recurrences on a yearly basis, often related to the cessation of mouthwash and topical creams. The OLP and vulvar lichen planus were successfully treated with as-needed use of a cyclosporine mouthwash swish-and-spit 3 times daily as well as halobetasol ointment 0.05% 3 times daily, respectively. Six years later, the patient was hospitalized for unrelated causes and was lost to follow-up for 2 years.

The patient experienced worsening dysphagia and odynophagia over a period of 2 years (mild dysphagia was first recorded 7 years prior to the initial presentation) and reported an unintentional weight loss of 20 pounds. An endoscopy was performed 3 years after the initial report of dysphagia and noted esophageal erosions (Figure 4A) and a stricture (Figure 4B), but all abnormal involvement was attributed to active gastroesophageal reflux disease. She underwent 8 esophageal dilations to treat the stricture but noted that the duration of symptomatic relief decreased with every subsequent dilation. An esophageal stent was placed 4 years after the initial concern of dysphagia, but it was not well tolerated and had to be removed soon thereafter. A year later, the patient underwent an esophageal bypass with a substernal gastric conduit that provided relief for 2 months but failed to permanently resolve the condition. In fact, her condition worsened over the next 1.5 years when she presented with extreme emaciation attributed to a low appetite and pain while eating. A review of the slides from a prior hospital esophageal biopsy revealed lichen planus (Figure 5). She was prescribed tofacitinib 5 mg BID as a dual-purpose treatment for the rheumatoid arthritis and OLP/ELP. At 1-month follow-up she noted that she had only taken one 5-mg pill daily without notable improvement, and after the visit she started the initial recommendation of 5 mg BID. Over the next several months, her condition continued to consistently improve; the odynophagia resolved, and she regained the majority of her lost weight. Tofacitinib was well tolerated across the course of treatment, and no adverse side effects were noted. Furthermore, the patient regained a full range of motion in the previously immobile arthritic right shoulder. She has experienced no recurrence of the genital lichen planus, OLP, or CLP since starting tofacitinib. To date, the patient is still taking only tofacitinib 5 mg BID with no recurrence of the cutaneous, mucosal, or esophageal lichen planus and has experienced no adverse events from the medication.

Clinical Presentation—Lichen planus—CLP and OLP—most frequently presents between the ages of 40 and 60 years, with a slight female predilection.^1,2 The lesions typically present with the 5 P’s—purple, pruritic, polygonal papules and plaques—with some lesions revealing white lacy lines overlying them called Wickham striae.⁶ The lesions may be red at first before turning purple. They often present on the flexural surfaces of the wrists and ankles as well as the shins and back but rarely affect the face, perhaps because of increased chronic sun exposure.^2,6 Less common locations include the scalp, nails, and mucosal areas (eg, oral, vulvar, conjunctival, laryngeal, esophageal, anal).¹

If CLP is diagnosed, the patient likely will also have oral lesions, which occur in 50% of patients.² Once any form of lichen planus is found, it is important to examine all of the most frequently involved locations—mucocutaneous and cutaneous as well as the nails and scalp. Special care should be taken when examining OLP and genital lichen planus, as long-standing lesions have a 2% to 5% chance of transforming into squamous cell carcinoma.²

Although cases of traditional OLP and CLP are ubiquitous in the literature, ELP rarely is documented because of frequent misdiagnoses. Esophageal lichen planus has a closer histopathologic resemblance to OLP compared to CLP, and its highly variable presentation often results in an inconclusive diagnosis.³ A review of 27 patients with lichen planus highlighted the difficult nature of diagnosing ELP; ELP manifested up to 20 years after initial lichen planus diagnosis, and patients underwent an average of 2.5 dilations prior to the successful diagnosis of ELP. Interestingly, 2 patients in the study presented with ELP in isolation, which emphasizes the importance of secondary examination for lichen planus in the presence of esophageal strictures.⁷ The eTable provides common patient demographics and symptoms to more effectively identify ELP.Differential Diagnosis—Because lichen planus can present anywhere on the body, it may be difficult to differentiate it from other skin conditions. Clinical appearance alone often is insufficient for diagnosing lichen planus, and a punch biopsy often is needed.^2,20 Cutaneous lichen planus may resemble eczema, lichen simplex chronicus, pityriasis rosea, prurigo nodularis, and psoriasis, while OLP may resemble bite trauma, leukoplakia, pemphigus, and thrush.²⁰ Dermoscopy of the tissue makes Wickham striae easier to visualize and assists in the diagnosis of lichen planus. Furthermore, thickening of the stratum granulosum, a prevalence of lymphocytes in the dermoepidermal junction, and vacuolar alteration of the stratum basale help to distinguish between lichen planus and other inflammatory dermatoses.²⁰ A diagnosis of lichen planus merits a full-body skin examination—hair, nails, eyes, oral mucosa, and genitalia—to rule out additional involvement.

Esophageal lichen planus most frequently presents as dysphagia, odynophagia, and weight loss, but other symptoms including heartburn, hoarseness, choking, and epigastric pain may suggest esophageal involvement.⁴ Typically, ELP presents in the proximal and/or central esophagus, assisting in the differentiation between ELP and other esophageal conditions.³ Special consideration should be taken when both ELP and gastroesophageal reflux disease are considered in a differential diagnosis, and it is recommended to pair an upper endoscopy with pH monitoring to avoid misdiagnosis.⁸ Screening endoscopies also are helpful, as they assist in identifying the characteristic white webs, skin peeling, skin surface erosion, and strictures of ELP.⁴ Taken together, dermatologists should encourage patients with cutaneous or mucocutaneous lichen planus to undergo an esophagogastroduodenoscopy, especially in the presence of any of ELP’s common symptoms (eTable).

Etiology—Although the exact etiology of lichen planus is not well established, there are several known correlative factors, including hepatitis C; increased stress; dental materials; oral medications, most frequently antihypertensives and nonsteroidal anti-inflammatory drugs; systemic diseases; and tobacco usage.^6,21

Dental materials used in oral treatments such as silver amalgam, gold, cobalt, palladium, chromium, epoxy resins, and dentures can trigger or exacerbate OLP, and patch testing of a patient’s dental materials can help determine if the reaction was caused by the materials.^6,22 The removal of material contributing to lesions often will cause OLP to resolve.²²

It also has been suggested that the presence of thyroid disorders, autoimmune disease, various cancers, hypertension, type 2 diabetes mellitus, hyperlipidemia, oral sedative usage, and/or vitamin D deficiency may be associated with OLP.^21,23 Although OLP patients who were initially deficient in vitamin D demonstrated marked improvement with supplementation, it is unlikely that vitamin D supplements impacted our patient’s presentation of OLP, as she had been consistently taking them for more than 5 years with no change in OLP presentation.²⁴

Pathogenesis—Lichen planus is thought to be a cytotoxic CD8⁺ T cell–mediated autoimmune disease to a virally modified epidermal self-antigen on keratinocytes. The cytotoxic T cells target the modified self-antigens on basal keratinocytes and induce apoptosis.²⁵ The cytokine-mediated lymphocyte homing mechanism is human leukocyte antigen dependent and involves tumor necrosis factor α as well as IFN-γ and IL-1. The latter cytokines lead to upregulation of vascular adhesion molecules on endothelial vessels of subepithelial vascular plexus as well as a cascade of nonspecific mechanisms such as mast cell degranulation and matrix metalloproteinase activation, resulting in increased basement membrane disruption.⁶

Shao et al¹⁹ underscored the role of IFN-γ in CD8⁺ T cell–mediated cytotoxic cellular responses, noting that the Janus kinase (JAK)–signal transducer and activator of transcription pathway may play a key role in the pathogenesis of lichen planus. They proposed using JAK inhibitors for the treatment of lichen planus, specifically tofacitinib, a JAK1/JAK3 inhibitor, and baricitinib, a JAK1/JAK2 inhibitor, as top therapeutic agents for lichen planus (eTable).¹⁹ Tofacitinib has been reported to successfully treat conditions such as psoriasis, psoriatic arthritis, alopecia areata, vitiligo, atopic dermatitis, sarcoidosis, pyoderma gangrenosum, and lichen planopilaris.²⁶ Additionally, the efficacy of tofacitinib has been established in patients with erosive lichen planus; tofacitinib resulted in marked improvement while prednisone, acitretin, methotrexate, mycophenolate mofetil, and cyclosporine treatment failed.²⁷ Although more studies on tofacitinib’s long-term efficacy, cost, and safety are necessary, tofacitinib may soon play an integral role in the battle against inflammatory dermatoses.

Conclusion

Esophageal lichen planus is an underreported form of lichen planus that often is misdiagnosed. It frequently causes dysphagia and odynophagia, resulting in a major decrease in a patient’s quality of life. We present the case of an 89-year-old woman who underwent procedures to dilate her esophagus that worsened her condition. We emphasize the importance of considering ELP in the differential diagnosis of patients presenting with lichen planus in another region. In our patient, tofacitinib 5 mg BID resolved her condition without any adverse effects.

Dermatology providers are at an increased risk for blood-borne pathogen (BBP) exposures during procedures in clinical practice.^1-3 Current data regarding the characterization of these exposures are limited. Prior studies are based on surveys that result in low response rates and potential for selection bias. Donnelly et al¹ reported a 26% response rate in a national survey-based study evaluating BBP exposures in resident physicians, fellows, and practicing dermatologists, with 85% of respondents reporting at least 1 injury. Similarly, Goulart et al² reported a 35% response rate in a survey evaluating sharps injuries in residents and medical students, with 85% reporting a sharps injury. In addition, there are conflicting data regarding characteristics of these exposures, including common implicated instruments and procedures.^1-3 Prior studies also have not evaluated exposures in all members of dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff.

To make appropriate quality improvements in dermatologic procedures, a more comprehensive understanding of BBP exposures is needed. We conducted a retrospective review of BBP incidence reports to identify the incidence of BBP events among all dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff. We further investigated the type of exposure, the type of procedure associated with each exposure, anatomic locations of exposures, and instruments involved in each exposure.

Methods

Data on BBP exposures in the dermatology departments were obtained from the occupational health departments at each of 3 Mayo Clinic sites—Scottsdale, Arizona; Jacksonville, Florida; and Rochester, Minnesota—from March 2010 through January 2021. The institutional review board at Mayo Clinic, Scottsdale, Arizona, granted approval of this study (IRB #20-012625). A retrospective review of each exposure was conducted to identify the incidence of BBP exposures. Occupational BBP exposure was defined as any percutaneous injury or mucosal exposure with foreign blood, tissue, or other bodily fluids that placed the health care worker at risk for communicable infections. Secondary aims included identification of the type of exposure, type of procedure associated with each exposure, common anatomic locations of exposures, and common instruments involved in each exposure.

Statistical Analysis—Variables were summarized using counts and percentages. The 3 most common categories for each variable were then compared among occupational groups using the Fisher exact test. All other categories were grouped for analysis purposes. Medical staff were categorized into 3 occupational groups: practicing dermatologists; resident physicians; and ancillary staff, including nurse/medical assistants, physician assistants, and clinical laboratory technologists. All analyses were 2 sided and considered statistically significant at P<.05. Analyses were performed using SAS 9.4 (SAS Institute Inc).

Results

Type of Exposure—A total of 222 BBP exposures were identified through the trisite retrospective review from March 2010 through January 2021. One hundred ninety-nine (89.6%) of 222 exposures were attributed to needlesticks and medical sharps, while 23 (10.4%) of 222 exposures were attributed to splash incidents (Table).

Anatomic Sites Affected—The anatomic location most frequently involved was the thumb (130/217 events [59.9%]), followed by the hand (39/217 events [18.0%]) and finger (22/217 events [10.1%]). The arm, face, and knee were affected with the lowest frequency, with only 1 event reported at each anatomic site (0.5%)(eTable). Five incidents were excluded from the analysis of anatomic location because of insufficient details of events.

