Cutis

The practice of dermatology is rife with bedside tools: swabs, smears, and scoring systems. First popularized in specialties such as emergency medicine and internal medicine, clinical scoring systems are now emerging in dermatology. These evidence-based scores can be calculated quickly at the bedside—often through a free smartphone app—to help guide clinical decision-making regarding diagnosis, prognosis, and management. As with any medical tool, scoring systems have limitations and should be used as a supplement, not substitute, for one’s clinical judgement. This article reviews 4 clinical scoring systems practical for dermatology residents.

SCORTEN Prognosticates Cases of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Perhaps the best-known scoring system in dermatology, the SCORTEN is widely used to predict hospital mortality from Stevens-Johnson syndrome/toxic epidermal necrolysis. The SCORTEN includes 7 variables of equal weight—age of 40 years or older, heart rate of 120 beats per minute or more, cancer/hematologic malignancy, involved body surface area (BSA) greater than 10%, serum urea greater than 10 mmol/L, serum bicarbonate less than 20 mmol/L, and serum glucose greater than 14 mmol/L—each contributing 1 point to the overall score if present.¹ The involved BSA is defined as the sum of detached and detachable epidermis.¹

The SCORTEN was developed and prospectively validated to be calculated at the end of the first 24 hours of admission; for this calculation, use the BSA affected at that time, and use the most abnormal values during the first 24 hours of admission for the other variables.¹ In addition, a follow-up study including some of the original coauthors recommends recalculating the SCORTEN at the end of hospital day 3, having found that the score’s predictive value was better on this day than hospital days 1, 2, 4, or 5.² Based on the original study, a SCORTEN of 0 to 1 corresponds to a mortality rate of 3.2%, 2 to 12.1%, 3 to 35.3%, 4 to 58.3%, and 5 or greater to 90.0%.¹

Limitations of the SCORTEN include its ability to overestimate or underestimate mortality as demonstrated by 2 multi-institutional cohorts.^3,4 Recently, the ABCD-10 score was developed as an alternative to the SCORTEN and was found to predict mortality similarly when validated in an internal cohort.⁵

PEST Screens for Psoriatic Arthritis

Dermatologists play an important role in screening for psoriatic arthritis, as an estimated 1 in 5 patients with psoriasis have psoriatic arthritis.⁶ To this end, several screening tools have been developed to help differentiate psoriatic arthritis from other arthritides. Joint guidelines from the American Academy of Dermatology and the National Psoriasis Foundation acknowledge that “. . . these screening tools have tended to perform less well when tested in groups of people other than those for which they were originally developed. As such, their usefulness in routine clinical practice remains controversial.”⁷ Nevertheless, the guidelines state, “[b]ecause screening and early detection of inflammatory arthritis are essential to optimize patient [quality of life] and reduce morbidity, providers may consider using a formal screening tool of their choice.”⁷

With these limitations in mind, I have found the Psoriasis Epidemiology Screening Tool (PEST) to be the most useful psoriatic arthritis screening tool. One study determined that the PEST has the best trade-off between sensitivity and specificity compared to 2 other psoriatic arthritis screening tools, the Psoriatic Arthritis Screening and Evaluation (PASE) and the Early Arthritis for Psoriatic Patients (EARP).⁸

The PEST is comprised of 5 questions: (1) Have you ever had a swollen joint (or joints)? (2) Has a doctor ever told you that you have arthritis? (3) Do your fingernails or toenails have holes or pits? (4) Have you had pain in your heel? (5) Have you had a finger or toe that was completely swollen and painful for no apparent reason? According to the PEST, a referral to a rheumatologist should be considered for patients answering yes to 3 or more questions, which is 97% sensitive and 79% specific for psoriatic arthritis.⁹ Patients who answer yes to fewer than 3 questions should still be referred to a rheumatologist if there is a strong clinical suspicion of psoriatic arthritis.¹⁰

The PEST can be accessed for free in 13 languages via the GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) app as well as downloaded for free from the National Psoriasis Foundation’s website (https://www.psoriasis.org/psa-screening/providers).

ALT-70 Differentiates Cellulitis From Pseudocellulitis

Overdiagnosing cellulitis in the United States has been estimated to result in up to 130,000 unnecessary hospitalizations and up to $515 million in avoidable health care spending.¹¹ Dermatologists are in a unique position to help fix this issue. In one retrospective study of 1430 inpatient dermatology consultations, 74.32% of inpatients evaluated for presumed cellulitis by a dermatologist were instead diagnosed with a cellulitis mimicker (ie, pseudocellulitis), such as stasis dermatitis or contact dermatitis.¹²

The ALT-70 score was developed and prospectively validated to help differentiate lower extremity cellulitis from pseudocellulitis in adult patients in the emergency department (ED).¹³ In addition, the score has retrospectively been shown to function similarly in the inpatient setting when calculated at 24 and 48 hours after ED presentation.¹⁴ Although the ALT-70 score was designed for use by frontline clinicians prior to dermatology consultation, I also have found it helpful to calculate as a consultant, as it provides an objective measure of risk to communicate to the primary team in support of one diagnosis or another.

ALT-70 is an acronym for the score’s 4 variables: asymmetry, leukocytosis, tachycardia, and age of 70 years or older.¹⁵ If present, each variable confers a certain number of points to the final score: 3 points for asymmetry (defined as unilateral leg involvement), 1 point for leukocytosis (white blood cell count ≥10,000/μL), 1 point for tachycardia (≥90 beats per minute), and 2 points for age of 70 years or older. An ALT-70 score of 0 to 2 corresponds to an 83.3% or greater chance of pseudocellulitis, suggesting that the diagnosis of cellulitis be reconsidered. A score of 3 to 4 is indeterminate, and additional information such as a dermatology consultation should be pursued. A score of 5 to 7 corresponds to an 82.2% or greater chance of cellulitis, signifying that empiric treatment with antibiotics be considered.¹⁵

The ALT-70 score does not apply to cases involving areas other than the lower extremities; intravenous antibiotic use within 48 hours before ED presentation; surgery within the last 30 days; abscess; penetrating trauma; burn; or known history of osteomyelitis, diabetic ulcer, or indwelling hardware at the site of infection.¹⁵ The ALT-70 score is available for free via the MDCalc app and website (https://www.mdcalc.com/alt-70-score-cellulitis).

Mohs AUC Determines the Appropriateness of Mohs Micrographic Surgery

In 2012, the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery published appropriate use criteria (AUC) to guide the decision to pursue Mohs micrographic surgery (MMS) in the United States.¹⁶ Based on various tumor and patient characteristics, the Mohs AUC assign scores to 270 different clinical scenarios. A score of 1 to 3 signifies that MMS is inappropriate and generally not considered acceptable. A score 4 to 6 indicates that the appropriateness of MMS is uncertain. A score 7 to 9 means that MMS is appropriate and generally considered acceptable.¹⁶

Since publication, the Mohs AUC have been criticized for classifying most primary superficial basal cell carcinomas as appropriate for MMS¹⁷ (which an AUC coauthor¹⁸ and others^19,20 have defended), excluding certain reasons for performing MMS (such as operating on multiple tumors on the same day),²¹ including counterintuitive scores,²² and omitting trials from Europe²³ (which AUC coauthors also have defended²⁴). As with any clinical scoring system, the Mohs AUC has limitations; the creators acknowledge that “. . . these criteria should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results, even for those indications scored as inappropriate.”¹⁶ The Mohs AUC app (https://www.aad.org/members/aad-apps/mohs-auc) is free and allows users to enter tumor and patient characteristics to determine the score for their specific scenario.

Final Thoughts

Scoring systems are emerging in dermatology as evidence-based bedside tools to help guide clinical decision-making. Despite their limitations, these scores have the potential to make a meaningful impact in dermatology as they have in other specialties.

The practice of dermatology is rife with bedside tools: swabs, smears, and scoring systems. First popularized in specialties such as emergency medicine and internal medicine, clinical scoring systems are now emerging in dermatology. These evidence-based scores can be calculated quickly at the bedside—often through a free smartphone app—to help guide clinical decision-making regarding diagnosis, prognosis, and management. As with any medical tool, scoring systems have limitations and should be used as a supplement, not substitute, for one’s clinical judgement. This article reviews 4 clinical scoring systems practical for dermatology residents.

