Opinion
VIEWPOINT
Lola V. Stamm, PhD Department of Epidemiology, University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Chapel Hill.
Corresponding Author: Lola V. Stamm, PhD, Department of Epidemiology, University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Program in Infectious Diseases, 3103 Hooker Research Center, S Columbia St, Chapel Hill, NC 275997435 (lstamm@email .unc.edu). jamadermatology.com
Yaws Renewed Hope for Eradication Yaws is the most common and severe of the endemic treponematoses (ie, yaws, begel, and pinta).1-3 This chronic, neglected tropical disease is caused by a noncultivable, spiral-shaped bacterium that is very closely related (approximately 99.8%) to the agent of venereal syphilis, Treponema pallidum subspecies pallidum (Table). Yaws primarily affects children ages 2 to 15 years who live in poor rural communities in forested tropical areas of Africa, Southeast Asia, and the Pacific Islands. Infection with the yaws agent, T pallidum subsp pertenue, is acquired through contact of broken skin with the fluid of an active yaws lesion. If left untreated, yaws can cause disfigurement and disability. Control of yaws is based on the interruption of transmission through identification and treatment of those who are infected and their contacts. Field diagnosis of yaws is usually based on clinical and epidemiological findings. However, because yaws can be confused with other diseases, field diagnosis should be confirmed with laboratory tests.1-3 Owing to the antigenic similarity of the yaws and syphilis agents, serological tests for syphilis are also used for the diagnosis of yaws, although these tests cannot differentiate the 2 diseases. Serodiagnosis of active yaws infection requires the detection of antibodies to nontreponemal (eg, cardiolipin) as well as to treponemal antigens. In early 2012, the World Health Organization (WHO) held a meeting in Morges, Switzerland, to develop a new strategy for eradication of yaws by target date 2020.4 The Morges strategy is based on initial mass treatment of individuals in endemic communities followed by clinical and serological surveys conducted by trained personnel at 6-month intervals to detect and treat remaining cases and their contacts. This is not the first time that yaws has been slated for eradication (ie, permanent reduction to zero of the global incidence of yaws). From 1952 to 1964, the WHO and the United Nations Children’s Fund mounted a massive eradication campaign in 46 countries that screened 300 million individuals and treated about 50 million. At the end of this campaign, the burden of yaws was reduced by 95%. However, in the late 1970s yaws reemerged, resulting in renewed eradication efforts in the 1980s that ultimately failed owing largely to a lack of resources and political will. Despite past failures, several experts believe that yaws eradication is now feasible owing to the currently more favorable political, donor, and public health climate. Four well-established prerequisites must be met to make eradication of an infectious disease possible (ie, biological and technical feasibility; adequate public health infrastructure; sufficient funding; and strong, sustained societal and political will). To date, only 1 infectious disease of humans (smallpox) and only 1 of animals (rinderpest) have been eradicated. Biological factors that fa-
Table. Comparison of Features of Yaws and Syphilis Feature
Yaws
Agent
T pallidum Treponema pallidum subspecies subspecies pallidum pertenue
Syphilis
Distribution
Africa, Southeast Asia, the Pacific Islands
Global
Age group affected
Children
Adults
Transmission mode
Skin to skin
Sexual, congenital
Site of primary lesion
Skin
Mucosa (genital, anal, oral)
Latent infection
Yes
Yes
Vaccine
No
No
Treatment
Penicillin, azithromycin
Penicillina
Reservoir
Humans, nonhuman primates (?)
Humans
Cultivableb
No
No
Eradicable
Possibly
Unlikely
a
Penicillin is the standard treatment; widespread azithromycin resistance has compromised the use of this second-line drug for treatment of syphilis.
b
Cannot be grown in vitro for sustained time periods; can be grown in animal models.