Incident Tasks and Tools—Most BBP exposures occurred during suturing or assisting with suturing (64/210 events [30.5%]), followed by handling of sharps, wires, or instruments (40/210 events [19.0%]) and medication administration (37/210 events [17.6%])(eTable). Twelve incidents were excluded from the analysis of implicated tasks because of insufficient details of events.

The tools involved in exposure events with the greatest prevalence included the suture needle (76/201 events [37.8%]), injection syringe/needle (43/201 events [21.4%]), and shave biopsy razor (24/201 events [11.9%])(eTable). Twenty-one incidents were excluded from the analysis of implicated instruments because of insufficient details of events.

Providers Affected by BBP Exposures—Resident physicians experienced the greatest number of BBP exposures (105/222 events [47.3%]), followed by ancillary providers (84/222 events [37.8%]) and practicing dermatologists (33/222 events [14.9%]). All occupational groups experienced more BBP exposures through needlesticks/medical sharps compared with splash incidents (resident physicians, 88.6%; ancillary staff, 91.7%; practicing dermatologists, 87.9%; P=.725)(Table).

Among resident physicians, practicing dermatologists, and ancillary staff, the most frequent site of injury was the thumb. Suturing/assisting with suturing was the most common task leading to injury, and the suture needle was the most common instrument of injury for both resident physicians and practicing dermatologists. Handling of sharps, wires, or instruments was the most common task leading to injury for ancillary staff, and the injection syringe/needle was the most common instrument of injury in this cohort.

Resident physicians experienced the lowest rate of BBP exposures during administration of medications (12.7%; P=.003). Ancillary staff experienced the highest rate of BBP exposures with an injection needle (35.5%; P=.001). There were no statistically significant differences among occupational groups for the anatomic location of injury (P=.074)(eTable).

Comment

In the year 2000, the annual global incidence of occupational BBP exposures among health care workers worldwide for hepatitis B virus, hepatitis C virus, and HIV was estimated at 2.1 million, 926,000, and 327,000, respectively. Most of these exposures were due to sharps injuries.⁴ Dermatologists are particularly at risk for BBP exposures given their reliance on frequent procedures in practice. During an 11-year period, 222 BBP exposures were documented in the dermatology departments at 3 Mayo Clinic institutions. Most exposures were due to needlestick/sharps across all occupational groups compared with splash injuries. Prior survey studies confirm that sharps injuries are frequently implicated, with 75% to 94% of residents and practicing dermatologists reporting at least 1 sharps injury.¹

Among occupational groups, resident physicians had the highest rate of BBP exposures, followed by nurse/medical assistants and practicing dermatologists, which may be secondary to lack of training or experience. Data from other surgical fields, including general surgery, support that resident physicians have the highest rate of sharps injuries.⁵ In a survey study (N=452), 51% of residents reported that extra training in safe techniques would be beneficial.² Safety training may be beneficial in reducing the incidence of BBP exposures in residency programs.

The most common implicated task in resident physicians and practicing dermatologists was suturing or assisting with suturing, and the most common implicated instrument was the suture needle. Prior studies showed conflicting data regarding common implicated tasks and instruments in this cohort.^1,2 The task of suturing and the suture needle also were the most implicated means of injury among other surgical specialties.⁶ Ancillary staff experienced most BBP exposures during handling of sharps, wires, or instruments, as well as the use of an injection needle. The designation of tasks among dermatologic staff likely explains the difference among occupational groups. This new information may provide the opportunity to improve safety measures among all members of the dermatologic team.

Limitations—There are several limitations to this study. This retrospective review was conducted at a single health system at 3 institutions. Hence, similar safety protocols likely were in place across all sites, which may reduce the generalizability of the results. In addition, there is risk of nonreporting bias among staff, as only documented incidence reports were evaluated. Prior studies demonstrated a nonreporting prevalence of 33% to 64% among dermatology staff.^1-3 We also did not evaluate whether injuries resulted in BBP exposure or transmission. The rates of postexposure prophylaxis also were not studied. This information was not available for review because of concerns for privacy. Demographic features, such as gender or years of training, also were not evaluated.

Conclusion

This study provides additional insight on the incidence of BBP exposures in dermatology, as well as the implicated tasks, instruments, and anatomic locations of injury. Studies show that implementing formal education regarding the risks of BBP exposure may result in reduction of sharps injuries.⁷ Formal education in residency programs may be needed in the field of dermatology to reduce BBP exposures. Quality improvement measures should focus on identified risk factors among occupational groups to reduce BBP exposures in the workplace.

Dermatology providers are at an increased risk for blood-borne pathogen (BBP) exposures during procedures in clinical practice.^1-3 Current data regarding the characterization of these exposures are limited. Prior studies are based on surveys that result in low response rates and potential for selection bias. Donnelly et al¹ reported a 26% response rate in a national survey-based study evaluating BBP exposures in resident physicians, fellows, and practicing dermatologists, with 85% of respondents reporting at least 1 injury. Similarly, Goulart et al² reported a 35% response rate in a survey evaluating sharps injuries in residents and medical students, with 85% reporting a sharps injury. In addition, there are conflicting data regarding characteristics of these exposures, including common implicated instruments and procedures.^1-3 Prior studies also have not evaluated exposures in all members of dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff.

To make appropriate quality improvements in dermatologic procedures, a more comprehensive understanding of BBP exposures is needed. We conducted a retrospective review of BBP incidence reports to identify the incidence of BBP events among all dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff. We further investigated the type of exposure, the type of procedure associated with each exposure, anatomic locations of exposures, and instruments involved in each exposure.

Methods

Data on BBP exposures in the dermatology departments were obtained from the occupational health departments at each of 3 Mayo Clinic sites—Scottsdale, Arizona; Jacksonville, Florida; and Rochester, Minnesota—from March 2010 through January 2021. The institutional review board at Mayo Clinic, Scottsdale, Arizona, granted approval of this study (IRB #20-012625). A retrospective review of each exposure was conducted to identify the incidence of BBP exposures. Occupational BBP exposure was defined as any percutaneous injury or mucosal exposure with foreign blood, tissue, or other bodily fluids that placed the health care worker at risk for communicable infections. Secondary aims included identification of the type of exposure, type of procedure associated with each exposure, common anatomic locations of exposures, and common instruments involved in each exposure.

Statistical Analysis—Variables were summarized using counts and percentages. The 3 most common categories for each variable were then compared among occupational groups using the Fisher exact test. All other categories were grouped for analysis purposes. Medical staff were categorized into 3 occupational groups: practicing dermatologists; resident physicians; and ancillary staff, including nurse/medical assistants, physician assistants, and clinical laboratory technologists. All analyses were 2 sided and considered statistically significant at P<.05. Analyses were performed using SAS 9.4 (SAS Institute Inc).

Results

Type of Exposure—A total of 222 BBP exposures were identified through the trisite retrospective review from March 2010 through January 2021. One hundred ninety-nine (89.6%) of 222 exposures were attributed to needlesticks and medical sharps, while 23 (10.4%) of 222 exposures were attributed to splash incidents (Table).

Anatomic Sites Affected—The anatomic location most frequently involved was the thumb (130/217 events [59.9%]), followed by the hand (39/217 events [18.0%]) and finger (22/217 events [10.1%]). The arm, face, and knee were affected with the lowest frequency, with only 1 event reported at each anatomic site (0.5%)(eTable). Five incidents were excluded from the analysis of anatomic location because of insufficient details of events.

Incident Tasks and Tools—Most BBP exposures occurred during suturing or assisting with suturing (64/210 events [30.5%]), followed by handling of sharps, wires, or instruments (40/210 events [19.0%]) and medication administration (37/210 events [17.6%])(eTable). Twelve incidents were excluded from the analysis of implicated tasks because of insufficient details of events.

The tools involved in exposure events with the greatest prevalence included the suture needle (76/201 events [37.8%]), injection syringe/needle (43/201 events [21.4%]), and shave biopsy razor (24/201 events [11.9%])(eTable). Twenty-one incidents were excluded from the analysis of implicated instruments because of insufficient details of events.

Providers Affected by BBP Exposures—Resident physicians experienced the greatest number of BBP exposures (105/222 events [47.3%]), followed by ancillary providers (84/222 events [37.8%]) and practicing dermatologists (33/222 events [14.9%]). All occupational groups experienced more BBP exposures through needlesticks/medical sharps compared with splash incidents (resident physicians, 88.6%; ancillary staff, 91.7%; practicing dermatologists, 87.9%; P=.725)(Table).

Among resident physicians, practicing dermatologists, and ancillary staff, the most frequent site of injury was the thumb. Suturing/assisting with suturing was the most common task leading to injury, and the suture needle was the most common instrument of injury for both resident physicians and practicing dermatologists. Handling of sharps, wires, or instruments was the most common task leading to injury for ancillary staff, and the injection syringe/needle was the most common instrument of injury in this cohort.

Resident physicians experienced the lowest rate of BBP exposures during administration of medications (12.7%; P=.003). Ancillary staff experienced the highest rate of BBP exposures with an injection needle (35.5%; P=.001). There were no statistically significant differences among occupational groups for the anatomic location of injury (P=.074)(eTable).

Comment

In the year 2000, the annual global incidence of occupational BBP exposures among health care workers worldwide for hepatitis B virus, hepatitis C virus, and HIV was estimated at 2.1 million, 926,000, and 327,000, respectively. Most of these exposures were due to sharps injuries.⁴ Dermatologists are particularly at risk for BBP exposures given their reliance on frequent procedures in practice. During an 11-year period, 222 BBP exposures were documented in the dermatology departments at 3 Mayo Clinic institutions. Most exposures were due to needlestick/sharps across all occupational groups compared with splash injuries. Prior survey studies confirm that sharps injuries are frequently implicated, with 75% to 94% of residents and practicing dermatologists reporting at least 1 sharps injury.¹

Among occupational groups, resident physicians had the highest rate of BBP exposures, followed by nurse/medical assistants and practicing dermatologists, which may be secondary to lack of training or experience. Data from other surgical fields, including general surgery, support that resident physicians have the highest rate of sharps injuries.⁵ In a survey study (N=452), 51% of residents reported that extra training in safe techniques would be beneficial.² Safety training may be beneficial in reducing the incidence of BBP exposures in residency programs.

The most common implicated task in resident physicians and practicing dermatologists was suturing or assisting with suturing, and the most common implicated instrument was the suture needle. Prior studies showed conflicting data regarding common implicated tasks and instruments in this cohort.^1,2 The task of suturing and the suture needle also were the most implicated means of injury among other surgical specialties.⁶ Ancillary staff experienced most BBP exposures during handling of sharps, wires, or instruments, as well as the use of an injection needle. The designation of tasks among dermatologic staff likely explains the difference among occupational groups. This new information may provide the opportunity to improve safety measures among all members of the dermatologic team.

Limitations—There are several limitations to this study. This retrospective review was conducted at a single health system at 3 institutions. Hence, similar safety protocols likely were in place across all sites, which may reduce the generalizability of the results. In addition, there is risk of nonreporting bias among staff, as only documented incidence reports were evaluated. Prior studies demonstrated a nonreporting prevalence of 33% to 64% among dermatology staff.^1-3 We also did not evaluate whether injuries resulted in BBP exposure or transmission. The rates of postexposure prophylaxis also were not studied. This information was not available for review because of concerns for privacy. Demographic features, such as gender or years of training, also were not evaluated.

Conclusion

This study provides additional insight on the incidence of BBP exposures in dermatology, as well as the implicated tasks, instruments, and anatomic locations of injury. Studies show that implementing formal education regarding the risks of BBP exposure may result in reduction of sharps injuries.⁷ Formal education in residency programs may be needed in the field of dermatology to reduce BBP exposures. Quality improvement measures should focus on identified risk factors among occupational groups to reduce BBP exposures in the workplace.