SCORTEN Prognosticates Cases of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Perhaps the best-known scoring system in dermatology, the SCORTEN is widely used to predict hospital mortality from Stevens-Johnson syndrome/toxic epidermal necrolysis. The SCORTEN includes 7 variables of equal weight—age of 40 years or older, heart rate of 120 beats per minute or more, cancer/hematologic malignancy, involved body surface area (BSA) greater than 10%, serum urea greater than 10 mmol/L, serum bicarbonate less than 20 mmol/L, and serum glucose greater than 14 mmol/L—each contributing 1 point to the overall score if present.¹ The involved BSA is defined as the sum of detached and detachable epidermis.¹

The SCORTEN was developed and prospectively validated to be calculated at the end of the first 24 hours of admission; for this calculation, use the BSA affected at that time, and use the most abnormal values during the first 24 hours of admission for the other variables.¹ In addition, a follow-up study including some of the original coauthors recommends recalculating the SCORTEN at the end of hospital day 3, having found that the score’s predictive value was better on this day than hospital days 1, 2, 4, or 5.² Based on the original study, a SCORTEN of 0 to 1 corresponds to a mortality rate of 3.2%, 2 to 12.1%, 3 to 35.3%, 4 to 58.3%, and 5 or greater to 90.0%.¹

Limitations of the SCORTEN include its ability to overestimate or underestimate mortality as demonstrated by 2 multi-institutional cohorts.^3,4 Recently, the ABCD-10 score was developed as an alternative to the SCORTEN and was found to predict mortality similarly when validated in an internal cohort.⁵

PEST Screens for Psoriatic Arthritis

Dermatologists play an important role in screening for psoriatic arthritis, as an estimated 1 in 5 patients with psoriasis have psoriatic arthritis.⁶ To this end, several screening tools have been developed to help differentiate psoriatic arthritis from other arthritides. Joint guidelines from the American Academy of Dermatology and the National Psoriasis Foundation acknowledge that “. . . these screening tools have tended to perform less well when tested in groups of people other than those for which they were originally developed. As such, their usefulness in routine clinical practice remains controversial.”⁷ Nevertheless, the guidelines state, “[b]ecause screening and early detection of inflammatory arthritis are essential to optimize patient [quality of life] and reduce morbidity, providers may consider using a formal screening tool of their choice.”⁷

With these limitations in mind, I have found the Psoriasis Epidemiology Screening Tool (PEST) to be the most useful psoriatic arthritis screening tool. One study determined that the PEST has the best trade-off between sensitivity and specificity compared to 2 other psoriatic arthritis screening tools, the Psoriatic Arthritis Screening and Evaluation (PASE) and the Early Arthritis for Psoriatic Patients (EARP).⁸

The PEST is comprised of 5 questions: (1) Have you ever had a swollen joint (or joints)? (2) Has a doctor ever told you that you have arthritis? (3) Do your fingernails or toenails have holes or pits? (4) Have you had pain in your heel? (5) Have you had a finger or toe that was completely swollen and painful for no apparent reason? According to the PEST, a referral to a rheumatologist should be considered for patients answering yes to 3 or more questions, which is 97% sensitive and 79% specific for psoriatic arthritis.⁹ Patients who answer yes to fewer than 3 questions should still be referred to a rheumatologist if there is a strong clinical suspicion of psoriatic arthritis.¹⁰

The PEST can be accessed for free in 13 languages via the GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) app as well as downloaded for free from the National Psoriasis Foundation’s website (https://www.psoriasis.org/psa-screening/providers).

ALT-70 Differentiates Cellulitis From Pseudocellulitis

Overdiagnosing cellulitis in the United States has been estimated to result in up to 130,000 unnecessary hospitalizations and up to $515 million in avoidable health care spending.¹¹ Dermatologists are in a unique position to help fix this issue. In one retrospective study of 1430 inpatient dermatology consultations, 74.32% of inpatients evaluated for presumed cellulitis by a dermatologist were instead diagnosed with a cellulitis mimicker (ie, pseudocellulitis), such as stasis dermatitis or contact dermatitis.¹²

The ALT-70 score was developed and prospectively validated to help differentiate lower extremity cellulitis from pseudocellulitis in adult patients in the emergency department (ED).¹³ In addition, the score has retrospectively been shown to function similarly in the inpatient setting when calculated at 24 and 48 hours after ED presentation.¹⁴ Although the ALT-70 score was designed for use by frontline clinicians prior to dermatology consultation, I also have found it helpful to calculate as a consultant, as it provides an objective measure of risk to communicate to the primary team in support of one diagnosis or another.

ALT-70 is an acronym for the score’s 4 variables: asymmetry, leukocytosis, tachycardia, and age of 70 years or older.¹⁵ If present, each variable confers a certain number of points to the final score: 3 points for asymmetry (defined as unilateral leg involvement), 1 point for leukocytosis (white blood cell count ≥10,000/μL), 1 point for tachycardia (≥90 beats per minute), and 2 points for age of 70 years or older. An ALT-70 score of 0 to 2 corresponds to an 83.3% or greater chance of pseudocellulitis, suggesting that the diagnosis of cellulitis be reconsidered. A score of 3 to 4 is indeterminate, and additional information such as a dermatology consultation should be pursued. A score of 5 to 7 corresponds to an 82.2% or greater chance of cellulitis, signifying that empiric treatment with antibiotics be considered.¹⁵

The ALT-70 score does not apply to cases involving areas other than the lower extremities; intravenous antibiotic use within 48 hours before ED presentation; surgery within the last 30 days; abscess; penetrating trauma; burn; or known history of osteomyelitis, diabetic ulcer, or indwelling hardware at the site of infection.¹⁵ The ALT-70 score is available for free via the MDCalc app and website (https://www.mdcalc.com/alt-70-score-cellulitis).

Mohs AUC Determines the Appropriateness of Mohs Micrographic Surgery

In 2012, the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery published appropriate use criteria (AUC) to guide the decision to pursue Mohs micrographic surgery (MMS) in the United States.¹⁶ Based on various tumor and patient characteristics, the Mohs AUC assign scores to 270 different clinical scenarios. A score of 1 to 3 signifies that MMS is inappropriate and generally not considered acceptable. A score 4 to 6 indicates that the appropriateness of MMS is uncertain. A score 7 to 9 means that MMS is appropriate and generally considered acceptable.¹⁶

Since publication, the Mohs AUC have been criticized for classifying most primary superficial basal cell carcinomas as appropriate for MMS¹⁷ (which an AUC coauthor¹⁸ and others^19,20 have defended), excluding certain reasons for performing MMS (such as operating on multiple tumors on the same day),²¹ including counterintuitive scores,²² and omitting trials from Europe²³ (which AUC coauthors also have defended²⁴). As with any clinical scoring system, the Mohs AUC has limitations; the creators acknowledge that “. . . these criteria should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results, even for those indications scored as inappropriate.”¹⁶ The Mohs AUC app (https://www.aad.org/members/aad-apps/mohs-auc) is free and allows users to enter tumor and patient characteristics to determine the score for their specific scenario.

Final Thoughts

Scoring systems are emerging in dermatology as evidence-based bedside tools to help guide clinical decision-making. Despite their limitations, these scores have the potential to make a meaningful impact in dermatology as they have in other specialties.

The practice of dermatology is rife with bedside tools: swabs, smears, and scoring systems. First popularized in specialties such as emergency medicine and internal medicine, clinical scoring systems are now emerging in dermatology. These evidence-based scores can be calculated quickly at the bedside—often through a free smartphone app—to help guide clinical decision-making regarding diagnosis, prognosis, and management. As with any medical tool, scoring systems have limitations and should be used as a supplement, not substitute, for one’s clinical judgement. This article reviews 4 clinical scoring systems practical for dermatology residents.

SCORTEN Prognosticates Cases of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Perhaps the best-known scoring system in dermatology, the SCORTEN is widely used to predict hospital mortality from Stevens-Johnson syndrome/toxic epidermal necrolysis. The SCORTEN includes 7 variables of equal weight—age of 40 years or older, heart rate of 120 beats per minute or more, cancer/hematologic malignancy, involved body surface area (BSA) greater than 10%, serum urea greater than 10 mmol/L, serum bicarbonate less than 20 mmol/L, and serum glucose greater than 14 mmol/L—each contributing 1 point to the overall score if present.¹ The involved BSA is defined as the sum of detached and detachable epidermis.¹

The SCORTEN was developed and prospectively validated to be calculated at the end of the first 24 hours of admission; for this calculation, use the BSA affected at that time, and use the most abnormal values during the first 24 hours of admission for the other variables.¹ In addition, a follow-up study including some of the original coauthors recommends recalculating the SCORTEN at the end of hospital day 3, having found that the score’s predictive value was better on this day than hospital days 1, 2, 4, or 5.² Based on the original study, a SCORTEN of 0 to 1 corresponds to a mortality rate of 3.2%, 2 to 12.1%, 3 to 35.3%, 4 to 58.3%, and 5 or greater to 90.0%.¹

Limitations of the SCORTEN include its ability to overestimate or underestimate mortality as demonstrated by 2 multi-institutional cohorts.^3,4 Recently, the ABCD-10 score was developed as an alternative to the SCORTEN and was found to predict mortality similarly when validated in an internal cohort.⁵