vored smallpox eradication were the availability of an effective vaccine, the lack of a nonhuman reservoir, the ease and reliability of clinical diagnosis without the need for laboratory confirmation, and the absence of latent infection. Unfortunately, there is no vaccine for yaws, nonhuman primates may be a reservoir of infection, clinical diagnosis can be problematic, and latent infections occur that can reactivate.1-3 Furthermore, because yaws mostly affects those who live in remote communities and migratory groups, reliable surveillance data are lacking concerning the true burden and distribution of yaws and access to these individuals is a logistical problem. Despite these issues, 2 new advances for treatment and diagnosis of yaws have renewed hope for eradication. First, Mitjà et al5 reported that single dose oral azithromycin (30 mg/kg with a maximum of 2 g) is as effective as intramuscular benzathine penicillin (0.6 MU for children; 1.2 MU for adults) for treatment of yaws in children in Papua New Guinea. Although azithromycin is safer than penicillin and should make mass treatment significantly easier, its use will require monitoring for emergence of resistance due to 23S ribosomal RNA point mutations, as observed with the syphilis agent.6 Second, Ayove et al7 showed that, when compared with standard serological tests for syphilis, a rapid, point-of-care test (Dual Path Platform Syphilis Screen and Confirm) is sufficiently sensitive and specific for diagnosis of active yaws cases in high prevalence settings under field conditions using JAMA Dermatology September 2014 Volume 150, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 06/04/2015
933
Opinion Viewpoint
finger stick blood. This is an important development since it obviates the need to obtain serum samples by venipuncture and to rely on a distant laboratory for sample testing. Furthermore, although additional data are needed, there is some indication that the Dual Path Platform Syphilis Screen and Confirm test may be useful for monitoring the effectiveness of treatment for individual patients. Much has been learned in the decades following the failure of previous yaws eradication campaigns. While the task of eradication of this ARTICLE INFORMATION Published Online: August 6, 2014. doi:10.1001/jamadermatol.2014.1277. Conflict of Interest Disclosures: None reported. REFERENCES 1. Giacani L, Lukehart SA. The endemic treponematoses. Clin Microbiol Rev. 2014;27(1): 89-115.
“end of the road” neglected tropical disease is daunting, recent advances for treatment and diagnosis of yaws, although not without caveats, are expected to significantly aid eradication efforts. However, because novel challenges are likely to arise once the initiative has begun, continued support for basic and applied research will be critical to refine eradication tools and strategies. Perhaps, with sufficient resources and sustained commitment, the old adage “third time’s a charm” will prove true this time for yaws eradication.
2. Mitjà O, Asiedu K, Mabey D. Yaws. Lancet. 2013; 381(9868):763-773.
an open-label, non-inferiority, randomised trial. Lancet. 2012;379(9813):342-347.
3. Kazadi WM, Asiedu KB, Agana N, Mitjà O. Epidemiology of yaws: an update. Clin Epidemiol. 2014;6:119-128.
6. Stamm LV. Global challenge of antibiotic-resistant Treponema pallidum. Antimicrob Agents Chemother. 2010;54(2):583-589.
4. Eradication of yaws: the Morges strategy. Wkly Epidemiol Rec. 2012;87(20):189-194.
7. Ayove T, Houniei W, Wangnapi R, et al. Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study [published online May 30, 2014]. Lancet Glob Health. doi:10.1016/S2214-109X(14)70231-1.
5. Mitjà O, Hays R, Ipai A, et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea:
NOTABLE NOTES
Leprology and Betrayal in Shakespeare’s Hamlet Canting Guo, BS; Scott A. Norton, MD, MPH
Before Hansen discovered the lepra bacillus in 1873, there had been dozens of theories on leprosy’s etiology. The most dramatic hypothesis (literally and figuratively) may have been proposed by the ghost of Prince Hamlet’s father in Shakespeare’s play, Hamlet. The ghost recounted the onset of a lethal “lazar-like … vile and loathsome crust” after being poisoned with a “leperous distilment” by the king’s regicidal brother, Claudius (who then usurped the throne—and queen—of Denmark) (Hamlet. Act 1, scene 5): Upon my secure hour thy uncle stole, With juice of cursed hebenon in a vial, And in the porches of my ears did pour The leperous distilment [that caused] … a most instant tetter bark’d about, Most lazar-like, with vile and loathsome crust, All my smooth body. Let’s explicate this passage: “While I was sleeping, your uncle Claudius poured a vial of poisonous henbane extract into my external ear canals. This leprosy-causing solution instantly changed my previously smooth skin into a scaly and scabby eruption, like a leper covered with a hideous crust.” And now, let’s break it down further: Cursed hebenon: Controversy surrounds the identity of “cursed hebenon.” Possibilities include poisonous plant-derived extracts from henbane, ebony, nightshade, hemlock, tobacco, and yew. We believe that several clues help identify the poison. Alchemists frequently distilled henbane for its oil, used orally as a hallucinogen and topically as an anesthetic salve.1 Furthermore, the passage reports absorption through the skin. Of the proposed poisons, only henbane is absorbed transdermally.1 Henbane (Hyoscyamus niger) contains scopolamine, an alkaloid now used in transdermal patches to reduce motion sickness. Scopolamine also blocks muscarinic receptors on vascular smooth muscle, leading to un-
934