Dermatology providers are at an increased risk for blood-borne pathogen (BBP) exposures during procedures in clinical practice.^1-3 Current data regarding the characterization of these exposures are limited. Prior studies are based on surveys that result in low response rates and potential for selection bias. Donnelly et al¹ reported a 26% response rate in a national survey-based study evaluating BBP exposures in resident physicians, fellows, and practicing dermatologists, with 85% of respondents reporting at least 1 injury. Similarly, Goulart et al² reported a 35% response rate in a survey evaluating sharps injuries in residents and medical students, with 85% reporting a sharps injury. In addition, there are conflicting data regarding characteristics of these exposures, including common implicated instruments and procedures.^1-3 Prior studies also have not evaluated exposures in all members of dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff.

To make appropriate quality improvements in dermatologic procedures, a more comprehensive understanding of BBP exposures is needed. We conducted a retrospective review of BBP incidence reports to identify the incidence of BBP events among all dermatologic staff, including resident physicians, practicing dermatologists, and ancillary staff. We further investigated the type of exposure, the type of procedure associated with each exposure, anatomic locations of exposures, and instruments involved in each exposure.

Methods

Data on BBP exposures in the dermatology departments were obtained from the occupational health departments at each of 3 Mayo Clinic sites—Scottsdale, Arizona; Jacksonville, Florida; and Rochester, Minnesota—from March 2010 through January 2021. The institutional review board at Mayo Clinic, Scottsdale, Arizona, granted approval of this study (IRB #20-012625). A retrospective review of each exposure was conducted to identify the incidence of BBP exposures. Occupational BBP exposure was defined as any percutaneous injury or mucosal exposure with foreign blood, tissue, or other bodily fluids that placed the health care worker at risk for communicable infections. Secondary aims included identification of the type of exposure, type of procedure associated with each exposure, common anatomic locations of exposures, and common instruments involved in each exposure.

Statistical Analysis—Variables were summarized using counts and percentages. The 3 most common categories for each variable were then compared among occupational groups using the Fisher exact test. All other categories were grouped for analysis purposes. Medical staff were categorized into 3 occupational groups: practicing dermatologists; resident physicians; and ancillary staff, including nurse/medical assistants, physician assistants, and clinical laboratory technologists. All analyses were 2 sided and considered statistically significant at P<.05. Analyses were performed using SAS 9.4 (SAS Institute Inc).

Results

Type of Exposure—A total of 222 BBP exposures were identified through the trisite retrospective review from March 2010 through January 2021. One hundred ninety-nine (89.6%) of 222 exposures were attributed to needlesticks and medical sharps, while 23 (10.4%) of 222 exposures were attributed to splash incidents (Table).

Anatomic Sites Affected—The anatomic location most frequently involved was the thumb (130/217 events [59.9%]), followed by the hand (39/217 events [18.0%]) and finger (22/217 events [10.1%]). The arm, face, and knee were affected with the lowest frequency, with only 1 event reported at each anatomic site (0.5%)(eTable). Five incidents were excluded from the analysis of anatomic location because of insufficient details of events.

Incident Tasks and Tools—Most BBP exposures occurred during suturing or assisting with suturing (64/210 events [30.5%]), followed by handling of sharps, wires, or instruments (40/210 events [19.0%]) and medication administration (37/210 events [17.6%])(eTable). Twelve incidents were excluded from the analysis of implicated tasks because of insufficient details of events.

The tools involved in exposure events with the greatest prevalence included the suture needle (76/201 events [37.8%]), injection syringe/needle (43/201 events [21.4%]), and shave biopsy razor (24/201 events [11.9%])(eTable). Twenty-one incidents were excluded from the analysis of implicated instruments because of insufficient details of events.

Providers Affected by BBP Exposures—Resident physicians experienced the greatest number of BBP exposures (105/222 events [47.3%]), followed by ancillary providers (84/222 events [37.8%]) and practicing dermatologists (33/222 events [14.9%]). All occupational groups experienced more BBP exposures through needlesticks/medical sharps compared with splash incidents (resident physicians, 88.6%; ancillary staff, 91.7%; practicing dermatologists, 87.9%; P=.725)(Table).

Among resident physicians, practicing dermatologists, and ancillary staff, the most frequent site of injury was the thumb. Suturing/assisting with suturing was the most common task leading to injury, and the suture needle was the most common instrument of injury for both resident physicians and practicing dermatologists. Handling of sharps, wires, or instruments was the most common task leading to injury for ancillary staff, and the injection syringe/needle was the most common instrument of injury in this cohort.

Resident physicians experienced the lowest rate of BBP exposures during administration of medications (12.7%; P=.003). Ancillary staff experienced the highest rate of BBP exposures with an injection needle (35.5%; P=.001). There were no statistically significant differences among occupational groups for the anatomic location of injury (P=.074)(eTable).

Comment

In the year 2000, the annual global incidence of occupational BBP exposures among health care workers worldwide for hepatitis B virus, hepatitis C virus, and HIV was estimated at 2.1 million, 926,000, and 327,000, respectively. Most of these exposures were due to sharps injuries.⁴ Dermatologists are particularly at risk for BBP exposures given their reliance on frequent procedures in practice. During an 11-year period, 222 BBP exposures were documented in the dermatology departments at 3 Mayo Clinic institutions. Most exposures were due to needlestick/sharps across all occupational groups compared with splash injuries. Prior survey studies confirm that sharps injuries are frequently implicated, with 75% to 94% of residents and practicing dermatologists reporting at least 1 sharps injury.¹

Among occupational groups, resident physicians had the highest rate of BBP exposures, followed by nurse/medical assistants and practicing dermatologists, which may be secondary to lack of training or experience. Data from other surgical fields, including general surgery, support that resident physicians have the highest rate of sharps injuries.⁵ In a survey study (N=452), 51% of residents reported that extra training in safe techniques would be beneficial.² Safety training may be beneficial in reducing the incidence of BBP exposures in residency programs.

The most common implicated task in resident physicians and practicing dermatologists was suturing or assisting with suturing, and the most common implicated instrument was the suture needle. Prior studies showed conflicting data regarding common implicated tasks and instruments in this cohort.^1,2 The task of suturing and the suture needle also were the most implicated means of injury among other surgical specialties.⁶ Ancillary staff experienced most BBP exposures during handling of sharps, wires, or instruments, as well as the use of an injection needle. The designation of tasks among dermatologic staff likely explains the difference among occupational groups. This new information may provide the opportunity to improve safety measures among all members of the dermatologic team.

Limitations—There are several limitations to this study. This retrospective review was conducted at a single health system at 3 institutions. Hence, similar safety protocols likely were in place across all sites, which may reduce the generalizability of the results. In addition, there is risk of nonreporting bias among staff, as only documented incidence reports were evaluated. Prior studies demonstrated a nonreporting prevalence of 33% to 64% among dermatology staff.^1-3 We also did not evaluate whether injuries resulted in BBP exposure or transmission. The rates of postexposure prophylaxis also were not studied. This information was not available for review because of concerns for privacy. Demographic features, such as gender or years of training, also were not evaluated.

Conclusion

This study provides additional insight on the incidence of BBP exposures in dermatology, as well as the implicated tasks, instruments, and anatomic locations of injury. Studies show that implementing formal education regarding the risks of BBP exposure may result in reduction of sharps injuries.⁷ Formal education in residency programs may be needed in the field of dermatology to reduce BBP exposures. Quality improvement measures should focus on identified risk factors among occupational groups to reduce BBP exposures in the workplace.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

An 81-year-old man was admitted to our skilled nursing facility (SNF) after hospitalization for an acute kidney injury secondary to bladder outflow obstruction. While at the hospital, he received hemodialysis for the acute kidney injury, underwent transurethral resection of the prostate for benign prostatic hyperplasia (BPH), and had lithotripsy for nephrolithiasis. He was admitted to our SNF with an indwelling urinary catheter that had been placed 3 days prior to discharge from the hospital for urinary retention and a serum creatinine level of 3.28 mg/dL (normal range, 0.7-1.3 mg/dL [male]). Four days after his admission, the nursing staff reported acute onset of purple urine in his catheter and collection bag (FIGURE).

Physical examination revealed an older man whose vital signs were normal and who had a regular heart rate and rhythm. He denied any pain, and his abdomen was soft and nontender with normal bowel sounds. There was no suprapubic or costovertebral angle tenderness, and his urinary catheter was correctly placed. His urine output was within normal limits, but the urine in the catheter and collection bag was purple.

The patient’s medical history was remarkable for mild cognitive impairment, BPH, and hypertension. A urine culture was significant for > 100,000 CFU/mL pan-sensitive Pseudomonas aeruginosa.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The diagnosis of purple urine bag syndrome (PUBS) was made based on the patient’s clinical presentation and medical history. PUBS is generally a benign condition that can occur in patients who have urinary catheters for prolonged periods of time and urinary tract infections (UTIs), often with ­constipation.¹

PUBS was first described in the literature in 1978.² Its prevalence has been estimated to be 9.8% in long-term wards and higher in patients with chronic catheters.^3-5 PUBS is reported more often in institutionalized older women, although it has been documented in men as well.¹ Risk factors include having a chronic indwelling urinary catheter; alkaline urine; the use of plastic, polyvinylchloride urine bags³; chronic constipation⁶; renal failure^4,5; and dementia.¹ In many cases, patients with PUBS have been found to have stable vitals and lack systemic symptoms, such as fever, that could indicate an infection.^1,5

Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.

The pathogenesis of PUBS has been associated with tryptophan.³ Gut bacteria metabolize tryptophan to indole, which is converted to indoxyl sulfate in the liver.^3,7 Then certain bacteria associated with UTIs, including Pseudomonas, Escherichia coli, Proteus mirabilis, Providencia spp, Enterococcus faecalis, and Klebsiella,^5-7 which contain indoxyl phosphatase and sulfatase enzymes, can convert indoxyl sulfate into indirubin (red) and indigo (blue) compounds; this results in a purple hue in the urine seen in a Foley catheter and bag.

Differential is generally limited to medication and food consumption

Clinical presentation and a detailed history and review of medication and/or food ingestion may distinguish PUBS from other conditions.

Medications and foods, such as rifampicin or beets, may discolor urine and need to be ruled out as a cause with a thorough history.³

Cyanide toxicity in those taking vitamin B₁₂can result in purple-tinged urine.⁸ Signs and symptoms can alsoinclude reddening of the skin, dyspnea, nausea, headache, erythema at the injection site, and a modest increase in blood pressure.⁸

Identify the infection and treat as needed

There have been some case reports regarding the progression of PUBS to Fournier gangrene,⁴ but such cases are rare and associated with immunocompromised patients.⁹ PUBS is generally a benign condition associated with UTIs. Management involves identifying the underlying infection, treating with antibiotics if indicated (ie, patient is symptomatic or immunocompromised),³ providing proper treatment of constipation if needed, and replacing the Foley catheter.⁴ Some studies suggest that simply exchanging the catheter may resolve PUBS, particularly in asymptomatic patients.⁵

In light of his complicated urologic history, our patient was treated with a 10-day course of renally dosed intravenous cefepime (500 mg every 24 hours based on calculated creatine clearance of 21 mL/min) and Foley exchange. The patient’s urine color returned to normal after Foley exchange and 24 hours of antibiotics. His kidney function continued to improve and normalized by the time he was discharged from the facility approximately 2 weeks later.

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; [email protected]

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; [email protected]

THE CASE

A 44-year-old man with a history of morbid obesity reestablished care in our clinic. He had been treated in our health care system about 5 years previously, and prior lab testing showed a total cholesterol of 203 mg/dL; triglycerides, 191 mg/dL; high-density lipoprotein (HDL), 56 mg/dL; and low-density lipoprotein (LDL), 109 mg/dL. At that time, he weighed 299 lbs (BMI, 39.4). He then started a strict ketogenic diet and a regular exercise program (running ~ 16 miles per week and lifting weights), which he maintained for several years. He had experienced remarkable weight loss; upon reestablishing care, he weighed 199 lbs (BMI, 26.33).