PEST Screens for Psoriatic Arthritis

Dermatologists play an important role in screening for psoriatic arthritis, as an estimated 1 in 5 patients with psoriasis have psoriatic arthritis.⁶ To this end, several screening tools have been developed to help differentiate psoriatic arthritis from other arthritides. Joint guidelines from the American Academy of Dermatology and the National Psoriasis Foundation acknowledge that “. . . these screening tools have tended to perform less well when tested in groups of people other than those for which they were originally developed. As such, their usefulness in routine clinical practice remains controversial.”⁷ Nevertheless, the guidelines state, “[b]ecause screening and early detection of inflammatory arthritis are essential to optimize patient [quality of life] and reduce morbidity, providers may consider using a formal screening tool of their choice.”⁷

With these limitations in mind, I have found the Psoriasis Epidemiology Screening Tool (PEST) to be the most useful psoriatic arthritis screening tool. One study determined that the PEST has the best trade-off between sensitivity and specificity compared to 2 other psoriatic arthritis screening tools, the Psoriatic Arthritis Screening and Evaluation (PASE) and the Early Arthritis for Psoriatic Patients (EARP).⁸

The PEST is comprised of 5 questions: (1) Have you ever had a swollen joint (or joints)? (2) Has a doctor ever told you that you have arthritis? (3) Do your fingernails or toenails have holes or pits? (4) Have you had pain in your heel? (5) Have you had a finger or toe that was completely swollen and painful for no apparent reason? According to the PEST, a referral to a rheumatologist should be considered for patients answering yes to 3 or more questions, which is 97% sensitive and 79% specific for psoriatic arthritis.⁹ Patients who answer yes to fewer than 3 questions should still be referred to a rheumatologist if there is a strong clinical suspicion of psoriatic arthritis.¹⁰

The PEST can be accessed for free in 13 languages via the GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) app as well as downloaded for free from the National Psoriasis Foundation’s website (https://www.psoriasis.org/psa-screening/providers).

ALT-70 Differentiates Cellulitis From Pseudocellulitis

Overdiagnosing cellulitis in the United States has been estimated to result in up to 130,000 unnecessary hospitalizations and up to $515 million in avoidable health care spending.¹¹ Dermatologists are in a unique position to help fix this issue. In one retrospective study of 1430 inpatient dermatology consultations, 74.32% of inpatients evaluated for presumed cellulitis by a dermatologist were instead diagnosed with a cellulitis mimicker (ie, pseudocellulitis), such as stasis dermatitis or contact dermatitis.¹²

The ALT-70 score was developed and prospectively validated to help differentiate lower extremity cellulitis from pseudocellulitis in adult patients in the emergency department (ED).¹³ In addition, the score has retrospectively been shown to function similarly in the inpatient setting when calculated at 24 and 48 hours after ED presentation.¹⁴ Although the ALT-70 score was designed for use by frontline clinicians prior to dermatology consultation, I also have found it helpful to calculate as a consultant, as it provides an objective measure of risk to communicate to the primary team in support of one diagnosis or another.

ALT-70 is an acronym for the score’s 4 variables: asymmetry, leukocytosis, tachycardia, and age of 70 years or older.¹⁵ If present, each variable confers a certain number of points to the final score: 3 points for asymmetry (defined as unilateral leg involvement), 1 point for leukocytosis (white blood cell count ≥10,000/μL), 1 point for tachycardia (≥90 beats per minute), and 2 points for age of 70 years or older. An ALT-70 score of 0 to 2 corresponds to an 83.3% or greater chance of pseudocellulitis, suggesting that the diagnosis of cellulitis be reconsidered. A score of 3 to 4 is indeterminate, and additional information such as a dermatology consultation should be pursued. A score of 5 to 7 corresponds to an 82.2% or greater chance of cellulitis, signifying that empiric treatment with antibiotics be considered.¹⁵

The ALT-70 score does not apply to cases involving areas other than the lower extremities; intravenous antibiotic use within 48 hours before ED presentation; surgery within the last 30 days; abscess; penetrating trauma; burn; or known history of osteomyelitis, diabetic ulcer, or indwelling hardware at the site of infection.¹⁵ The ALT-70 score is available for free via the MDCalc app and website (https://www.mdcalc.com/alt-70-score-cellulitis).

Mohs AUC Determines the Appropriateness of Mohs Micrographic Surgery

In 2012, the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery published appropriate use criteria (AUC) to guide the decision to pursue Mohs micrographic surgery (MMS) in the United States.¹⁶ Based on various tumor and patient characteristics, the Mohs AUC assign scores to 270 different clinical scenarios. A score of 1 to 3 signifies that MMS is inappropriate and generally not considered acceptable. A score 4 to 6 indicates that the appropriateness of MMS is uncertain. A score 7 to 9 means that MMS is appropriate and generally considered acceptable.¹⁶

Since publication, the Mohs AUC have been criticized for classifying most primary superficial basal cell carcinomas as appropriate for MMS¹⁷ (which an AUC coauthor¹⁸ and others^19,20 have defended), excluding certain reasons for performing MMS (such as operating on multiple tumors on the same day),²¹ including counterintuitive scores,²² and omitting trials from Europe²³ (which AUC coauthors also have defended²⁴). As with any clinical scoring system, the Mohs AUC has limitations; the creators acknowledge that “. . . these criteria should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results, even for those indications scored as inappropriate.”¹⁶ The Mohs AUC app (https://www.aad.org/members/aad-apps/mohs-auc) is free and allows users to enter tumor and patient characteristics to determine the score for their specific scenario.

Final Thoughts

Scoring systems are emerging in dermatology as evidence-based bedside tools to help guide clinical decision-making. Despite their limitations, these scores have the potential to make a meaningful impact in dermatology as they have in other specialties.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

There are 4 variants of psoriasis: plaque, guttate, pustular, and erythroderma (in order of prevalence).² Guttate psoriasis is characterized by small, 2- to 10-mm, raindroplike lesions on the skin.¹ It accounts for approximately 2% of total psoriasis cases and is commonly triggered by group A streptococcal pharyngitis or tonsillitis.^3,4

Hand-foot-and-mouth disease (HFMD) is an illness most commonly caused by a coxsackievirus A infection but also can be caused by other enteroviruses.^5,6 Coxsackievirus is a serotype of the Enterovirus species within the Picornaviridae family.⁷ Hand-foot-and-mouth disease is characterized by a brief fever and vesicular rashes on the palms, soles, or buttocks, as well as oropharyngeal ulcers.⁸ Typically, the rash is benign and short-lived.⁹ In rare cases, neurologic complications develop. There have been no reported cases of guttate psoriasis following a coxsackievirus A infection.

The involvement of coxsackievirus B in the etiopathogenesis of psoriasis has been previously reported.¹⁰ We report the case of guttate psoriasis following presumed coxsackievirus A HFMD.

Case Report

A 56-year-old woman presented with a vesicular rash on the hands, feet, and lips. The patient reported having a sore throat that started around the same time that the rash developed. The severity of the sore throat was rated as moderate. No fever was reported. One day prior, the patient’s primary care physician prescribed a tapered course of prednisone for the rash. The patient reported a medical history of herpes zoster virus, sunburn, and genital herpes. She was taking clonazepam and had a known allergy to penicillin.

Physical examination revealed erythematous vesicular and papular lesions on the extensor surfaces of the hands and feet. Vesicles also were noted on the vermilion border of the lip. Examination of the patient’s mouth showed blisters and shallow ulcerations in the oral cavity. A clinical diagnosis of coxsackievirus A HFMD was made, and the treatment plan included triamcinolone acetonide ointment 0.025% applied twice daily for 2 weeks and oral valacyclovir hydrochloride 1 g taken 3 times daily for 7 days. A topical emollient also was recommended for the lips when necessary. The lesions all resolved within a 2-week period with no sequela.

The patient returned 1 month later, citing newer red abdominal skin lesions. Fever was denied. She reported that both prescribed treatments had not been helping for the newer lesions. She noticed similar lesions on the groin and brought them to the attention of her gynecologist. Physical examination revealed salmon pink papules and plaques with silvery scaling involving the abdomen, bilateral upper extremities and ears, and scalp. The patient was then clinically diagnosed with guttate psoriasis. A shave biopsy of a representative lesion on the abdomen was performed. The treatment plan included betamethasone dipropionate cream 0.05% applied twice daily for 2 weeks, clobetasol propionate solution 0.05% applied twice daily for 14 days (for the scalp), and hydrocortisone valerate cream 0.2% applied twice daily for 14 days (for the groin).

The skin biopsy shown in the Figure was received in 10% buffered formalin, measuring 5×4×1 mm of skin. Sections showed an acanthotic epidermis with foci of spongiosis and hypergranulosis covered by mounds of parakeratosis infiltrated by neutrophils. Superficial perivascular and interstitial lymphocytic inflammation was present. Tortuous blood vessels within the papillary dermis also were present. Results showed psoriasiform dermatitis with mild spongiosis. Periodic acid–Schiff stain did not reveal any fungal organisms. These findings were consistent with a diagnosis of guttate psoriasis.