opposed sympathetic vasoconstriction and cutaneous blanching. The sudden appearance of lighter skin, like a pharmacologic nevus anemicus, is another similarity between henbane toxicity and leprosy. Henbane has anesthetic and vasoconstrictive properties that can produce an anesthetic, hypopigmented patch.1,2 These qualities, albeit temporary, mimic leprosy, perhaps explaining the notion that henbane causes leprosy. We have established that henbane (1) is pharmacologically active when applied topically, (2) can cause cutaneous anesthesia, and (3) can cause vasoconstriction that resembles hypopigmentation. Tetter bark’d: “Tetter” means a generalized scurfy, scabrous (scaly, scabby) eruption. This term could apply to most acute, generalized eczematous or papulosquamous disorders. Although leprosy was well known in Shakespearian England, tetter probably referred more often to conditions we now know as psoriasis and extensive tinea corporis. Lazar-like: The parable of Lazarus3 describes a “beggar named Lazarus, which was laid at [the rich man’s] gate, full of sores” (Luke 16:20 [King James Version]). Throughout medieval Europe, Lazarus’s sores were regarded as leprosy. We believe the Ghost’s account of a poison inducing a fatal, leprosylike condition can be explained only if that poison were henbane. Author Affiliations: State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo (Guo); Dermatology Division, Children’s National Medical Center, Washington, DC (Norton). Corresponding Author: Scott A. Norton, MD, MPH, Dermatology Division, Children’s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010 ([email protected]). 1. Kotsias BA. Scopolamine and the murder of King Hamlet. Arch Otolaryngol Head Neck Surg. 2002;128(7):847-849. 2. Rivers RJ, Duling BR. Arteriolar endothelial cell barrier separates two populations of muscarinic receptors. Am J Physiol. 1992;262(4, pt 2):H1311-H1315. 3. Manchester K, Knüsel C. A medieval sculpture of leprosy in the Cistercian Abbaye de Cadouin. Med Hist. 1994;38(2):204-206.
JAMA Dermatology September 2014 Volume 150, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 06/04/2015
jamadermatology.com
VIEWPOINT
Lola V. Stamm, PhD Department of Epidemiology, University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Chapel Hill.
Corresponding Author: Lola V. Stamm, PhD, Department of Epidemiology, University of North Carolina at Chapel Hill, Gillings School of Global Public Health, Program in Infectious Diseases, 3103 Hooker Research Center, S Columbia St, Chapel Hill, NC 275997435 (lstamm@email .unc.edu). jamadermatology.com
Yaws Renewed Hope for Eradication Yaws is the most common and severe of the endemic treponematoses (ie, yaws, begel, and pinta).1-3 This chronic, neglected tropical disease is caused by a noncultivable, spiral-shaped bacterium that is very closely related (approximately 99.8%) to the agent of venereal syphilis, Treponema pallidum subspecies pallidum (Table). Yaws primarily affects children ages 2 to 15 years who live in poor rural communities in forested tropical areas of Africa, Southeast Asia, and the Pacific Islands. Infection with the yaws agent, T pallidum subsp pertenue, is acquired through contact of broken skin with the fluid of an active yaws lesion. If left untreated, yaws can cause disfigurement and disability. Control of yaws is based on the interruption of transmission through identification and treatment of those who are infected and their contacts. Field diagnosis of yaws is usually based on clinical and epidemiological findings. However, because yaws can be confused with other diseases, field diagnosis should be confirmed with laboratory tests.1-3 Owing to the antigenic similarity of the yaws and syphilis agents, serological tests for syphilis are also used for the diagnosis of yaws, although these tests cannot differentiate the 2 diseases. Serodiagnosis of active yaws infection requires the detection of antibodies to nontreponemal (eg, cardiolipin) as well as to treponemal antigens. In early 2012, the World Health Organization (WHO) held a meeting in Morges, Switzerland, to develop a new strategy for eradication of yaws by target date 2020.4 The Morges strategy is based on initial mass treatment of individuals in endemic communities followed by clinical and serological surveys conducted by trained personnel at 6-month intervals to detect and treat remaining cases and their contacts. This is not the first time that yaws has been slated for eradication (ie, permanent reduction to zero of the global incidence of yaws). From 1952 to 1964, the WHO and the United Nations Children’s Fund mounted a massive eradication campaign in 46 countries that screened 300 million individuals and treated about 50 million. At the end of this campaign, the burden of yaws was reduced by 95%. However, in the late 1970s yaws reemerged, resulting in renewed eradication efforts in the 1980s that ultimately failed owing largely to a lack of resources and political will. Despite past failures, several experts believe that yaws eradication is now feasible owing to the currently more favorable political, donor, and public health climate. Four well-established prerequisites must be met to make eradication of an infectious disease possible (ie, biological and technical feasibility; adequate public health infrastructure; sufficient funding; and strong, sustained societal and political will). To date, only 1 infectious disease of humans (smallpox) and only 1 of animals (rinderpest) have been eradicated. Biological factors that fa-
Table. Comparison of Features of Yaws and Syphilis Feature
Yaws
Agent
T pallidum Treponema pallidum subspecies subspecies pallidum pertenue
Syphilis
Distribution
Africa, Southeast Asia, the Pacific Islands
Global
Age group affected
Children
Adults
Transmission mode
Skin to skin
Sexual, congenital
Site of primary lesion
Skin
Mucosa (genital, anal, oral)
Latent infection
Yes
Yes
Vaccine
No
No
Treatment
Penicillin, azithromycin
Penicillina
Reservoir
Humans, nonhuman primates (?)