However, lipid testing revealed a severely elevated total cholesterol of 334 mg/dL; LDL, 248 mg/dL; HDL, 67 mg/dL; and triglycerides, 95 mg/dL. He was advised to start statin therapy and to stop his ketogenic diet, but he was hesitant to take either step. He elected to have his lab work reevaluated in 6 months.

About 4 months later, he presented with new and increasing burning pain in his mid chest and upper abdomen. He rated the pain 6/10 in severity and said it occurred during exertion or at night when lying down. Resting would relieve the pain. Reduced intake of spicy foods and caffeine had also helped. He denied dyspnea, diaphoresis, palpitations, or nausea.

The patient was a nonsmoker but did have a strong family history of cardiovascular disease. His vital signs and physical examination were unremarkable, apart from mild epigastric and periumbilical tenderness on palpation.

THE DIAGNOSIS

The patient’s chest pain had features of both gastroesophageal reflux disease (GERD) and coronary artery disease (CAD) with exertional angina. His high-fat diet, nightly symptoms, and the partial relief he achieved by cutting back on spicy foods and caffeine suggested GERD, but the exertional nature of the chest pain and gradual relief with rest was highly suggestive of angina, so an outpatient electrocardiogram treadmill stress test was ordered.

The stress test was markedly abnormal, showing worsening ST depressions and T-wave inversions with exertion, and he experienced chest pain during testing. An urgent left heart catheterization was performed, showing severe multivessel CAD. He subsequently underwent 3-vessel coronary artery bypass grafting. A familial hypercholesterolemia panel failed to reveal any significant variants.

As a result of these findings, the patient received a diagnosis of severe ketogenic diet–associated hypercholesterolemia and early-onset CAD.

Continue to: DISCUSSION

Low-carbohydrate (low-carb) and ketogenic diets have grown in popularity throughout the United States over the past decade, particularly for weight loss, and the diet has entered the popular consciousness with several celebrities publicly supporting it.¹ Simultaneously, there also has been a growing interest in these diets for the treatment of chronic diseases, such as type 2 diabetes.² However, the long-term cardiovascular effects of low-carb diets are not well studied, and there is significant heterogeneity among these diets.

Low-carb vs low-fat. Multiple meta-analyses comparing low-carb diets to low-fat diets have found that those following low-carb diets have significantly higher total cholesterol and LDL levels.^3,4,5 The National Lipid Association’s review of evidence determined that LDL and total cholesterol responses vary in individuals following a low-carb diet, but that increasing LDL levels in particular were concerning enough to warrant lipid monitoring of patients on low-carb diets.⁶ Another meta-analysis evaluated the difference in estimated atherosclerotic cardiovascular disease (ASCVD) risk between low-carb and low-fat diets, finding those following a low-carb diet to have a lower estimated ASCVD risk but higher LDL levels.⁷

The severe worsening of this patient’s LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD.

Weighing the benefits and harms. Since our patient’s dramatic weight loss and greatly increased exercise level would be expected to lower his LDL levels, the severe worsening of his LDL levels was likely related to his ketogenic diet and was a factor in the early onset of CAD. The benefits of low-carb diets for weight loss, contrasted with the consistent worsening of LDL levels, has prompted a debate about which parameters should be considered in estimating the long-term risk of these diets for patients. Diamond et al⁸ posit that these diets have beneficial effects on “the most reliable [cardiovascular disease] risk factors,” but long-term, patient-oriented outcome data are lacking, and these diets may not be appropriate for certain patients, as our case demonstrates.

A reasonable strategy for patients contemplating a low-carb diet specifically for weight loss would be to use such a diet for 3 to 6 months to achieve initial and rapid results, then continue with a heart-healthy diet and increased exercise levels to maintain weight loss and reduce long-term cardiovascular risk.

Our patient was started on a post­operative medication regimen of aspirin 81 mg/d, evolocumab 140 mg every 14 days, metoprolol tartrate 25 mg bid, and rosuva­statin 10 mg/d. A year later, he was able to resume a high level of physical activity (6-mile runs) without chest pain. His follow-up lipid panel showed a total cholesterol of 153 mg/dL; LDL, 53 mg/dL; HDL, 89 mg/dL; and triglycerides, 55 mg/dL. He had also switched to a regular diet and had been able to maintain his weight loss.

THE TAKEAWAY

Growing evidence suggests that low-carb diets may have a significant and detrimental effect on LDL levels. The long-term safety of these diets hasn’t been well studied, particularly regarding cardiovascular outcomes. At a minimum, patients who initiate low-carb diets should be counseled on general dietary recommendations regarding saturated fat and cholesterol intake, and they should have a follow-up lipid screening to evaluate for any significant worsening in total cholesterol and LDL levels.

CORRESPONDENCE
Samuel Dickmann, MD, 13611 NW 1st Lane, Suite 200, Newberry, FL 32669; [email protected]

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Last year, after a long delay due to COVID, my father’s ashes were finally laid to rest at Arlington National Cemetery. Among the loved ones who came was my favorite aunt, Tante Ilse, who was suffering from dementia. While she wasn’t “following” everything that was going on, she did perk up when she heard my father’s name and would comment on how she liked him and how wonderful he had been to her.

After the ceremony, our family of about 30 gathered at a restaurant where we shared stories and old pictures. Tante Ilse seemed to relish the photos and the time with family. She was doing so well that when we went back to my mom’s home after the reception, my cousins decided to bring Tante Ilse there, too. She had a great time, as evidenced by her famous total-body laugh. In the months before her death, we all commented about that day and how happy she seemed.

I would have hoped for something better than merely clearing amyloid for my aunt.

My aunt’s decline comes to mind as I reflect on media reports of 2 Alzheimer drugs— aducanumab and lecanemab—that have been billed by some as “gamechangers.” These new drugs are monoclonal antibodies directed at amyloid, one of several agents thought to cause Alzheimer disease. The details of aducanumab’s approval by the US Food and Drug Administration (FDA) generated a great deal of criticism—with good reason.

Two manufacturer-sponsored studies of aducanumab were halted due to futility of finding a benefit.¹ The FDA’s scientific advisory panel recommended against approval due to a lack of evidence that it did anything more than remove amyloid plaque from the brain. And yet aducanumab received accelerated approval from the FDA. (This author collaborated on an additional analysis using data presented to the FDA, after its approval, which also reported no clinically meaningful effects.²) The other agent, lecanemab, also reduces markers of amyloid and was shown to be only moderately better than placebo in decreasing the rate of decline on various measures of cognition.³ Quite notably, both aducanumab and lecanemab, which are administered parenterally, cost more than $25,000 per year^4,5 and cause amyloid-related imaging abnormalities (brain edema or hemorrhage).

Expensive agents without meaningful benefit. So far, neither of these agents has shown a reduction in things that are truly important to our patients and their families/caregivers: a reduction in caregiver burden and a reduction in the need for placement in long-term care facilities.

This is in contrast to cholinesterase inhibitors, which also slow the rate of cognitive decline.⁶ Among the differences that exist between these agents: Cholinesterase inhibitors are taken orally and are available as generics, which cost less than a thousand dollars per year.⁷ Limited data also suggest that they are associated with a lower risk for nursing home placement.^8,9 (A February 2023 search of clinicaltrials.gov did not reveal any completed or planned head-to-head comparisons of monoclonal antibodies and anticholinergic agents.)

Our patients, their families, and caregivers hold out hope for something that will improve the patient’s cognition and extend the meaningful time they have with their loved ones. So far, the best we have to offer falls far short of these goals. I certainly would have hoped for something better than merely clearing amyloid for my aunt.

It’s time that the FDA adopt more rigorous standards requiring new drugs to, among other things, demonstrate meaningful clinical benefits, provide real cost savings, and be safer than currently available therapies. Other nations seem to be able to do this.^10,11 It is bad enough to provide “hope in a bottle”; it is worse when what is offered is false hope.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

Much of the work of the Advisory Committee on Immunization Practices (ACIP) in 2022 was devoted to vaccines to protect against coronavirus ­disease 2019 (COVID-19); details about the 4 available products can be found on the ­Centers for Disease Control and Prevention’s ­COVID vaccine website (www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html).^1,2 However, ACIP also issued recommendations about 5 other (non-COVID) vaccines last year, and those are the focus of this Practice Alert.

A second MMR vaccine option

The United States has had only 1 measles, mumps, and rubella (MMR) vaccine approved for use since 1978: M-M-R II (Merck). In June 2022, the US Food and Drug Administration (FDA) approved a second MMR vaccine, ­PRIORIX (GlaxoSmithKline Biologicals), which ACIP now recommends as an option when MMR vaccine is indicated.³

ACIP considers the 2 MMR options fully interchangeable.³ Both vaccines produce similar levels of immunogenicity and the safety profiles are also equivalent—including the rate of febrile seizures 6 to 11 days after vaccination, estimated at 3.3 to 8.7 per 10,000 doses.⁴ Since PRIORIX has been used in other countries since 1997, the MMR workgroup was able to include 13 studies on immunogenicity and 4 on safety in its evidence assessment; these are summarized on the CDC website.⁴

It is desirable to have multiple manufacturers of recommended vaccines to prevent shortages if there a disruption in the supply chain of 1 manufacturer, as well as to provide competition for cost control. A second MMR vaccine is therefore a welcome addition to the US vaccine supply. However, there remains only 1 combination measles, mumps, rubella, and varicella vaccine approved for use in the United States: ProQuad (Merck).

Pneumococcal vaccine recommendations are revised and simplified

Adults. Last year, ACIP made recommendations regarding 2 new vaccine options for use against pneumococcal infections in adults: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). These have been described in detail in a CDC publication and summarized in a recent Practice Alert.^5,6

ACIP revised and simplified its recommendations on vaccination to prevent pneumococcal disease in adults as follows⁵:

1. Maintained the cutoff of age 65 years for universal pneumococcal vaccination

2. Recommended pneumococcal vaccination (with either PCV15 or PCV20) for all adults ages 65 years and older and for those younger than 65 years with chronic medical conditions or immunocompromise

3. Recommended that if PCV15 is used, it should be followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23, Merck).

These revisions created a number of uncertain clinical situations, since patients could have already started and/or completed their pneumococcal vaccination with previously available products, including PCV7, PCV13, and PPSV23. At the October 2022 ACIP meeting, the pneumococcal workgroup addressed a number of “what if” clinical questions. These clinical considerations will soon be published in the Morbidity and Mortality Weekly Report (MMWR) but also can be reviewed by looking at the October ACIP meeting materials.⁷ The main considerations are summarized below⁷:

• For those who have previously received PCV7, either PCV15 or PCV20 should be given.
• If PPSV23 was inadvertently administered first, it should be followed by PCV15 or PCV20 at least 1 year later.
• Adults who have only received PPSV23 should receive a dose of either PCV20 or PCV15 at least 1 year after their last PPSV23 dose. When PCV15 is used in those with a history of PPSV23 receipt, it need not be followed by another dose of PPSV23.
• Adults who have received PCV13 only are recommended to complete their pneumococcal vaccine series by receiving either a dose of PCV20 at least 1 year after the PCV13 dose or PPSV23 as previously recommended.
• Shared clinical decision-making is recommended regarding administration of PCV20 for adults ages ≥ 65 years who have completed their recommended vaccine series with both PCV13 and PPSV23 but have not received PCV15 or PCV20. If a decision to administer PCV20 is made, a dose of PCV20 is recommended at least 5 years after the last pneumococcal vaccine dose.