Comment

Enterovirus-derived HFMD likely is caused by coxsackie-virus A. Current evidence supports the theory that guttate psoriasis can be environmentally triggered in genetically susceptible individuals, often but not exclusively by a streptococcal infection. The causative agent elicits a T-cell–mediated reaction leading to increased type 1 helper T cells, IFN-γ, and IL-2 cytokine levels. HLA-Cw^∗0602–positive patients are considered genetically susceptible and more likely to develop guttate psoriasis following an environmental trigger. Based on the coincidence in timing of both diagnoses, this reported case of guttate psoriasis may have been triggered by a coxsackievirus A infection.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Photolichenoid dermatitis is an uncommon eruptive dermatitis of variable clinical presentation. It has a histopathologic pattern of lichenoid inflammation and is best characterized as a photoallergic reaction.¹ Photolichenoid dermatitis was first described in 1954 in association with the use of quinidine in the treatment of malaria.² Subsequently, it has been associated with various medications, including trimethoprim-sulfamethoxazole, azithromycin, and nonsteroidal anti-inflammatory drugs.^1,2 Photolichenoid dermatitis has been documented in patients with human immunodeficiency virus (HIV) with variable clinical presentations. Photolichenoid dermatitis in patients with HIV has been described both with and without an associated photosensitizing systemic agent, suggesting that HIV infection is an independent risk factor for the development of this eruption in patients with HIV.^3-6

Case Report

A 62-year-old African man presented for evaluation of asymptomatic hypopigmented and depigmented patches in a photodistributed pattern. The eruption began the preceding summer when he noted a pink patch on the right side of the forehead. It progressed over 2 months to involve the face, ears, neck, and arms. His medical history was negative. The only medication he was taking was hydroxychloroquine, which was prescribed by another dermatologist when the patient first developed the eruption. The patient was unsure of the indication for the medication and admitted to poor compliance. A review of systems was negative. There was no personal or family history of autoimmune disease. A detailed sexual history and illicit drug history were not obtained. Physical examination revealed hypopigmented and depigmented patches, some with overlying erythema and collarettes of fine scale. The patches were photodistributed on the face, conchal bowls, neck, dorsal aspect of the hands, and extensor forearms (Figures 1 and 2). Macules of repigmentation were noted within some of the patches. There also were large hyperpigmented patches with peripheral hypopigmentation on the legs.

A punch biopsy taken from the left posterior neck revealed a patchy bandlike lymphocytic infiltrate in the superficial dermis with lymphocytes present at the dermoepidermal junction and scattered dyskeratotic keratinocytes extending into the mid spinous layer (Figure 3). Histopathologic findings were consistent with photolichenoid dermatitis.

Comment

Prevalence of Photosensitive Eruptions
Photodermatitis is an uncommon clinical manifestation of HIV occurring in approximately 5% of patients who are HIV positive.³ Photosensitive eruptions previously described in association with HIV include porphyria cutanea tarda, pseudoporphyria, chronic actinic dermatitis, granuloma annulare, photodistributed dyspigmentation, and lichenoid photodermatitis.⁷ These HIV-associated photosensitive eruptions have been found to disproportionally affect patients of African and Native American descent.^5,7,8 Therefore, a new photodistributed eruption in a patient of African or Native American descent should prompt evaluation of possible underlying HIV infection.

Presenting Sign of HIV Infection
We report a case of photolichenoid dermatitis presenting with loss of pigmentation as a presenting sign of HIV. The patient had no known history of HIV or prior opportunistic infections and was not taking any medications at the time of onset or presentation to clinic. Similar cases of photodistributed depigmentation with lichenoid inflammation on histopathology occurring in patients with HIV have been previously described.^4-6,9 In these cases, most patients were of African descent with previously diagnosed advanced HIV and CD4 counts of less than 50 cells/mL³. The additional clinical findings of lichenoid papules and plaques were noted in several of these cases.^5,6

Exposure to Photosensitizing Drugs
Photodermatitis in patients with HIV often is attributed to exposure to a photosensitizing drug. Many reported cases are retrospective and identify a temporal association between the onset of photodermatitis following the initiation of a photosensitizing drug. The most commonly implicated drugs have included nonsteroidal anti-inflammatory drugs, trimethoprim-sulfamethoxazole, and azithromycin. Other potential offenders may include saquinavir, dapsone, ketoconazole, and efavirenz.^3,5 In cases in which temporal association with a new medication could not be identified, the photodermatitis often has been presumed to be due to polypharmacy and the potential synergistic effect of multiple photosensitizing drugs.^3,5-8

Advanced HIV
There are several reported cases of photodermatitis occurring in patients who were not exposed to systemic photosensitizers. These patients had advanced HIV, meeting criteria for AIDS with a CD4 count of less than 200 cells/mL³. The majority of patients had an even lower CD4 count of less than 50 cells/mL³. Clinical presentations have included photodistributed lichenoid papules and plaques as well as depigmented patches.^4,5,8,10

Evaluating HIV as a Risk Factor for Photodermatitis
Discerning the validity of the correlation between photodermatitis and HIV is difficult, as all previously reported cases are case reports and small retrospective case series. One study of 34 patients with HIV and photodermatitis showed that there was no significant increase in incidence of photodermatitis in patients who were exposed to a photosensitizing drug vs those who were not,³ which further validates that HIV infection may be an independent risk factor in the development of photodermatitis.

Conclusion

This case represents an uncommon presentation of photolichenoid dermatitis as the presenting sign of HIV infection.¹⁰ Although most reported cases of photodermatitis in HIV are attributed to photosensitizing drugs, we propose that HIV may be an independent risk factor for the development of photodermatitis. We recommend consideration of HIV testing in patients who present with photodistributed depigmenting eruptions, even in the absence of a photosensitizing drug, particularly in patients of African and Native American descent.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Infection with Mycobacterium haemophilum, a rare, slow-growing organism, most commonly presents as ulcerating cutaneous lesions and subcutaneous nodules in immunocompromised adults.¹ The most common clinical presentation in adults includes cutaneous lesions, nodules, cysts, and papules, with signs and symptoms of erythema, pain, pruritus, and drainage.² Disseminated disease states of septic arthritis, pulmonary infiltration, and osteomyelitis, though life-threatening, are less common manifestations reported in highly immunocompromised persons.³

Infection with M haemophilum presents a challenge to the dermatology community because it is infrequently suspected and misidentified, resulting in delayed diagnosis. Additionally, M haemophilum is an extremely fastidious organism that requires heme-supplemented culture media and a carefully regulated low temperature for many consecutive weeks to yield valid culture results.¹ These features contribute to complications and delays in diagnosis of an already overlooked source of infection.

We discuss the clinical presentation, diagnosis, and treatment of 3 unusual cases of cutaneous M haemophilum infection involving the upper arms. The findings in these cases highlight the challenges inherent in diagnosis as well as the obstacles that arise in providing effective, long-term treatment of this infection.

Case Reports

Patient 1
A 69-year-old woman with a medical history of a single functioning kidney and moderate psoriasis managed with low-dosage methotrexate presented with an erythematous nonhealing wound on the left forearm that developed after she was scratched by a dog. The pustules, appearing as bright red, tender, warm abscesses, had been present for 3 months and were distributed on the left proximal and distal dorsal forearm (Figure 1A). The patient reported no recent travel, sick contacts, allergies, or new medications.

A shave biopsy was initially obtained. Swab specimens were sent for bacterial, fungal, and mycobacterial culture following discontinuation of methotrexate. Initial histopathologic analysis revealed aggregates of histiocytes and multinucleated giant cells within the dermis, surrounded by infiltrates of lymphocytes and neutrophils (Figure 2), consistent with a dermal noncaseating granulomatosis. Acid-fast bacilli (AFB), periodic acid–Schiff, Gram, and Grocott-Gomori methenamine-silver stains were negative for pathogenic microorganisms. There was no evidence of vasculitis.

Despite negative special stains, an infectious cause was still suspected. Oral doxycycline monohydrate 100 mg twice daily, oral fluconazole 200 mg daily, and econazole cream 1% were prescribed because of concern for mycobacterial infection and initial growth of Candida parapsilosis in the swab culture.

A punch biopsy also was performed at this time for both repeat histopathologic analysis and tissue culture. Follow-up appointments were scheduled every 2 weeks. Staining by AFB of the repeat histopathologic specimen was negative.

The patient demonstrated symptomatic and aesthetic improvement (Figure 1B) during consecutive regular follow-up appointments while culture results were pending. No lesions appeared above the left elbow and she had no lymphadenopathy. Results of blood chemistry analyses and complete blood cell count throughout follow-up were normal.