Humans
Cultivableb
No
No
Eradicable
Possibly
Unlikely
a
Penicillin is the standard treatment; widespread azithromycin resistance has compromised the use of this second-line drug for treatment of syphilis.
b
Cannot be grown in vitro for sustained time periods; can be grown in animal models.
vored smallpox eradication were the availability of an effective vaccine, the lack of a nonhuman reservoir, the ease and reliability of clinical diagnosis without the need for laboratory confirmation, and the absence of latent infection. Unfortunately, there is no vaccine for yaws, nonhuman primates may be a reservoir of infection, clinical diagnosis can be problematic, and latent infections occur that can reactivate.1-3 Furthermore, because yaws mostly affects those who live in remote communities and migratory groups, reliable surveillance data are lacking concerning the true burden and distribution of yaws and access to these individuals is a logistical problem. Despite these issues, 2 new advances for treatment and diagnosis of yaws have renewed hope for eradication. First, Mitjà et al5 reported that single dose oral azithromycin (30 mg/kg with a maximum of 2 g) is as effective as intramuscular benzathine penicillin (0.6 MU for children; 1.2 MU for adults) for treatment of yaws in children in Papua New Guinea. Although azithromycin is safer than penicillin and should make mass treatment significantly easier, its use will require monitoring for emergence of resistance due to 23S ribosomal RNA point mutations, as observed with the syphilis agent.6 Second, Ayove et al7 showed that, when compared with standard serological tests for syphilis, a rapid, point-of-care test (Dual Path Platform Syphilis Screen and Confirm) is sufficiently sensitive and specific for diagnosis of active yaws cases in high prevalence settings under field conditions using JAMA Dermatology September 2014 Volume 150, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 06/04/2015
933
Opinion Viewpoint
finger stick blood. This is an important development since it obviates the need to obtain serum samples by venipuncture and to rely on a distant laboratory for sample testing. Furthermore, although additional data are needed, there is some indication that the Dual Path Platform Syphilis Screen and Confirm test may be useful for monitoring the effectiveness of treatment for individual patients. Much has been learned in the decades following the failure of previous yaws eradication campaigns. While the task of eradication of this ARTICLE INFORMATION Published Online: August 6, 2014. doi:10.1001/jamadermatol.2014.1277. Conflict of Interest Disclosures: None reported. REFERENCES 1. Giacani L, Lukehart SA. The endemic treponematoses. Clin Microbiol Rev. 2014;27(1): 89-115.
“end of the road” neglected tropical disease is daunting, recent advances for treatment and diagnosis of yaws, although not without caveats, are expected to significantly aid eradication efforts. However, because novel challenges are likely to arise once the initiative has begun, continued support for basic and applied research will be critical to refine eradication tools and strategies. Perhaps, with sufficient resources and sustained commitment, the old adage “third time’s a charm” will prove true this time for yaws eradication.
2. Mitjà O, Asiedu K, Mabey D. Yaws. Lancet. 2013; 381(9868):763-773.
an open-label, non-inferiority, randomised trial. Lancet. 2012;379(9813):342-347.
3. Kazadi WM, Asiedu KB, Agana N, Mitjà O. Epidemiology of yaws: an update. Clin Epidemiol. 2014;6:119-128.
6. Stamm LV. Global challenge of antibiotic-resistant Treponema pallidum. Antimicrob Agents Chemother. 2010;54(2):583-589.