Continue to: Children

Children. In 2022, PCV15 was licensed for use in children and adolescents ages 6 weeks to 17 years. PCV15 contains all the serotypes in the PCV13 vaccine, plus 22F and 33F. In June 2022, ACIP adopted recommendations regarding the use of PCV15 in children. The main recommendation is that PCV13 and PCV15 can be used interchangeably. The recommended schedule for PCV use in children and the catch-up schedule have not changed, nor has the use of PPSV23 in children with underlying medical conditions.^8,9

It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions.

Those who have been vaccinated with PCV13 do not need to be revaccinated with PCV15, and an incomplete series of PCV13 can be completed with PCV15. It is anticipated that in 2023, PCV20 will be FDA approved for use in children and adolescents, and this will probably change the recommendations for the use of PPSV23 in children with underlying medical conditions. The recommended routine immunization and catch-up immunization schedules are published on the CDC website,⁹ and the pneumococcal-specific recommendations are described in a recent MMWR.⁸

Preferential choice for influenza vaccine in those ≥ 65 years

The ACIP now recommends 1 of 3 influenza vaccines be used preferentially in those ages 65 years and older: the high-dose quadrivalent vaccine (HD-IIV4), Fluzone; the adjuvanted quadrivalent influenza vaccine (aIIV4), Fluad; or the recombinant quadrivalent influenza vaccine (RIV4), Flublok. However, if none of these options are available, a standard-dose vaccine is acceptable.

Both HD-IIV4 and aIIV4 are approved only for those ≥ 65 years of age. The RIV4 is approved for ages ≥ 18 years and is produced by a process that does not involve eggs. These 3 products produce better antibody levels and improved clinical outcomes in older adults compared to other, standard-dose flu vaccines, but there is no convincing evidence that any 1 of these is more effective than the others. A more in-depth discussion of flu vaccines and the considerations that went into this preferential recommendation were described in a previous Practice Alert.¹⁰

Updates for 2 travel vaccines

Tick-borne encephalitis (TBE). A TBE vaccine (Ticovac; Pfizer) has been available in other countries for more than 20 years, with no serious safety concerns identified. The vaccine was approved for use in the United States by the FDA in August 2021, and in early 2022, the ACIP made 3 recommendations for its use (to be discussed shortly).

TBE is a neuroinvasive flavivirus spread by ticks in parts of Europe and Asia. There are 3 main subtypes of the virus, and they cause serious illness, with a fatality rate of 1% to 20% and a sequelae rate of 10% to 50%.¹¹ TBE ­infection is rare among US travelers, with only 11 cases documented between 2001 and 2020. There were 9 cases within the US military between 2006 and 2020.¹¹

The TBE vaccine contains inactivated TBE virus, which is produced in chick embryo cells. It is administered in 3 doses over a 12-month timeframe, and those with continued exposure should receive a booster after 3 years.¹² (See TABLE¹² for administration schedule.) More information about the vaccine, contraindications, and rates of adverse reactions is available in the FDA package insert.¹³

Continue to: The ACIP has made...

The ACIP has made the following recommendations for the TBE vaccine^11,12:

1. Vaccination is recommended for laboratory workers with a potential for exposure to TBE virus.

2. TBE vaccine also is recommended for individuals who are moving abroad or traveling to a TBE-endemic area and who will have extensive exposure to ticks based on their planned outdoor activities and itinerary.

3. TBE vaccine can be considered for people traveling or moving to a TBE-endemic area who might engage in outdoor activities in areas where ticks are likely to be found. The decision to vaccinate should be based on an assessment of the patient’s planned activities and itinerary, risk factors for a poorer medical outcome, and personal perception and tolerance of risk.

Cholera. ACIP now recommends CVD 103-HgR (PaxVax, VAXCHORA), a single-dose, live attenuated oral cholera vaccine, for travelers as young as 2 years who plan to visit an area that has active cholera transmission.¹⁴ In February 2022, ACIP expanded its recommendation for adults ages 18 to 64 years to include children and adolescents ages 2 to 17 years. This followed a 2020 FDA approval for the vaccine in the younger age group. Details about the vaccine were described in an MMWR publication.¹⁴

Cholera is caused by toxigenic bacteria. Infection occurs by ingestion of contaminated water or food and can be prevented by consumption of safe water and food, along with good sanitation and handwashing. Cholera produces a profuse watery diarrhea that can rapidly lead to death in 50% of those infected who do not receive rehydration therapy.¹⁵ Cholera is endemic is many countries and can cause large outbreaks. The World Health Organization estimates that 1 to 4 million cases of cholera and 21,000 to 143,000 related deaths occur globally each year.¹⁶

Staying current is moreimportant than ever

Vaccines are one of the most successful public health interventions of the past century, and maintaining a robust vaccine approval and safety monitoring system is an important priority. However, to gain the most benefit from vaccines, physicians need to stay current on vaccine recommendations—something that is becoming increasingly difficult to accomplish as the options expand. Consulting the literature and visiting the CDC’s website (www.cdc.gov) with frequency can be helpful to that end.

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

This patient had erythroderma, which involves widespread erythema and scaling of the majority of the skin. Erythroderma can be caused by severe variants of several skin disorders, including atopic dermatitis, contact dermatitis, and psoriasis. In this case, a punch biopsy from the forearm was most consistent with erythrodermic psoriasis.

Erythrodermic psoriasis is a rare subtype of psoriasis and most often develops as an exacerbation of preexisting plaque psoriasis and is defined by erythema, scale, and desquamation covering 75% to 90% of the body surface.¹ The alteration in the skin negatively affects heat exchange and hemodynamics and can be life threatening. Many cases develop as a rebound reaction in patients with preexisting psoriasis treated with systemic steroids that are discontinued. Patients with dehydration, poor urinary output, hypotension, or significant weakness may benefit from supportive inpatient care while treatment is initiated.¹

Initial treatment options for patients with erythrodermic psoriasis include biologics and steroid-sparing immunosuppressants, such as cyclosporine and acitretin. While a patient awaits the initiation of a definitive therapy, topical triamcinolone 0.1% may be applied over the entire skin surface twice daily and covered with 2 layers of scrubs or pajamas. The pair closest to the skin should be slightly damp and the outer pair should be dry to help retain heat. These are referred to as wet wraps or wet pajama wraps.

The patient described here was hemodynamically stable and was allowed to initiate wet pajama wrap therapy at home while awaiting initiation of adalimumab as an outpatient. He has improved dramatically with adalimumab given subcutaneously every 2 weeks.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Etiology

Calcareous soils of central and southwest China are home to Primula obconica¹ (also known as German primrose and Libre Magenta).²Primula obconica was introduced to Europe in the 1880s, where it became a popular ornamental and decorative household plant (Figure).³ It also is a frequent resident of greenhouses.

Primula obconica is a member of the family Primulaceae, which comprises semi-evergreen perennials. The genus name Primula is derived from Latin meaning “first”; obconica refers to the conelike shape of the plant’s vivid, cerise-red flowers.

Allergens From P obconica

The allergens primin (2-methoxy-6-pentyl-1,4-benzoquinone) and miconidin (2-methoxy-6-pentyl-1, 4-dihydroxybenzene) have been isolated from P obconica stems, leaves, and flowers. Allergies to P obconica are much more commonly detected in Europe than in the United States because the plant is part of standard allergen screening in dermatology clinics in Europe.⁴ In a British patch test study of 234 patients with hand dermatitis, 34 displayed immediate or delayed sensitization to P obconica allergens.⁵ However, in another study, researchers who surveyed the incidence of P obconica allergic contact dermatitis (CD) in the United Kingdom found a notable decline in the number of primin-positive patch tests from 1995 to 2000, which likely was attributable to a decrease in the number of plant retailers who stocked P obconica and the availability of primin-free varieties from 50% of suppliers.³ Furthermore, a study in the United States of 567 consecutive patch tests that included primin as part of standard screening found only 1 positive reaction, suggesting that routine patch testing for P obconica in the United States would have a low yield unless the patient has a relevant history.⁴

Cutaneous Presentation

Clinical features of P obconica–induced dermatitis include fingertip dermatitis, as well as facial, hand, and forearm dermatitis.⁶ Patients typically present with lichenification and fissuring of the fingertips; fingertip vesicular dermatitis; or linear erythematous streaks, vesicles, and bullae on the forearms, hands, and face. Vesicles and bullae can be hemorrhagic in patients with pompholyxlike lesions.⁷

Some patients have been reported to present with facial angioedema; the clinical diagnosis of CD can be challenging when facial edema is more prominent than eczema.⁶ Furthermore, in a reported case of P obconica CD, the patient’s vesicular hand dermatitis became pustular and spread to the face.⁸

Allergy Testing

Patch testing is performed with synthetic primin to detect allergens of P obconica in patients who are sensitive to them, which can be useful because Primula dermatitis can have variable presentations and cases can be missed if patch testing is not performed.⁹ Diagnostic mimics—herpes simplex, pompholyx, seborrheic dermatitis, and scabies—should be considered before patch testing.⁷

Prevention and Treatment

Preventive Measures—Ideally, once CD occurs in response to P obconica, handling of and other exposure to the plant should be halted; thus, prevention becomes the mainstay of treatment. Alternatively, when exposure is a necessary occupational hazard, nitrile gloves should be worn; allergenicity can be decreased by overwatering or introducing more primin-free varieties.^3,10

Cultivating the plant outdoors during the winter in milder climates can potentially decrease sensitivity because allergen production is lowest during cold months and highest during summer.¹¹ Because P obconica is commonly grown indoors, allergenicity can persist year-round.

Pharmacotherapy—Drawing on experience treating CD caused by other plants, acute and chronic P obconica CD are primarily treated with a topical steroid or, if the face or genitals are affected, with a steroid-sparing agent, such as tacrolimus.¹² A cool compress of water, saline, or Burow solution (aluminum acetate in water) can help decrease acute inflammation, especially in the setting of vesiculation.¹³

Mild CD also can be treated with a barrier cream and lipid-rich moisturizer. Their effectiveness likely is due to increased hydration and aiding impaired skin-barrier repair.¹⁴

Some success in treating chronic CD also has been reported with psoralen plus UVA and UVB light therapy, which function as local immunosuppressants, thus decreasing inflammation.¹⁵

Final Thoughts

Contact dermatitis caused by P obconica is common in Europe but less common in the United States and therefore often is underrecognized. Avoiding contact with the plant should be strongly recommended to allergic persons. Primula obconica allergic CD can be treated with a topical steroid.

Etiology

Calcareous soils of central and southwest China are home to Primula obconica¹ (also known as German primrose and Libre Magenta).²Primula obconica was introduced to Europe in the 1880s, where it became a popular ornamental and decorative household plant (Figure).³ It also is a frequent resident of greenhouses.

Primula obconica is a member of the family Primulaceae, which comprises semi-evergreen perennials. The genus name Primula is derived from Latin meaning “first”; obconica refers to the conelike shape of the plant’s vivid, cerise-red flowers.