The final tissue culture report obtained 7 weeks after initial presentation showed growth of M haemophilum despite a negative smear. The swab culture that initially was taken did not grow pathogenic organisms.

The patient was referred to an infectious disease specialist who confirmed that the atypical mycobacterial infection likely was the main source of the cutaneous lesions. She was instructed to continue econazole cream 1% and was given prescriptions for clarithromycin 500 mg twice daily, ciprofloxacin 500 mg twice daily, and rifampin 300 mg twice daily for a total duration of 12 to 18 months. The patient has remained on this triple-drug regimen and demonstrated improvement in the lesions. She has been off methotrexate while on antibiotic therapy.

Patient 2
A 79-year-old man with a medical history of chronic lymphocytic leukemia, basal cell carcinoma, and squamous cell carcinoma presented with a nonhealing, painful, red lesion on the left forearm of 1 week’s duration. Physical examination revealed a violaceous nontender plaque with erosions and desquamation that was initially diagnosed as a carbuncle. The patient reported a similar eruption on the right foot that was successfully treated with silver sulfadiazine by another physician.

Biopsy was performed by the shave method for histologic analysis and tissue culture. Doxycycline 100 mg twice daily was prescribed because of high suspicion of infection. Histologic findings revealed granulomatous inflammation with pseudoepitheliomatous hyperplasia, reported as squamous cell carcinoma. A second opinion confirmed suspicion of an infectious process; the patient remained on doxycycline. During follow-up, the lesion progressed to a 5-cm plaque studded with pustules and satellite papules. Multiple additional tissue cultures were performed over 2 months until “light growth” of M haemophilum was reported.

The patient showed minimal improvement on tetracycline antibiotics. His condition was complicated by a photosensitivity reaction to doxycycline on the left and right forearms, hands, and nose. Consequently, triamcinolone was prescribed, doxycycline was discontinued, and minocycline 100 mg twice daily and ciprofloxacin 500 mg twice daily were prescribed.

Nine months after initial presentation, the lesions were still present but remarkably improved. The antibiotic regimen was discontinued after 11 months.

Patient 3
A 77-year-old woman with a history of rheumatoid arthritis treated with methotrexate and abatacept as well as cutaneous T-cell lymphoma treated with narrowband UVB radiation presented to the emergency department with fever and an inflamed right forearm (Figure 3A). Initial bacterial cultures of the wound and blood were negative.

Arm edema and pustules slowly resolved, but the eschar and verrucous plaques continued to slowly progress while the patient was off immunosuppression. She was kept off antibiotics until mycobacterial culture was positive at 4 weeks, at which time she was placed on doxycycline and clarithromycin. Final identification of M haemophilum was made at 6 weeks; consequently, doxycycline was discontinued and she was referred to infectious disease for multidrug therapy. She remained afebrile during the entire 6 weeks until cultures were final.

While immunosuppressants were discontinued and clarithromycin was administered, the plaque changed from an edematous pustular dermatitis to a verrucous crusted plaque. Neither epitrochlear nor axillary lymphadenopathy was noted during the treatment period. The infectious disease specialist prescribed azithromycin, ethambutol, and rifampin, which produced marked improvement (Figure 3B). The patient has remained off immunosuppressive therapy while on antibiotics.

Comment

Clinical Presentation and Diagnosis
Mycobacterium haemophilum is a rare infectious organism that affects primarily immunocompromised adults but also has been identified in immunocompetent adults and pediatric patients.² Commonly affected immunosuppressed groups include solid organ transplant recipients, bone marrow transplant recipients, human immunodeficiency virus–positive patients, and patients with rheumatoid arthritis.

The infection typically presents as small violaceous papules and pustules that become painful and erythematous, with progression and draining ulceration in later stages.² In our cases, all lesions tended to evolve into a verrucous plaque that slowly resolved with antibiotic therapy.

Due to the rarity of this infection, the initial differential diagnosis can include infection with other mycobacteria, Sporothrix, Staphylococcus aureus, and other fungal pathogens. Misdiagnosis is a common obstacle in the treatment of M haemophilum due to its rarity, often negative AFB stains, and slow growth on culture media; therefore, tissue culture is essential to successful diagnosis and management. The natural reservoir of M haemophilum is unknown, but infection has been associated with contaminated water sources.¹ In one case (patient 1), symptoms developed after a dog scratch; the other 2 patients were unaware of injury to the skin.Laboratory diagnosis of M haemophilum is inherently difficult and protracted. The species is a highly fastidious and slow-growing Mycobacterium that requires cooler (30°C) incubation for many weeks on agar medium enriched with hemin or ferric ammonium citrate to obtain valid growth.¹ To secure timely diagnosis, the organism’s slow agar growth warrants immediate tissue culture and biopsy when an immunocompromised patient presents with clinical features of atypical infection of an extremity. Mycobacterium haemophilum infection likely is underreported because of these difficulties in diagnosis.

Management
Although there are no standard guidelines for antibiotic treatment of M haemophilum, the current literature recommends triple-drug therapy with clarithromycin, ciprofloxacin, and rifamycin for at least 12 to 24 months.²

Upon clinical suspicion of an atypical Mycobacterium, we recommend a macrolide antibiotic over doxycycline, however, because this class of agents maintains broad coverage while being more specific for atypical mycobacteria. Although an atypical Mycobacterium was suspected early in the presentation in our cases, we discourage immediate use of triple-agent antibiotic therapy until laboratory evidence is procured to minimize antibiotic overuse in patients who do not have a final diagnosis. Single-agent therapy for prolonged treatment is discouraged for atypical mycobacterial infections because of the high risk of antibiotic resistance. Therapy should be tailored to the needs of the individual based on the extent of dissemination of disease and the severity of immunosuppression.^1,2

Additionally, underlying disease that results in immunosuppression might necessitate treatment reevaluation (as occurred in our cases) requiring cessation of immunosuppressive drugs, extended careful monitoring, and pharmacotherapeutic readjustment through the course of treatment. The degree to which antibiotics contribute to eradication of M haemophilum is unknown; therefore, it is recommended that long-term antibiotic use and treatment aimed at recovering the immunocompromised state (eg, highly active antiretroviral therapy in a patient with AIDS) be implemented.²

Conclusion

Our 3 cases of M haemophilum infection involved the upper extremities of immunosuppressed patients older than 65 years. This propensity to affect the upper extremities could possibly be due to the lower temperature required for growth of M haemophilum. Initial histopathologic study showed granulomatous and neutrophilic infiltrates, yet histopathologic specimens from all 3 patients failed to display positive AFB staining, which delayed the initial antibiotic choice. In all cases, diagnosis was made by tissue culture after swab culture failed to grow the pathogen. Furthermore, the 3 cases took approximately 6 weeks to achieve final identification of the organism. Neither clinical lymphadenopathy nor systemic spread was noted in our patients; immunosuppression was discontinued when possible.

Mycobacterium haemophilum is an uncommon but potentially life-threatening infection that should be suspected in immunocompromised adults who present with atypical cellulitis of the extremities. The ultimate diagnosis often is delayed because the organism grows slowly (as long as 8 weeks) in tissue culture. For that reason, empiric antibiotic treatment, including a macrolide, should be considered in patients with disseminated or severe infection or critical immunosuppression and in those who do not demonstrate improvement in symptoms once immunosuppressants are withheld. A prolonged course of multiple-drug antibiotic therapy has proved to be effective for treating cutaneous infection with M haemophilum.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

As the largest and most exposed organ in the body, the skin experiences trauma from both extrinsic and intrinsic aging factors, resulting in loss of elasticity, increased laxity, wrinkling, and rough-textured appearance.¹ Chronologically aged skin appears dry, thin, and finely wrinkled; photoaged skin appears leathery with coarse wrinkles and uneven pigmentation.² In recent years, numerous systemic nutrients have been proposed to improve skin appearance. This article reviews the efficacy of these vitamins and supplements.

Carotenoids

Carotenoids are a group of lipophilic molecules derived from vitamin A.^3,4 Ingestion of carotenoids may play a role in photoprotection against UV radiation (UVR) by acting as acceptors of reactive oxygen species.^4-6 Stahl et al⁷ investigated lycopene’s usefulness in protection against UVR-induced erythema. Over 10 weeks, 9 volunteers received 40 g of tomato paste containing 16 mg daily of lycopene while 10 controls received placebo. A solar simulator was used to induce erythema of the skin at weeks 0, 4, and 10. At week 10, erythema formation was 40% lower in the lycopene group compared to controls (P=.02).⁷

In another study assessing the photoprotective effects of a novel nutritional and phytonutrient blend of carotenoids, 36 women with Fitzpatrick skin types I and II were treated for 8 weeks.⁸ Presupplementation, UVR-induced erythema, and skin carotenoid concentrations were determined along with facial skin attributes and characteristics. Results showed protection against UVR-induced skin damage, with reductions in erythema at 3 minimal erythema doses (MEDs)(P=.01). Additionally, significant improvements were noted in facial skin elasticity, radiance, and overall appearance (all P<.05).⁸

In 2013, Meinke et al⁹ conducted an 8-week, double-blind, placebo-controlled study on 24 volunteers whose diets were supplemented with moderate amounts of carotenoids, including lutein, beta-carotene, and lycopene. Utilizing novel techniques to measure the skin’s ability to scavenge free radicals, they discovered that dietary carotenoids provided notable protection against stress-induced radical formation and increased baseline radical scavenging activity of the skin by 34%. The authors concluded that dietary supplementation could avoid premature skin aging.⁹

Vitamins C and E

Vitamin C is an essential vitamin that must be obtained through dietary sources.¹⁰ It functions as a free radical scavenger and is a necessary cofactor for the synthesis and stabilization of collagen.