4. Eradication of yaws: the Morges strategy. Wkly Epidemiol Rec. 2012;87(20):189-194.
7. Ayove T, Houniei W, Wangnapi R, et al. Sensitivity and specificity of a rapid point-of-care test for active yaws: a comparative study [published online May 30, 2014]. Lancet Glob Health. doi:10.1016/S2214-109X(14)70231-1.
5. Mitjà O, Hays R, Ipai A, et al. Single-dose azithromycin versus benzathine benzylpenicillin for treatment of yaws in children in Papua New Guinea:
NOTABLE NOTES
Leprology and Betrayal in Shakespeare’s Hamlet Canting Guo, BS; Scott A. Norton, MD, MPH
Before Hansen discovered the lepra bacillus in 1873, there had been dozens of theories on leprosy’s etiology. The most dramatic hypothesis (literally and figuratively) may have been proposed by the ghost of Prince Hamlet’s father in Shakespeare’s play, Hamlet. The ghost recounted the onset of a lethal “lazar-like … vile and loathsome crust” after being poisoned with a “leperous distilment” by the king’s regicidal brother, Claudius (who then usurped the throne—and queen—of Denmark) (Hamlet. Act 1, scene 5): Upon my secure hour thy uncle stole, With juice of cursed hebenon in a vial, And in the porches of my ears did pour The leperous distilment [that caused] … a most instant tetter bark’d about, Most lazar-like, with vile and loathsome crust, All my smooth body. Let’s explicate this passage: “While I was sleeping, your uncle Claudius poured a vial of poisonous henbane extract into my external ear canals. This leprosy-causing solution instantly changed my previously smooth skin into a scaly and scabby eruption, like a leper covered with a hideous crust.” And now, let’s break it down further: Cursed hebenon: Controversy surrounds the identity of “cursed hebenon.” Possibilities include poisonous plant-derived extracts from henbane, ebony, nightshade, hemlock, tobacco, and yew. We believe that several clues help identify the poison. Alchemists frequently distilled henbane for its oil, used orally as a hallucinogen and topically as an anesthetic salve.1 Furthermore, the passage reports absorption through the skin. Of the proposed poisons, only henbane is absorbed transdermally.1 Henbane (Hyoscyamus niger) contains scopolamine, an alkaloid now used in transdermal patches to reduce motion sickness. Scopolamine also blocks muscarinic receptors on vascular smooth muscle, leading to un-
934
opposed sympathetic vasoconstriction and cutaneous blanching. The sudden appearance of lighter skin, like a pharmacologic nevus anemicus, is another similarity between henbane toxicity and leprosy. Henbane has anesthetic and vasoconstrictive properties that can produce an anesthetic, hypopigmented patch.1,2 These qualities, albeit temporary, mimic leprosy, perhaps explaining the notion that henbane causes leprosy. We have established that henbane (1) is pharmacologically active when applied topically, (2) can cause cutaneous anesthesia, and (3) can cause vasoconstriction that resembles hypopigmentation. Tetter bark’d: “Tetter” means a generalized scurfy, scabrous (scaly, scabby) eruption. This term could apply to most acute, generalized eczematous or papulosquamous disorders. Although leprosy was well known in Shakespearian England, tetter probably referred more often to conditions we now know as psoriasis and extensive tinea corporis. Lazar-like: The parable of Lazarus3 describes a “beggar named Lazarus, which was laid at [the rich man’s] gate, full of sores” (Luke 16:20 [King James Version]). Throughout medieval Europe, Lazarus’s sores were regarded as leprosy. We believe the Ghost’s account of a poison inducing a fatal, leprosylike condition can be explained only if that poison were henbane. Author Affiliations: State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo (Guo); Dermatology Division, Children’s National Medical Center, Washington, DC (Norton). Corresponding Author: Scott A. Norton, MD, MPH, Dermatology Division, Children’s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010 ([email protected]). 1. Kotsias BA. Scopolamine and the murder of King Hamlet. Arch Otolaryngol Head Neck Surg. 2002;128(7):847-849. 2. Rivers RJ, Duling BR. Arteriolar endothelial cell barrier separates two populations of muscarinic receptors. Am J Physiol. 1992;262(4, pt 2):H1311-H1315. 3. Manchester K, Knüsel C. A medieval sculpture of leprosy in the Cistercian Abbaye de Cadouin. Med Hist. 1994;38(2):204-206.
JAMA Dermatology September 2014 Volume 150, Number 9
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archderm.jamanetwork.com/ by a University of Georgia User on 06/04/2015
jamadermatology.com