Allergens From P obconica

The allergens primin (2-methoxy-6-pentyl-1,4-benzoquinone) and miconidin (2-methoxy-6-pentyl-1, 4-dihydroxybenzene) have been isolated from P obconica stems, leaves, and flowers. Allergies to P obconica are much more commonly detected in Europe than in the United States because the plant is part of standard allergen screening in dermatology clinics in Europe.⁴ In a British patch test study of 234 patients with hand dermatitis, 34 displayed immediate or delayed sensitization to P obconica allergens.⁵ However, in another study, researchers who surveyed the incidence of P obconica allergic contact dermatitis (CD) in the United Kingdom found a notable decline in the number of primin-positive patch tests from 1995 to 2000, which likely was attributable to a decrease in the number of plant retailers who stocked P obconica and the availability of primin-free varieties from 50% of suppliers.³ Furthermore, a study in the United States of 567 consecutive patch tests that included primin as part of standard screening found only 1 positive reaction, suggesting that routine patch testing for P obconica in the United States would have a low yield unless the patient has a relevant history.⁴

Cutaneous Presentation

Clinical features of P obconica–induced dermatitis include fingertip dermatitis, as well as facial, hand, and forearm dermatitis.⁶ Patients typically present with lichenification and fissuring of the fingertips; fingertip vesicular dermatitis; or linear erythematous streaks, vesicles, and bullae on the forearms, hands, and face. Vesicles and bullae can be hemorrhagic in patients with pompholyxlike lesions.⁷

Some patients have been reported to present with facial angioedema; the clinical diagnosis of CD can be challenging when facial edema is more prominent than eczema.⁶ Furthermore, in a reported case of P obconica CD, the patient’s vesicular hand dermatitis became pustular and spread to the face.⁸

Allergy Testing

Patch testing is performed with synthetic primin to detect allergens of P obconica in patients who are sensitive to them, which can be useful because Primula dermatitis can have variable presentations and cases can be missed if patch testing is not performed.⁹ Diagnostic mimics—herpes simplex, pompholyx, seborrheic dermatitis, and scabies—should be considered before patch testing.⁷

Prevention and Treatment

Preventive Measures—Ideally, once CD occurs in response to P obconica, handling of and other exposure to the plant should be halted; thus, prevention becomes the mainstay of treatment. Alternatively, when exposure is a necessary occupational hazard, nitrile gloves should be worn; allergenicity can be decreased by overwatering or introducing more primin-free varieties.^3,10

Cultivating the plant outdoors during the winter in milder climates can potentially decrease sensitivity because allergen production is lowest during cold months and highest during summer.¹¹ Because P obconica is commonly grown indoors, allergenicity can persist year-round.

Pharmacotherapy—Drawing on experience treating CD caused by other plants, acute and chronic P obconica CD are primarily treated with a topical steroid or, if the face or genitals are affected, with a steroid-sparing agent, such as tacrolimus.¹² A cool compress of water, saline, or Burow solution (aluminum acetate in water) can help decrease acute inflammation, especially in the setting of vesiculation.¹³

Mild CD also can be treated with a barrier cream and lipid-rich moisturizer. Their effectiveness likely is due to increased hydration and aiding impaired skin-barrier repair.¹⁴

Some success in treating chronic CD also has been reported with psoralen plus UVA and UVB light therapy, which function as local immunosuppressants, thus decreasing inflammation.¹⁵

Final Thoughts

Contact dermatitis caused by P obconica is common in Europe but less common in the United States and therefore often is underrecognized. Avoiding contact with the plant should be strongly recommended to allergic persons. Primula obconica allergic CD can be treated with a topical steroid.

Etiology

Calcareous soils of central and southwest China are home to Primula obconica¹ (also known as German primrose and Libre Magenta).²Primula obconica was introduced to Europe in the 1880s, where it became a popular ornamental and decorative household plant (Figure).³ It also is a frequent resident of greenhouses.

Primula obconica is a member of the family Primulaceae, which comprises semi-evergreen perennials. The genus name Primula is derived from Latin meaning “first”; obconica refers to the conelike shape of the plant’s vivid, cerise-red flowers.

Allergens From P obconica

The allergens primin (2-methoxy-6-pentyl-1,4-benzoquinone) and miconidin (2-methoxy-6-pentyl-1, 4-dihydroxybenzene) have been isolated from P obconica stems, leaves, and flowers. Allergies to P obconica are much more commonly detected in Europe than in the United States because the plant is part of standard allergen screening in dermatology clinics in Europe.⁴ In a British patch test study of 234 patients with hand dermatitis, 34 displayed immediate or delayed sensitization to P obconica allergens.⁵ However, in another study, researchers who surveyed the incidence of P obconica allergic contact dermatitis (CD) in the United Kingdom found a notable decline in the number of primin-positive patch tests from 1995 to 2000, which likely was attributable to a decrease in the number of plant retailers who stocked P obconica and the availability of primin-free varieties from 50% of suppliers.³ Furthermore, a study in the United States of 567 consecutive patch tests that included primin as part of standard screening found only 1 positive reaction, suggesting that routine patch testing for P obconica in the United States would have a low yield unless the patient has a relevant history.⁴

Cutaneous Presentation

Clinical features of P obconica–induced dermatitis include fingertip dermatitis, as well as facial, hand, and forearm dermatitis.⁶ Patients typically present with lichenification and fissuring of the fingertips; fingertip vesicular dermatitis; or linear erythematous streaks, vesicles, and bullae on the forearms, hands, and face. Vesicles and bullae can be hemorrhagic in patients with pompholyxlike lesions.⁷

Some patients have been reported to present with facial angioedema; the clinical diagnosis of CD can be challenging when facial edema is more prominent than eczema.⁶ Furthermore, in a reported case of P obconica CD, the patient’s vesicular hand dermatitis became pustular and spread to the face.⁸

Allergy Testing

Patch testing is performed with synthetic primin to detect allergens of P obconica in patients who are sensitive to them, which can be useful because Primula dermatitis can have variable presentations and cases can be missed if patch testing is not performed.⁹ Diagnostic mimics—herpes simplex, pompholyx, seborrheic dermatitis, and scabies—should be considered before patch testing.⁷

Prevention and Treatment

Preventive Measures—Ideally, once CD occurs in response to P obconica, handling of and other exposure to the plant should be halted; thus, prevention becomes the mainstay of treatment. Alternatively, when exposure is a necessary occupational hazard, nitrile gloves should be worn; allergenicity can be decreased by overwatering or introducing more primin-free varieties.^3,10

Cultivating the plant outdoors during the winter in milder climates can potentially decrease sensitivity because allergen production is lowest during cold months and highest during summer.¹¹ Because P obconica is commonly grown indoors, allergenicity can persist year-round.

Pharmacotherapy—Drawing on experience treating CD caused by other plants, acute and chronic P obconica CD are primarily treated with a topical steroid or, if the face or genitals are affected, with a steroid-sparing agent, such as tacrolimus.¹² A cool compress of water, saline, or Burow solution (aluminum acetate in water) can help decrease acute inflammation, especially in the setting of vesiculation.¹³

Mild CD also can be treated with a barrier cream and lipid-rich moisturizer. Their effectiveness likely is due to increased hydration and aiding impaired skin-barrier repair.¹⁴

Some success in treating chronic CD also has been reported with psoralen plus UVA and UVB light therapy, which function as local immunosuppressants, thus decreasing inflammation.¹⁵

Final Thoughts

Contact dermatitis caused by P obconica is common in Europe but less common in the United States and therefore often is underrecognized. Avoiding contact with the plant should be strongly recommended to allergic persons. Primula obconica allergic CD can be treated with a topical steroid.

Dermatology remains one of the most competitive specialties in medicine. In 2022, there were 851 applicants (613 doctor of medicine seniors, 85 doctor of osteopathic medicine seniors) for 492 postgraduate year (PGY) 2 positions.¹ During the 2022 application season, the average matched dermatology candidate had 7.2 research experiences; 20.9 abstracts, presentations, or publications; 11 volunteer experiences; and a US Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge score of 257.¹ With hopes of matching into such a competitive field, students often seek advice from academic dermatology mentors. Such advice may substantially differ based on each mentor and may or may not be evidence based.

We sought to analyze the range of advice given to medical students applying to dermatology residency programs via a survey to members of the Association of Professors of Dermatology (APD) with the intent to help applicants and mentors understand how letters of intent, letters of recommendation (LORs), and Electronic Residency Application Service (ERAS) supplemental applications are used by dermatology programs nationwide.

Methods

The study was reviewed by The Ohio State University institutional review board and was deemed exempt. A branching-logic survey with common questions from medical students while applying to dermatology residency programs (Table) was sent to all members of APD through the email listserve. Study data were collected and managed using REDCap electronic data capture tools hosted at The Ohio State University (Columbus, Ohio) to ensure data security.

The survey was distributed from August 28, 2022, to September 12, 2022. A total of 101 surveys were returned from 646 listserve members (15.6%). Given the branching-logic questions, differing numbers of responses were collected for each question. Descriptive statistics were utilized to analyze and report the results.

Results

Residency Program Number—Members of the APD were asked if they recommend students apply to a certain number of programs, and if so, how many programs. Of members who responded, 62.2% (61/98) either always (22.4% [22/98]) or sometimes (40.2% [39/97]) suggested students apply to a certain number of programs. When mentors made a recommendation, 54.1% (33/61) recommended applying to 59 or fewer programs, with only 9.8% (6/61) recommending students apply to 80 or more programs.

Gap Year—We queried mentors about their recommendations for a research gap year and asked which applicants should pursue this extra year. Our survey found that 74.5% of mentors (73/98) almost always (4.1% [4/98]) or sometimes (70.4% [69/98]) recommended a research gap year, most commonly for those applicants with a strong research interest (71.8% [51/71]). Other reasons mentors recommended a dedicated research year during medical school included low USMLE Step scores (50.7% [36/71]), low grades (45.1% [32/71]), little research (46.5% [33/71]), and no home program (43.7% [31/71]).

Internship Choices—Our survey results indicated that nearly two-thirds (63.3% [62/98]) of mentors did not give applicants a recommendation on type of internship (PGY-1). If a recommendation was given, academic dermatologists more commonly recommended an internal medicine preliminary year (29.6% [29/98]) over a transitional year (7.1% [7/98]).

Communication of Interest Via a Letter of Intent—We asked mentors if they recommended applicants send a letter of intent and conversely if receiving a letter of intent impacted their rank list. Nearly half (48.5% [47/97]) of mentors indicated they did not recommend sending a letter of intent, with only 15.5% (15/97) of mentors regularly recommending this practice. Additionally, 75.8% of mentors indicated that a letter of intent never (42.1% [40/95]) or rarely (33.7% [32/95]) impacted their rank list.

Rotation Choices—We queried mentors if they recommended students complete away rotations, and if so, how many rotations did they recommend. We found that 85.9% (85/99) of mentors recommended students complete an away rotation; 63.1% (53/84) of them recommended performing 2 away rotations, and 14.3% (12/84) of respondents recommended students complete 3 away rotations. More than a quarter of mentors (27.1% [23/85]) indicated their home medical schools limited the number of away rotations a medical student could complete in any 1 specialty, and 42.4% (36/85) of respondents were unsure if such a limitation existed.

Letters of Recommendation—Our survey asked respondents to rank various factors on a 5-point scale (1=not important; 5=very important) when deciding who should write the students’ LORs. Mentors indicated that the most important factor for letter-writer selection was how well the letter writer knows the applicant, with 90.8% (89/98) of mentors rating the importance of this quality as a 4 or 5 (Figure). More than half of respondents rated the name recognition of the letter writer and program director letter as a 4 or 5 in importance (54.1% [53/98] and 58.2% [57/98], respectively). Type of letter (standardized vs nonstandardized), title of letter writer, letters from an away rotation, and chair letter scored lower, with fewer than half of mentors rating these as a 4 or 5 in importance.

Supplemental Application—When asked about the 2022 application cycle, respondents of our survey reported that the supplemental application was overall more important in deciding which applicants to interview vs which to rank highly. Prior experiences were important (ranked 4 or 5) for 58.8% (57/97) of respondents in choosing applicants to interview, and 49.4% (48/97) of respondents thought prior experiences were important for ranking. Similarly, 34.0% (33/97) of mentors indicated geographic preference was important (ranked 4 or 5) for interview compared with only 23.8% (23/97) for ranking. Finally, 57.7% (56/97) of our survey respondents denoted that program signals were important or very important in choosing which applicants to interview, while 32.0% (31/97) indicated that program signals were important in ranking applicants.

Comment

Residency Programs: Which Ones, and How Many?—The number of applications for dermatology residency programs has increased 33.9% from 2010 to 2019.² The American Association of Medical Colleges Apply Smart data from 2013 to 2017 indicate that dermatology applicants arrive at a point of diminishing return between 37 and 62 applications, with variation within that range based on USMLE Step 1 score,³ and our data support this with nearly two-thirds of dermatology advisors recommending students apply within this range. Despite this data, dermatology residency applicants applied to more programs over the last decade (64.8 vs 77.0),² likely to maximize their chance of matching.