A study evaluated the effect of UVR-induced oxidative stress and the association with vitamin C supplementation among 20 white patients with Fitzpatrick skin types II or III.¹¹ The volunteers were treated with UVR on two 1-cm sites on the buttock. Six punch biopsies of these sites and 2 control biopsies from nonexposed skin were taken. Volunteers took vitamin C supplements (500 mg) for 8 weeks, and the exposure and biopsy were repeated. Researchers concluded that supplementation with vitamin C had no effect on the MED, with identical concentrations at baseline and after 8 weeks of supplementation. Additionally, there was no evidence that vitamin C affects UVR-induced oxidative stress.¹¹

In 2007, Cosgrove et al¹² conducted a study to assess the associations between nutrient intake and skin aging in more than 4000 women aged 40 to 74 years. Higher dietary vitamin C intakes were associated with a significantly lower likelihood of senile xerosis and wrinkled appearance (P<.009).¹²

Vitamin E is a lipid-soluble, membrane-bound vitamin, and its most active form is α-tocopherol.^11,13 Vitamin E functions as an antioxidant and protects cellular membranes from lipid peroxidation by free radicals.^13-15 Once oxidized, vitamin E can be regenerated to its reduced form by vitamin C.¹¹ Their synergistic effects on skin protection have been studied extensively. A double-blind, placebo-controlled study of 10 patients compared 2 g of vitamin C combined with 1000 IU of vitamin E vs placebo.¹⁶ The patients’ skin reaction before and after 8 days of treatment were assessed by determination of MED and the cutaneous blood flow of skin irradiated with UV light. Results showed that the median MED of those taking vitamins increased from 80 to 96.5 mJ/cm² (P<.01) and decreased for the placebo group. Investigators concluded that the combination of vitamins C and E reduces the sunburn reaction and leads to a reduction in the sequelae of UV-induced skin damage.¹⁶ A prospective, randomized, placebo-controlled study by Fuchs and Kern¹⁷ replicated these findings, also concluding that combinations of vitamins C and E provide improved photoprotective effects than either vitamin alone.

Vitamin D

Vitamin D is a fat-soluble vitamin obtained through dietary intake and exposure to UV light.^3,18,19 Precursors of vitamin D require interaction with UV light for conversion into active forms. The highest concentrations of 7-dehydrocholesterol are found in keratinocytes in the basal cell and spinous cell layers of the skin where they are protected from UV light by melanin. As such, individuals with higher melanin content in their skin require more exposure to UV light to produce the same levels of vitamin D as those with less melanin,²⁰ leading to a high rate of vitamin D deficiency in dark-skinned individuals. Because of their prodifferentiating and antiproliferative effects, vitamin D analogs have been very effective in the treatment of psoriasis.^20,21 Vitamin D deficiency also has been implicated in the pathogenesis of vitiligo. A systematic review and meta-analysis conducted in 2016 found that a significant relationship existed between low 25-hydroxyvitamin D levels and vitiligo (P<.01), but no causal relationship could be established.²²

A 2017 double-blind, placebo-controlled study performed by Scott et al²³ aimed to elucidate the relationship between vitamin D concentrations and sunburn. Twenty adults received either placebo or high-dose vitamin D₃ (200,000 IU) 1 hour after experimental sunburn induced by an erythemogenic dose of UVR. Investigators measured participants’ concentrations of the proinflammatory mediators tumor necrosis factor α and nitric oxide synthase via skin biopsy 48 hours later. Patients in the experimental group were found to have significantly reduced expression of both tumor necrosis factor α (P=.04) and nitric oxide synthase (P=.02). Additionally, participants with significantly higher vitamin D₃ levels following supplementation (P=.007) demonstrated increased skin expression of the anti-inflammatory marker arginase-1 (P=.005) as well as a persistent reduction in skin redness (P=.02). Investigators concluded that vitamin D plays a large role in skin homeostasis and implicated vitamin D’s upregulation of arginase-1 as a potent mechanism of its anti-inflammatory effects.²³

Collagen

As humans age, the density of collagen in the dermis decreases, leading to sagging and wrinkling of skin.²⁴ Oral supplementation of collagen has been examined for its dermatologic benefits, primarily increasing the thickness and density of collagen in the dermal layer. In 2014, Proksch et al²⁵ performed a double-blind, placebo-controlled trial in which 69 women were randomized to receive 2.5 or 5 g of collagen peptides or placebo for 8 weeks. Both treatment groups demonstrated improvements in skin elasticity as well as improved skin moisture and decreased skin evaporation; however, changes in the latter 2 qualities failed to reach statistical significance.²⁵

The results of this study were replicated by Asserin et al.²⁶ One hundred six female patients were randomly assigned to receive 10 g of collagen peptides or placebo daily for 8 weeks. The collagen group demonstrated significantly improved skin hydration (P=.003) and increased density of collagen in the dermis (P=.007) relative to placebo.²⁶

In another randomized, double-blind, placebo-controlled study, 71 women consumed a 20-mL beverage containing either 3000 mg of collagen peptides or placebo for 12 weeks.²⁷ Participants in the treatment group demonstrated significant decreases in periorbital wrinkles (P<.05) and enhanced facial skin moisture (P<.001) and elasticity (P<.001) after 12 weeks. Researchers concluded that oral supplementation with collagen peptides holds promise as a natural supplement to provide cutaneous antiaging properties.²⁷

Ceramides

Ceramides are lipids composed of a sphingoid base conjugated to a fatty acid and serve as the main component of the stratum corneum of the skin. Ceramides are crucial for the maintenance of skin barrier integrity and for preventing transepidermal water loss.²⁸ In a 3-month study of 51 women with dry skin, Guillou et al²⁹ showed that a ceramide wheat extract capsule significantly increased corneometry measurements of skin hydration on the arms (P<.001) and the legs (P=.012) compared to placebo.

Mixed Supplements

The discovery that nutritional contents can affect skin appearance has energized the development of combination supplements containing multiple vitamins and micronutrients. Imedeen is a biomarine complex and antioxidant supplement with several different formulations, including Prime Renewal, Time Perfection, and Derma One (Pfizer Inc). The ingredients include a combination of a biomarine complex (blend of fish proteins and polysaccharides), lycopene, grape seed extract, vitamin C, vitamin E, and zinc. Several trials have been conducted to assess the efficacy of the supplements on improving the appearance of photodamaged and aged skin (Table).

A placebo-controlled, randomized study of 144 participants conducted by Kieffer and Efsen³⁰ assessed the efficacy of Imedeen supplements over 12 months. The trial included a 3-month placebo-controlled study and 9-month uncontrolled continuation. Imedeen’s efficacy was measured using clinical evaluation, transepidermal water loss, self-evaluation, and photograph evaluation. After 1 year of treatment, improvement occurred in photograph evaluation of fine lines, overall photoaging, telangiectasia and hyperpigmentation, and self-evaluation of skin condition.³⁰ Additional double-blind, placebo-controlled, randomized studies assessing the efficacy of Imedeen have shown increased dermal and epidermal thickness, improvement of stratum corneum moisturization, and improved overall facial complexion.^31-33

Several combined supplements containing collagen peptide as the main ingredient have been created for use in skin care. Collagen is found in the extracellular matrix of the dermis and is responsible for the resiliency and strength of skin.^34,35 Damage to the dermis can occur with prolonged UV light exposure and is seen histologically as disorganized collagen fibrils and grossly as wrinkles and photoaged skin.^35,36

A study assessed the effect of BioCell Collagen (BioCell Technology, LLC), a supplement containing type II collagen, on skin aging.³⁷ Twenty-six women underwent baseline visual assessments of their skin before taking 2 tablets of the supplement daily. Twelve weeks of supplementation led to significant reduction in global lines and wrinkles (13.2%; P=.028) as well as skin dryness and scaling (76%; P=.002). Assessment of collagen content at 6 weeks revealed a significant increase from baseline (6.3%; P=.002), though the difference after 12 weeks was not significant (3.5%; P=.134). The authors concluded that although preliminary data suggested that BioCell Collagen may reduce visible signs of aging, a controlled study was necessary to verify this finding.³⁷

A single-blind, case-controlled study assessed a similar supplement, Celergen, that contained marine collagen peptides.³⁸ Forty-one adults took 2 capsules each day for 60 days. Assessment of their skin physiology was conducted at the enrollment visit, 2 months later, and after the treatment period ended. Skin elasticity, transepidermal water loss, epidermal and dermal thickness, and density were measured. Investigators found that Celergen administration significantly enhanced skin elasticity and sebum production (P<.0001) but did not influence cutaneous moisture. The dermal thickness and homogenous distribution of collagen fibers were enhanced in 11 patients while properties of the epidermis remained unchanged. The study determined that supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers.³⁸

A double-blind, randomized, placebo-controlled study assessed a collagen- and antioxidant-containing supplement, Gold Collagen Forte, on skin properties.³⁹ The treatment and placebo groups each consisted of 60 patients who consumed 1 bottle (50 mL) of the product each day for 90 days. Patients completed a self-assessment of their skin regarding photoaging, focusing on the crow’s-feet area and nasolabial folds, while skin elasticity was assessed with the SkinLab USB elasticity module. Results showed a significant increase in skin elasticity (+7.5%; P≤.001). Self-assessment results showed improvements in both the treatment and placebo groups, and investigators concluded that Gold Collagen Forte may have photoprotective effects and help improve skin health.³⁹

Safety

Although trials have demonstrated vitamin supplementation to be safe and effective for skin enhancement, it is important to consider potential vitamin toxicities. High doses of vitamin C supplementation have been shown to cause damage via lipid peroxidation.⁴⁰ In a study assessing if high levels of beta-carotene and vitamin E were associated with a lower risk for lung cancer, data showed that these supplements may actually have harmful effects.^40,41 Additionally, consumption of high-dose dietary supplements has been associated with an increased risk for severe medical events, including disability and death among adolescents and young adults.⁴²

Conclusion

Numerous trials have indicated that the use of systemic vitamins can have beneficial effects on the protection and appearance of skin. Photodamage from UV light–induced erythema can be decreased by carotenoids and vitamins C and E. Similarly, supplements that combine multiple nutrients with collagen have been shown to improve the appearance of aging skin by decreasing the prominence of wrinkles. Given the growing number of products and advertisements that exist in the supplement marketplace, it is crucial for clinicians to ground their recommendations to patients in the scientific data of robust studies.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Identification

The South African fattail scorpion (Parabuthus transvaalicus)(Figure) is one of the most poisonous scorpions in southern Africa.¹ A member of the Buthidae scorpion family, it can grow as long as 15 cm and is dark brown-black with lighter red-brown pincers. Similar to other fattail scorpions, it has slender pincers (pedipalps) and a thick square tail (the telson). Parabuthus transvaalicus inhabits hot dry deserts, scrublands, and semiarid regions.^1,2 It also is popular in exotic pet collections, the most common source of stings in the United States.

Stings and Envenomation

Scorpions with thicker tails generally have more potent venom than those with slender tails and thick pincers. Venom is injected by a stinger at the tip of the telson¹; P transvaalicus also can spray venom as far as 3 m.^1,2 Venom is not known to cause toxicity through skin contact but could represent a hazard if sprayed in the eye.

Scorpion toxins are a group of complex neurotoxins that act on sodium channels, either retarding inactivation (α toxin) or enhancing activation (β toxin), causing massive depolarization of excitable cells.^1,3 The toxin causes neurons to fire repetitively.⁴ Neurotransmitters—noradrenaline, adrenaline, and acetylcholine—cause the observed sympathetic, parasympathetic, and skeletal muscle effects.¹

Incidence
Worldwide, more than 1.2 million individuals are stung by a scorpion annually, causing more than 3250 deaths a year.⁵ Adults are stung more often, but children experience more severe envenomation, are more likely to develop severe illness requiring intensive supportive care, and have a higher mortality.⁴

As many as one-third of patients stung by a Parabuthus scorpion develop neuromuscular toxicity, which can be life-threatening.⁶ In a study of 277 envenomations by P transvaalicus, 10% of patients developed severe symptoms and 5 died. Children younger than 10 years and adults older than 50 years are at greatest risk for adverse outcomes.⁶ Children have a case fatality rate as high as 10 times the adult fatality rate.⁷

Clinical Presentation
The clinical presentation of scorpion envenomation varies with the species involved, the amount of venom injected, and the victim’s weight and baseline health.¹ Scorpion envenomation is divided into 4 grades based on the severity of a sting:

• Grade I: pain and paresthesia at the envenomation site; usually, no local inflammation

• Grade II: local symptoms as well as more remote pain and paresthesia; pain can radiate up the affected limb

• Grade III: cranial nerve or somatic skeletal neuromuscular dysfunction; either presentation can have associated autonomic dysfunction

• Grade IV: both cranial nerve and somatic skeletal neuromuscular dysfunction, with associated auto-nomic dysfunction

 

 

The initial symptom of a scorpion sting is intense burning pain. The sting site might be unimpressive, with only a mild local reaction. Symptoms usually progress to maximum severity within 5 hours.¹ Muscle pain, cramps, and weakness are prominent. The patient might have difficulty walking and swallowing, with increased salivation and drooling, and visual disturbance with abnormal eye movements. Pulse, blood pressure, and temperature often are elevated. The patient might be hyperreflexic with clonus.^1,6

Symptoms of increased sympathetic activity are hypertension, tachycardia, cardiac dysrhythmia, perspiration, hyperglycemia, and restlessness.^1,2 Parasympathetic effects are increased salivation, hypotension, bradycardia, and gastric distension. Skeletal muscle effects include tremors and involuntary muscle movement, which can be severe. Cranial nerve dysfunction may manifest as dysphagia, drooling, abnormal eye movements, blurred vision, slurred speech, and tongue fasciculations. Subsequent development of muscle weakness, bulbar paralysis, and difficulty breathing may be caused by depletion of neurotransmitters after prolonged excessive neuronal activity.¹

Distinctive Signs in Younger Patients
A child who is stung by a scorpion might have symptoms similar to those seen in an adult victim but can also experience an extreme form of restlessness that indicates severe envenomation characterized by inability to lay still, violent muscle twitching, and uncontrollable flailing of extremities. The child might have facial grimacing, with lip-smacking and chewing motions. In addition, bulbar paralysis and respiratory distress are more likely in children who have been stung than in adults.^1,2

Management

Treatment of a P transvaalicus sting is directed at “scorpionism,” envenomation that is associated with systemic symptoms that can be life-threatening. Treatment comprises support of vital functions, symptomatic measures, and injection of antivenin.⁸

Support of Vital Functions
In adults, systemic symptoms can be delayed as long as 8 hours after the sting. However, most severe cases usually are evident within 60 minutes; infants can reach grade IV as quickly as 15 to 30 minutes.^9,10 Loss of pharyngeal reflexes and development of respiratory distress are ominous warning signs requiring immediate respiratory support. Respiratory failure is the most common cause of death.¹ An asymptomatic child should be admitted to a hospital for observation for a minimum of 12 hours if the species of scorpion was not identified.²

Pain Relief
Most patients cannot tolerate an ice pack because of severe hyperesthesia. Infiltration of the local sting site with an anesthetic generally is safe and can provide some local pain relief. Intravenous fentanyl has been used in closely monitored patients because the drug is not associated with histamine release. Medications that cause release of histamine, such as morphine, can exacerbate or confuse the clinical picture.

Antivenin
Scorpion antivenin contains purified IgG fragments; allergic reactions are now rare. The sooner antivenin is administered, the greater the benefit. When administered early, it can prevent many of the most serious complications.⁷ In a randomized, double-blind study of critically ill children with clinically significant signs of scorpion envenomation, intravenous administration of scorpion-specific fragment antigen-binding 2 (F[(ab’]₂) antivenin resulted in resolution of clinical symptoms within 4 hours.¹¹

When managing grade III or IV scorpion envenomation, all patients should be admitted to a medical facility equipped to provide intensive supportive care; consider consultation with a regional poison control center. The World Health Organization maintains an international poison control center (at https://www.who.int/ipcs/poisons/centre/en/) with regional telephone numbers; alternatively, in the United States, call the nationwide telephone number of the Poison Control Center (800-222-1222).