Research Gap Years During Medical School—Prior research has shown that nearly half of faculty indicated that a research year during medical school can distinguish similar applicants, and close to 25% of applicants completed a research gap year.^4,5 However, available data indicate that taking a research gap year has no effect on match rate or number of interview invites but does correlate with match rates at the highest ranked dermatology residency programs.^6-8

Our data indicate that the most commonly recommended reason for a research gap year was an applicants’ strong interest in research. However, nearly half of dermatology mentors recommended research years during medical school for reasons other than an interest in research. As research gap years increase in popularity, future research is needed to confirm the consequence of this additional year and which applicants, if any, will benefit from such a year.

Preferences for Intern Year—Prior research suggests that dermatology residency program directors favor PGY-1 preliminary medicine internships because of the rigor of training.^9,10 Our data continue to show a preference for internal medicine preliminary years over transitional years. However, given nearly two-thirds of dermatology mentors do not give applicants any recommendations on PGY-1 year, this preference may be fading.

Letters of Intent Not Recommended—Research in 2022 found that 78.8% of dermatology applicants sent a letter of intent communicating a plan to rank that program number 1, with nearly 13% sending such a letter to more than 1 program.¹¹ With nearly half of mentors in our survey actively discouraging this process and more than 75% of mentors not utilizing this letter, the APD issued a brief statement on the 2022-2023 application cycle stating, “Post-interview communication of preference—including ‘letters of intent’ and thank you letters—should not be sent to programs. These types of communication are typically not used by residency programs in decision-making and lead to downstream pressures on applicants.”¹²

Away Rotations—Prior to the COVID-19 pandemic, data demonstrated that nearly one-third of dermatology applicants (29%) matched at their home institution, and nearly one-fifth (18%) matched where they completed an away rotation.¹³ In-person away rotations were eliminated in 2020 and restricted to 1 away rotation in 2021. Restrictions regarding away rotations were removed in 2022. Our data indicate that dermatology mentors strongly supported an away rotation, with more than half of them recommending at least 2 away rotations.

Further research is needed to determine the effect numerous away rotations have on minimizing students’ exposure to other specialties outside their chosen field. Additionally, further studies are needed to determine the impact away rotations have on economically disadvantaged students, students without home programs, and students with families. In an effort to standardize the number of away rotations, the APD issued a statement for the 2023-2024 application cycle indicating that dermatology applicants should limit away rotations to 2 in-person electives. Students without a home dermatology program could consider completing up to 3 electives.¹⁴

Who Should Write LORs?—Research in 2014 demonstrated that LORs were very important in determining applicants to interview, with a strong preference for LORs from academic dermatologists and colleagues.¹⁵ Our data strongly indicated applicants should predominantly ask for letters from writers who know them well. The majority of mentors did not give value to the rank of the letter writer (eg, assistant professor, associate professor, professor), type of letter, chair letters, or letters from an away rotation. These data may help alleviate stress many students feel as they search for letter writers.

How is the Supplemental Application Used?—In 2022, the ERAS supplemental application was introduced, which allowed applicants to detail 5 meaningful experiences, describe impactful life challenges, and indicate preferences for geographic region. Dermatology residency applicants also were able to choose 3 residency programs to signal interest in that program. Our data found that the supplemental application was utilized predominantly to select applicants to interview, which is in line with the Association of American Medical Colleges’ and APD guidelines indicating that this tool is solely meant to assist with application review.¹⁶ Further research and data will hopefully inform approaches to best utilize the ERAS supplemental application data.

Limitations—Our data were limited by response rate and sample size, as only academic dermatologists belonging to the APD were queried. Additionally, we did not track personal information of the mentors, so more than 1 mentor may have responded from a single institution, making it possible that our data may not be broadly applicable to all institutions.

Conclusion

Although there is no algorithmic method of advising medical students who are interested in dermatology, our survey data help to describe the range of advice currently given to students, which can improve and guide future recommendations. Additionally, some of our data demonstrate a discrepancy between mentor advice and current medical student practice for the number of applications and use of a letter of intent. We hope our data will assist academic dermatology mentors in the provision of advice to mentees as well as inform organizations seeking to create standards and official recommendations regarding aspects of the application process.

Dermatology remains one of the most competitive specialties in medicine. In 2022, there were 851 applicants (613 doctor of medicine seniors, 85 doctor of osteopathic medicine seniors) for 492 postgraduate year (PGY) 2 positions.¹ During the 2022 application season, the average matched dermatology candidate had 7.2 research experiences; 20.9 abstracts, presentations, or publications; 11 volunteer experiences; and a US Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge score of 257.¹ With hopes of matching into such a competitive field, students often seek advice from academic dermatology mentors. Such advice may substantially differ based on each mentor and may or may not be evidence based.

We sought to analyze the range of advice given to medical students applying to dermatology residency programs via a survey to members of the Association of Professors of Dermatology (APD) with the intent to help applicants and mentors understand how letters of intent, letters of recommendation (LORs), and Electronic Residency Application Service (ERAS) supplemental applications are used by dermatology programs nationwide.

Methods

The study was reviewed by The Ohio State University institutional review board and was deemed exempt. A branching-logic survey with common questions from medical students while applying to dermatology residency programs (Table) was sent to all members of APD through the email listserve. Study data were collected and managed using REDCap electronic data capture tools hosted at The Ohio State University (Columbus, Ohio) to ensure data security.

The survey was distributed from August 28, 2022, to September 12, 2022. A total of 101 surveys were returned from 646 listserve members (15.6%). Given the branching-logic questions, differing numbers of responses were collected for each question. Descriptive statistics were utilized to analyze and report the results.

Results

Residency Program Number—Members of the APD were asked if they recommend students apply to a certain number of programs, and if so, how many programs. Of members who responded, 62.2% (61/98) either always (22.4% [22/98]) or sometimes (40.2% [39/97]) suggested students apply to a certain number of programs. When mentors made a recommendation, 54.1% (33/61) recommended applying to 59 or fewer programs, with only 9.8% (6/61) recommending students apply to 80 or more programs.

Gap Year—We queried mentors about their recommendations for a research gap year and asked which applicants should pursue this extra year. Our survey found that 74.5% of mentors (73/98) almost always (4.1% [4/98]) or sometimes (70.4% [69/98]) recommended a research gap year, most commonly for those applicants with a strong research interest (71.8% [51/71]). Other reasons mentors recommended a dedicated research year during medical school included low USMLE Step scores (50.7% [36/71]), low grades (45.1% [32/71]), little research (46.5% [33/71]), and no home program (43.7% [31/71]).

Internship Choices—Our survey results indicated that nearly two-thirds (63.3% [62/98]) of mentors did not give applicants a recommendation on type of internship (PGY-1). If a recommendation was given, academic dermatologists more commonly recommended an internal medicine preliminary year (29.6% [29/98]) over a transitional year (7.1% [7/98]).

Communication of Interest Via a Letter of Intent—We asked mentors if they recommended applicants send a letter of intent and conversely if receiving a letter of intent impacted their rank list. Nearly half (48.5% [47/97]) of mentors indicated they did not recommend sending a letter of intent, with only 15.5% (15/97) of mentors regularly recommending this practice. Additionally, 75.8% of mentors indicated that a letter of intent never (42.1% [40/95]) or rarely (33.7% [32/95]) impacted their rank list.

Rotation Choices—We queried mentors if they recommended students complete away rotations, and if so, how many rotations did they recommend. We found that 85.9% (85/99) of mentors recommended students complete an away rotation; 63.1% (53/84) of them recommended performing 2 away rotations, and 14.3% (12/84) of respondents recommended students complete 3 away rotations. More than a quarter of mentors (27.1% [23/85]) indicated their home medical schools limited the number of away rotations a medical student could complete in any 1 specialty, and 42.4% (36/85) of respondents were unsure if such a limitation existed.

Letters of Recommendation—Our survey asked respondents to rank various factors on a 5-point scale (1=not important; 5=very important) when deciding who should write the students’ LORs. Mentors indicated that the most important factor for letter-writer selection was how well the letter writer knows the applicant, with 90.8% (89/98) of mentors rating the importance of this quality as a 4 or 5 (Figure). More than half of respondents rated the name recognition of the letter writer and program director letter as a 4 or 5 in importance (54.1% [53/98] and 58.2% [57/98], respectively). Type of letter (standardized vs nonstandardized), title of letter writer, letters from an away rotation, and chair letter scored lower, with fewer than half of mentors rating these as a 4 or 5 in importance.

Supplemental Application—When asked about the 2022 application cycle, respondents of our survey reported that the supplemental application was overall more important in deciding which applicants to interview vs which to rank highly. Prior experiences were important (ranked 4 or 5) for 58.8% (57/97) of respondents in choosing applicants to interview, and 49.4% (48/97) of respondents thought prior experiences were important for ranking. Similarly, 34.0% (33/97) of mentors indicated geographic preference was important (ranked 4 or 5) for interview compared with only 23.8% (23/97) for ranking. Finally, 57.7% (56/97) of our survey respondents denoted that program signals were important or very important in choosing which applicants to interview, while 32.0% (31/97) indicated that program signals were important in ranking applicants.

Comment

Residency Programs: Which Ones, and How Many?—The number of applications for dermatology residency programs has increased 33.9% from 2010 to 2019.² The American Association of Medical Colleges Apply Smart data from 2013 to 2017 indicate that dermatology applicants arrive at a point of diminishing return between 37 and 62 applications, with variation within that range based on USMLE Step 1 score,³ and our data support this with nearly two-thirds of dermatology advisors recommending students apply within this range. Despite this data, dermatology residency applicants applied to more programs over the last decade (64.8 vs 77.0),² likely to maximize their chance of matching.

Research Gap Years During Medical School—Prior research has shown that nearly half of faculty indicated that a research year during medical school can distinguish similar applicants, and close to 25% of applicants completed a research gap year.^4,5 However, available data indicate that taking a research gap year has no effect on match rate or number of interview invites but does correlate with match rates at the highest ranked dermatology residency programs.^6-8

Our data indicate that the most commonly recommended reason for a research gap year was an applicants’ strong interest in research. However, nearly half of dermatology mentors recommended research years during medical school for reasons other than an interest in research. As research gap years increase in popularity, future research is needed to confirm the consequence of this additional year and which applicants, if any, will benefit from such a year.

Preferences for Intern Year—Prior research suggests that dermatology residency program directors favor PGY-1 preliminary medicine internships because of the rigor of training.^9,10 Our data continue to show a preference for internal medicine preliminary years over transitional years. However, given nearly two-thirds of dermatology mentors do not give applicants any recommendations on PGY-1 year, this preference may be fading.

Letters of Intent Not Recommended—Research in 2022 found that 78.8% of dermatology applicants sent a letter of intent communicating a plan to rank that program number 1, with nearly 13% sending such a letter to more than 1 program.¹¹ With nearly half of mentors in our survey actively discouraging this process and more than 75% of mentors not utilizing this letter, the APD issued a brief statement on the 2022-2023 application cycle stating, “Post-interview communication of preference—including ‘letters of intent’ and thank you letters—should not be sent to programs. These types of communication are typically not used by residency programs in decision-making and lead to downstream pressures on applicants.”¹²

Away Rotations—Prior to the COVID-19 pandemic, data demonstrated that nearly one-third of dermatology applicants (29%) matched at their home institution, and nearly one-fifth (18%) matched where they completed an away rotation.¹³ In-person away rotations were eliminated in 2020 and restricted to 1 away rotation in 2021. Restrictions regarding away rotations were removed in 2022. Our data indicate that dermatology mentors strongly supported an away rotation, with more than half of them recommending at least 2 away rotations.

Further research is needed to determine the effect numerous away rotations have on minimizing students’ exposure to other specialties outside their chosen field. Additionally, further studies are needed to determine the impact away rotations have on economically disadvantaged students, students without home programs, and students with families. In an effort to standardize the number of away rotations, the APD issued a statement for the 2023-2024 application cycle indicating that dermatology applicants should limit away rotations to 2 in-person electives. Students without a home dermatology program could consider completing up to 3 electives.¹⁴

Who Should Write LORs?—Research in 2014 demonstrated that LORs were very important in determining applicants to interview, with a strong preference for LORs from academic dermatologists and colleagues.¹⁵ Our data strongly indicated applicants should predominantly ask for letters from writers who know them well. The majority of mentors did not give value to the rank of the letter writer (eg, assistant professor, associate professor, professor), type of letter, chair letters, or letters from an away rotation. These data may help alleviate stress many students feel as they search for letter writers.

How is the Supplemental Application Used?—In 2022, the ERAS supplemental application was introduced, which allowed applicants to detail 5 meaningful experiences, describe impactful life challenges, and indicate preferences for geographic region. Dermatology residency applicants also were able to choose 3 residency programs to signal interest in that program. Our data found that the supplemental application was utilized predominantly to select applicants to interview, which is in line with the Association of American Medical Colleges’ and APD guidelines indicating that this tool is solely meant to assist with application review.¹⁶ Further research and data will hopefully inform approaches to best utilize the ERAS supplemental application data.

Limitations—Our data were limited by response rate and sample size, as only academic dermatologists belonging to the APD were queried. Additionally, we did not track personal information of the mentors, so more than 1 mentor may have responded from a single institution, making it possible that our data may not be broadly applicable to all institutions.

Conclusion

Although there is no algorithmic method of advising medical students who are interested in dermatology, our survey data help to describe the range of advice currently given to students, which can improve and guide future recommendations. Additionally, some of our data demonstrate a discrepancy between mentor advice and current medical student practice for the number of applications and use of a letter of intent. We hope our data will assist academic dermatology mentors in the provision of advice to mentees as well as inform organizations seeking to create standards and official recommendations regarding aspects of the application process.

Dermatology remains one of the most competitive specialties in medicine. In 2022, there were 851 applicants (613 doctor of medicine seniors, 85 doctor of osteopathic medicine seniors) for 492 postgraduate year (PGY) 2 positions.¹ During the 2022 application season, the average matched dermatology candidate had 7.2 research experiences; 20.9 abstracts, presentations, or publications; 11 volunteer experiences; and a US Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge score of 257.¹ With hopes of matching into such a competitive field, students often seek advice from academic dermatology mentors. Such advice may substantially differ based on each mentor and may or may not be evidence based.

We sought to analyze the range of advice given to medical students applying to dermatology residency programs via a survey to members of the Association of Professors of Dermatology (APD) with the intent to help applicants and mentors understand how letters of intent, letters of recommendation (LORs), and Electronic Residency Application Service (ERAS) supplemental applications are used by dermatology programs nationwide.

Methods

The study was reviewed by The Ohio State University institutional review board and was deemed exempt. A branching-logic survey with common questions from medical students while applying to dermatology residency programs (Table) was sent to all members of APD through the email listserve. Study data were collected and managed using REDCap electronic data capture tools hosted at The Ohio State University (Columbus, Ohio) to ensure data security.

The survey was distributed from August 28, 2022, to September 12, 2022. A total of 101 surveys were returned from 646 listserve members (15.6%). Given the branching-logic questions, differing numbers of responses were collected for each question. Descriptive statistics were utilized to analyze and report the results.

Results

Residency Program Number—Members of the APD were asked if they recommend students apply to a certain number of programs, and if so, how many programs. Of members who responded, 62.2% (61/98) either always (22.4% [22/98]) or sometimes (40.2% [39/97]) suggested students apply to a certain number of programs. When mentors made a recommendation, 54.1% (33/61) recommended applying to 59 or fewer programs, with only 9.8% (6/61) recommending students apply to 80 or more programs.

Gap Year—We queried mentors about their recommendations for a research gap year and asked which applicants should pursue this extra year. Our survey found that 74.5% of mentors (73/98) almost always (4.1% [4/98]) or sometimes (70.4% [69/98]) recommended a research gap year, most commonly for those applicants with a strong research interest (71.8% [51/71]). Other reasons mentors recommended a dedicated research year during medical school included low USMLE Step scores (50.7% [36/71]), low grades (45.1% [32/71]), little research (46.5% [33/71]), and no home program (43.7% [31/71]).

Internship Choices—Our survey results indicated that nearly two-thirds (63.3% [62/98]) of mentors did not give applicants a recommendation on type of internship (PGY-1). If a recommendation was given, academic dermatologists more commonly recommended an internal medicine preliminary year (29.6% [29/98]) over a transitional year (7.1% [7/98]).

Communication of Interest Via a Letter of Intent—We asked mentors if they recommended applicants send a letter of intent and conversely if receiving a letter of intent impacted their rank list. Nearly half (48.5% [47/97]) of mentors indicated they did not recommend sending a letter of intent, with only 15.5% (15/97) of mentors regularly recommending this practice. Additionally, 75.8% of mentors indicated that a letter of intent never (42.1% [40/95]) or rarely (33.7% [32/95]) impacted their rank list.

Rotation Choices—We queried mentors if they recommended students complete away rotations, and if so, how many rotations did they recommend. We found that 85.9% (85/99) of mentors recommended students complete an away rotation; 63.1% (53/84) of them recommended performing 2 away rotations, and 14.3% (12/84) of respondents recommended students complete 3 away rotations. More than a quarter of mentors (27.1% [23/85]) indicated their home medical schools limited the number of away rotations a medical student could complete in any 1 specialty, and 42.4% (36/85) of respondents were unsure if such a limitation existed.

Letters of Recommendation—Our survey asked respondents to rank various factors on a 5-point scale (1=not important; 5=very important) when deciding who should write the students’ LORs. Mentors indicated that the most important factor for letter-writer selection was how well the letter writer knows the applicant, with 90.8% (89/98) of mentors rating the importance of this quality as a 4 or 5 (Figure). More than half of respondents rated the name recognition of the letter writer and program director letter as a 4 or 5 in importance (54.1% [53/98] and 58.2% [57/98], respectively). Type of letter (standardized vs nonstandardized), title of letter writer, letters from an away rotation, and chair letter scored lower, with fewer than half of mentors rating these as a 4 or 5 in importance.

Supplemental Application—When asked about the 2022 application cycle, respondents of our survey reported that the supplemental application was overall more important in deciding which applicants to interview vs which to rank highly. Prior experiences were important (ranked 4 or 5) for 58.8% (57/97) of respondents in choosing applicants to interview, and 49.4% (48/97) of respondents thought prior experiences were important for ranking. Similarly, 34.0% (33/97) of mentors indicated geographic preference was important (ranked 4 or 5) for interview compared with only 23.8% (23/97) for ranking. Finally, 57.7% (56/97) of our survey respondents denoted that program signals were important or very important in choosing which applicants to interview, while 32.0% (31/97) indicated that program signals were important in ranking applicants.

Comment

Residency Programs: Which Ones, and How Many?—The number of applications for dermatology residency programs has increased 33.9% from 2010 to 2019.² The American Association of Medical Colleges Apply Smart data from 2013 to 2017 indicate that dermatology applicants arrive at a point of diminishing return between 37 and 62 applications, with variation within that range based on USMLE Step 1 score,³ and our data support this with nearly two-thirds of dermatology advisors recommending students apply within this range. Despite this data, dermatology residency applicants applied to more programs over the last decade (64.8 vs 77.0),² likely to maximize their chance of matching.

Research Gap Years During Medical School—Prior research has shown that nearly half of faculty indicated that a research year during medical school can distinguish similar applicants, and close to 25% of applicants completed a research gap year.^4,5 However, available data indicate that taking a research gap year has no effect on match rate or number of interview invites but does correlate with match rates at the highest ranked dermatology residency programs.^6-8

Our data indicate that the most commonly recommended reason for a research gap year was an applicants’ strong interest in research. However, nearly half of dermatology mentors recommended research years during medical school for reasons other than an interest in research. As research gap years increase in popularity, future research is needed to confirm the consequence of this additional year and which applicants, if any, will benefit from such a year.

Preferences for Intern Year—Prior research suggests that dermatology residency program directors favor PGY-1 preliminary medicine internships because of the rigor of training.^9,10 Our data continue to show a preference for internal medicine preliminary years over transitional years. However, given nearly two-thirds of dermatology mentors do not give applicants any recommendations on PGY-1 year, this preference may be fading.

Letters of Intent Not Recommended—Research in 2022 found that 78.8% of dermatology applicants sent a letter of intent communicating a plan to rank that program number 1, with nearly 13% sending such a letter to more than 1 program.¹¹ With nearly half of mentors in our survey actively discouraging this process and more than 75% of mentors not utilizing this letter, the APD issued a brief statement on the 2022-2023 application cycle stating, “Post-interview communication of preference—including ‘letters of intent’ and thank you letters—should not be sent to programs. These types of communication are typically not used by residency programs in decision-making and lead to downstream pressures on applicants.”¹²

Away Rotations—Prior to the COVID-19 pandemic, data demonstrated that nearly one-third of dermatology applicants (29%) matched at their home institution, and nearly one-fifth (18%) matched where they completed an away rotation.¹³ In-person away rotations were eliminated in 2020 and restricted to 1 away rotation in 2021. Restrictions regarding away rotations were removed in 2022. Our data indicate that dermatology mentors strongly supported an away rotation, with more than half of them recommending at least 2 away rotations.

Further research is needed to determine the effect numerous away rotations have on minimizing students’ exposure to other specialties outside their chosen field. Additionally, further studies are needed to determine the impact away rotations have on economically disadvantaged students, students without home programs, and students with families. In an effort to standardize the number of away rotations, the APD issued a statement for the 2023-2024 application cycle indicating that dermatology applicants should limit away rotations to 2 in-person electives. Students without a home dermatology program could consider completing up to 3 electives.¹⁴

Who Should Write LORs?—Research in 2014 demonstrated that LORs were very important in determining applicants to interview, with a strong preference for LORs from academic dermatologists and colleagues.¹⁵ Our data strongly indicated applicants should predominantly ask for letters from writers who know them well. The majority of mentors did not give value to the rank of the letter writer (eg, assistant professor, associate professor, professor), type of letter, chair letters, or letters from an away rotation. These data may help alleviate stress many students feel as they search for letter writers.

How is the Supplemental Application Used?—In 2022, the ERAS supplemental application was introduced, which allowed applicants to detail 5 meaningful experiences, describe impactful life challenges, and indicate preferences for geographic region. Dermatology residency applicants also were able to choose 3 residency programs to signal interest in that program. Our data found that the supplemental application was utilized predominantly to select applicants to interview, which is in line with the Association of American Medical Colleges’ and APD guidelines indicating that this tool is solely meant to assist with application review.¹⁶ Further research and data will hopefully inform approaches to best utilize the ERAS supplemental application data.

Limitations—Our data were limited by response rate and sample size, as only academic dermatologists belonging to the APD were queried. Additionally, we did not track personal information of the mentors, so more than 1 mentor may have responded from a single institution, making it possible that our data may not be broadly applicable to all institutions.

Conclusion

Although there is no algorithmic method of advising medical students who are interested in dermatology, our survey data help to describe the range of advice currently given to students, which can improve and guide future recommendations. Additionally, some of our data demonstrate a discrepancy between mentor advice and current medical student practice for the number of applications and use of a letter of intent. We hope our data will assist academic dermatology mentors in the provision of advice to mentees as well as inform organizations seeking to create standards and official recommendations regarding aspects of the application process.