The World Health Organization has identified declining production of antivenin as a crisis.¹²

Resolution
Symptoms of envenomation typically resolve 9 to 30 hours after a sting in a patient with grade III or IV envenomation not treated with antivenin.⁴ However, pain and paresthesia occasionally last as long as 2 weeks. In rare cases, more long-term sequelae of burning paresthesia persist for months.⁴

Conclusion

It is important for dermatologists to be aware of the potential for life-threatening envenomation by certain scorpion species native to southern Africa. In the United States, stings of these species most often are seen in patients with a pet collection, but late sequelae also can be seen in travelers returning from an endemic region. The site of a sting often appears unimpressive initially, but severe hyperesthesia is common. Patients with cardiac, neurologic, or respiratory symptoms require intensive supportive care. Proper care can be lifesaving.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Practice Gap

Management of nonmelanoma skin cancer (NMSC) in elderly patients can cause morbidity because these patients frequently struggle to care for their biopsy sites and experience biopsy- and surgery-related complications. To minimize this treatment-related morbidity, we designed a knifeless treatment approach that employs reflectance confocal microscopy (RCM) in lieu of skin biopsy to establish the diagnosis of NMSC, then uses either intralesional or topical chemotherapy or immunotherapy (as appropriate, depending on depth of invasion) to cure the NMSC. With this approach, the patient is spared both biopsy- and surgery-related difficulties, though both intralesional and topical chemotherapy are accompanied by their own risks for adverse effects.

The Technique

Elderly patients, diabetic patients, and patients with lesions suspicious for NMSC on areas prone to poor wound healing or to notable treatment-related morbidity (eg, lower legs, genitals, the face of younger patients) are offered skin biopsy or RCM; the latter is performed during the appointment by an RCM-trained medical assistant. Patients who elect to undergo RCM and who have a diagnosis of superficial basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in situ are then treated with topical imiquimod or 5-fluorouracil. Patients with an invasive subtype of either BCC, SCC, or keratoacanthoma receive intralesional 5-fluorouracil injected at a concentration of 50 mg/cc at weekly intervals until the lesion blanches, with ongoing follow-up until the lesion is observed to have resolved under dermoscopic inspection.

When resolution is uncertain, RCM is repeated to assess for tumor clearance. Repeat RCM is performed at least 4 weeks after termination of treatment to avoid misinterpretation caused by treatment-related tissue inflammation. Patients who are not cured using this management approach are offered appropriate surgical management.

Practice Implications

Reflectance confocal microscopy has emerged as an effective modality for confirming the diagnosis of NMSC with high sensitivity and specificity.^1,2 Emergence of this technology presents an opportunity for improving the way the NMSC is managed because RCM allows dermatologists to confirm the diagnosis of BCC and SCC by interpretation of RCM mosaics rather than by histopathologic examination of biopsied tissue. Our knifeless approach to skin cancer management is especially beneficial when biopsy and dermatologic surgery are likely to confer notable morbidity, such as managing NMSC on the face of a young adult, in the frail elderly population, or in diabetic patients, and when treating sites on the lower extremity prone to poor wound healing.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.

Neglected tropical diseases (NTDs) are a group of 20 diseases that typically are chronic and cause long-term disability, which negatively impacts work productivity, child survival, and school performance and attendance with adverse effect on future earnings.¹ Data from the 2013 Global Burden of Disease study revealed that half of the world’s NTDs occur in poor populations living in wealthy countries.² Neglected tropical diseases with skin manifestations include parasitic infections (eg, American trypanosomiasis, African trypanosomiasis, dracunculiasis, echinococcosis, foodborne trematodiases, leishmaniasis, lymphatic filariasis, onchocerciasis, scabies and other ectoparasites, schistosomiasis, soil-transmitted helminths, taeniasis/cysticercosis), bacterial infections (eg, Buruli ulcer, leprosy, yaws), fungal infections (eg, mycetoma, chromoblastomycosis, deep mycoses), and viral infections (eg, dengue, chikungunya). Rabies and snakebite envenomization involve the skin through inoculation. Within the larger group of NTDs, the World Health Organization has identified “skin NTDs” as a subgroup of NTDs that present primarily with changes in the skin.³ In the absence of early diagnosis and treatment of these diseases, chronic and lifelong disfigurement, disability, stigma, and socioeconomic losses ensue.

The Department of Health of the Government of Western Australia stated:

Stigma is a mark of disgrace that sets a person apart from others. When a person is labeled by their illness they are no longer seen as an individual but as part of a stereotyped group. Negative attitudes and beliefs toward this group create prejudice which leads to negative actions and discrimination.⁴

Stigma associated with skin NTDs exemplifies how skin diseases can have enduring impact on individuals.⁵ For example, scarring from inactive cutaneous leishmaniasis carries heavy psychosocial burden. Young women reported that facial scarring from cutaneous leishmaniasis led to marriage rejections.⁶ Some even reported extreme suicidal ideations.⁷ Recently, major depressive disorder associated with scarring from inactive cutaneous leishmaniasis has been recognized as a notable contributor to disease burden from cutaneous leishmaniasis.⁸

Lymphatic filariasis is a major cause of leg and scrotal lymphedema worldwide. Even when the condition is treated, lymphedema often persists due to chronic irreversible lymphatic damage. A systematic review of 18 stigma studies in lymphatic filariasis found common themes related to the deleterious consequences of stigma on social relationships; work and education opportunities; health outcomes from reduced treatment-seeking behavior; and mental health, including anxiety, depression, and suicidal tendencies.⁹ In one subdistrict in India, implementation of a community-based lymphedema management program that consisted of teaching hygiene and limb care for more than 20,000 lymphedema patients and performing community outreach activities (eg, street plays, radio programs, informational brochures) to teach people about lymphatic filariasis and lymphedema care was associated with community members being accepting of patients and an improvement in their understanding of disease etiology.¹⁰

Skin involvement from onchocerciasis infection (onchocercal skin disease) is another condition associated with notable stigma.⁹ Through the African Programme for Onchocerciasis Control, annual mass drug administration of ivermectin in onchocerciasis-endemic communities has reduced the rate of onchocercal skin disease in these communities. In looking at perception of stigma in onchocercal skin diseases before community-directed ivermectin therapy and 7 to 10 years after, avoidance of people with onchocercal skin disease decreased from 32.7% to 4.3%. There also was an improvement in relationships between healthy people and those with onchocercal skin disease.¹¹

One of the most stigmatizing conditions is leprosy, often referred to as Hansen disease to give credit to the person who discovered that leprosy was caused by Mycobacterium leprae and not from sin, being cursed, or genetic inheritance. Even with this knowledge, stigma persists that can lead to family abandonment and social isolation, which further impacts afflicted individuals’ willingness to seek care, thus leading to disease progression. More recently, there has been research looking at interventions to reduce the stigma that individuals afflicted with leprosy face. In a study from Indonesia where individuals with leprosy were randomized to counseling, socioeconomic development, or contact between community members and affected people, all interventions were associated with a reduction in stigma.¹² A rights-based counseling module integrated individual, family, and group forms of counseling and consisted of 5 sessions that focused on medical knowledge of leprosy and rights of individuals with leprosy, along with elements of cognitive behavioral therapy. Socioeconomic development involved opportunities for business training, creation of community groups through which microfinance services were administered, and other assistance to improve livelihood. Informed by evidence from the field of human immunodeficiency virus and mental health that contact with affected people reduces negative attitudes and behavior among those participating in the intervention, contact between community members and persons affected by leprosy occurred through dialogue and interaction at events held in schools, village halls, and mosques. Furthermore, early detection and subsequent early treatment of leprosy can prevent individuals from the disability and disfigurement that we commonly associate with the disease, which often is not the message that afflicted individuals and their communities are hearing and seeing. Targeting media portrayal, the New Face of Leprosy project seeks to shift the messaging around leprosy to one of hope and positivity by promoting positive images—not presenting severe disfigurement as the representative image of leprosy—and strong messaging that the disease is curable.¹³

Although steps are being taken to address the psychosocial burden of skin NTDs, there is still much work to be done. From the public health lens that largely governs the policies and approaches toward addressing NTDs, the focus often is on interrupting and eliminating disease transmission. Morbidity management, including reduction in stigma and functional impairment, is not always the priority. It is in this space that dermatologists are uniquely positioned to advocate for management approaches that address the morbidity associated with skin NTDs. We have an intimate understanding of how impactful skin diseases can be, even if they are not commonly fatal. Globally, skin diseases are the fourth leading cause of nonfatal disease burden,¹⁴ yet dermatology lacks effective evidence-based interventions for reducing stigma in our patients with visible chronic diseases.¹⁵

Every day, we see firsthand how skin diseases affect not only our patients but also their families, friends, and caregivers. Although we may not see skin NTDs on a regular basis in our clinics, we can understand almost intuitively how devastating skin NTDs could be on individuals, families, and communities. For patients with skin NTDs, receiving medical therapy is only one component of treatment. In addition to optimizing early diagnosis and treatment, interventions taken to educate families and communities affected by skin NTDs are vitally important. Stigma reduction is possible, as we have seen from the aforementioned interventions used in communities with lymphatic filariasis, onchocerciasis, and leprosy. We call upon our fellow dermatologists to take interest in creating, evaluating, and promoting interventions that address stigma in skin NTDs; it is critical in achieving and maintaining health and well-being for our patients.