The
NEW ENGLAND JOURNAL
MEDICINE
Perspective FEBRUARY 19, 2015
Yaws Eradication — A Goal Finally within Reach Jam es
W.
Kazura,
M.D. Related article, p. 703
aws is a chronic infectious disease caused by Treponem a pallidum subspecies pertenue, a gram negative bacterium that is genetically closely re lated to the less common nonvenereal endemic
Y
treponematoses, bejel and pinta, and T. pallidum subspecies pallidum, the causative agent of syphilis. As one o f the 17 neglected tropi cal diseases that the World Health Organization (WHO) has classi fied as disproportionately affect ing economically disadvantaged populations, yaws was added to the list o f those endorsed for global eradication by a 2013 reso lution of the World Health Assem bly (WHA66.12). Transmission of T. pallidum per tenue occurs by the direct contact of minor abrasions o f the skin of an uninfected person with conta gious skin lesions of an infected person. The median period be tween inoculation and the appear ance o f a primary yaws lesion is
21 days (range, 9 to 90). Primary yaws manifests as a papule, pap illoma, and ulcer of the skin that can range in diameter from 2 to 5 cm (see photo). The lesions most commonly involve the skin o f the lower leg and ankle, and less frequently the arm, hand, or buttocks. Primary yaws resolves over the course of 3 to 6 months, but if it is not treated with anti biotics, hematogenous and lym phatic dissemination of the bac teria may occur and lead to the development o f secondary yaws, a condition characterized by con tagious, superficial patchy scal ing o f the skin and plaques of the palms and soles accompa nied by arthralgia and malaise. If untreated, yaws may become a
N EN G LJ
M E D 3 7 2 |8
N E J M .O R G
F E B R U A R Y 19> 2 0 1 5
chronic, relapsing disease mani fested in periostitis, dactylitis, destructive ulceration of the pal ate and nasopharynx, and defor mities o f long bones of the ex tremities.1 As of 2013, the presence of symptomatic yaws was document ed in 13 countries in Africa, Southeast Asia, and the Western Pacific region (see map), although such documentation probably rep resents an underestimate o f the global distribution of yaws, given the lack o f systematic mapping. From an epidemiologic perspec tive, yaws primarily affects chil dren living in rural areas of the tropics, where rainfall and hu midity are high and poverty and poor hygiene favor person-to-person transmission. Periods of high seasonal rainfall in tropical rain forests are known to be associat ed with increased rates of trans mission. There is not thought to be a zoonotic reservoir for yaws,
693
YAWS
Yaws Cutaneous Ulcer Involving the Lower Leg o f a 10-Year-O id Child in Papua N e w G uinea.
The ulcer resolved after the administration o f intram uscular penicillin G benzathine.
although wild gorillas in central Africa have been found to be in fected with T. pallidum pertenue. The current WHO strategy for eradicating yaws was formulated at an international meeting of experts held in Morges, Switzer land, in 2012.2 Key concepts of the strategy include total com munity treatment — treatment o f all eligible members of com munities in which yaws is en demic with oral azithromycin (or intramuscular penicillin G ben zathine if azithromycin is contra indicated). Azithromycin is a macrolide antibiotic that has been shown to be noninferior to the previous standard treatment reg imen, intramuscular injection of long-acting penicillin.3 The use o f an oral antibiotic is a major advantage, since it obviates the need for, and the additional cost of, administering intramuscular injections on a community-wide basis.
694
E R A D IC A T IO N
A second important element of the strategy is to follow mass treatment with active surveillance and targeted treatment of symp tomatic as well as latent (asymp tomatic) yaws at approximately 6-month intervals, particularly in children, who represent the ma jor reservoir of contagious cases required for continuing transmis sion. An effort promulgated by the WHO and the United Nations Children’s Fund from 1952 to 1964 to eliminate yaws in 46 countries by mass treatment with injectable long-acting penicillin did not succeed, largely because of a failure to focus on treating children with latent yaws (al though the number of active yaws cases in the world was re duced by an estimated 95%). The article by Mitja and col leagues in this issue o f the Jour nal (pages 703-710) provides strong empirical evidence that the Morges strategy should result in the eradication of yaws, if it is implemented and sustained long enough. A total of 83% o f 16,092 residents o f rural villages on Lihir Island, Papua New Guinea, were given mass treatment con sisting of single-dose azithromycin and were monitored for 1 year for active infectious yaws and clinically silent latent yaws in children (as determined by seropositivity on rapid plasma reagin [RPR] testing). The prevalence of active yaws in the community de creased from 2.4% before treat ment to 0.3% a year after treat ment. Latent yaws with high-titer seroreactivity (RPR, >1:16) was observed in 18.9% o f 874 chil dren 6 to 15 years of age on pre treatment testing and in 7.3% of 796 children on testing 1 year after treatment. The reduction in the prevalence of high-titer latent yaws cases among children 1 to
N EN G LJ
M E D 3 7 2 ,8
N E J M .O R G
FEBRUARY 19, 2015
------ A G O A L
F IN A L L Y
W IT H IN
REACH
5 years of age was even more dramatic. Molecular analyses to detect T. pallidum pertenue and Hae m ophilus ducreyi DNA showed that both organisms caused cutaneous ulcers. The proportion of ulcers containing T. pallidum species DNA but not H. ducreyi DNA decreased after treatment. There was no evidence of the emergence of ge netic markers of macrolide resis tance in T. pallidum species after the administration of azithromy cin. Collectively, these findings indicate that the benefit o f mass treatment with azithromycin to eliminate yaws far outweighs the risks o f side effects of such treat ment and of the emergence of anti microbial resistance beyond yaws. There are clear challenges ahead if yaws eradication — de fined as the absence o f active yaws and latent yaws (serologic negativity for T. pallidum pertenue infection in children younger than 5 years of age) for 3 consecutive years with active surveillance — is to be achieved by the stated goal of 2020. First, mass treat ment and targeted treatment pro grams with high-quality, regular monitoring for both active and latent yaws need to be main tained for a minimum of 3 years. Second, yaws elimination efi forts will be conducted by local health systems that must place high priority on other infectiousdisease control programs, such as deworming in children and malaria and filariasis elimination efforts. Many yaws control pro grams will be executed in areas where the public health infra structure is weak and constrained by limited human and financial resources. Third, since yaws is highly focal and heterogeneous in its geograph ic distribution, better mapping will be needed in order to prioritize
A rle n e D e n t, M .D ., P h.D .
PERSPECTIVE
PERSPECTIVE
YAWS
E R A D IC A T IO N
—
A G O AL
F IN A L L Y W IT H IN
REACH
C am eroon Benin
Central A frican R epublic Papua N ew G uinea
/ lvor>' Coast
Togp Ghana
D em ocratic
S olom on Islands
R epublic o f Congo
’Indonesia East T im o rVanuatu
Congo
C o u n t r ie s W h e r e Y a w s Is C u r r e n t l y K n o w n t o B e E n d e m i c .
areas for the initiation of elimi nation programs. Initial mapping of areas of high endemicity could be based on surveys conducted by local field teams using picto rial guides of clinical manifesta tions of yaws. Progress toward the elimination of transmission could be monitored by means of point-of-care serologic surveys for latent yaws in children.4 Finally, as with mass drugadministration programs for con trolling and eliminating other infectious diseases, maintaining
high levels of community partici pation in treatment and monitor ing will be essential. Azithromy cin uptake by 80% or more of eligible community participants, as Mitja et al. report in Papua New Guinea, with continued tar geted community treatment will be critical if local elimination and, ultimately, global eradica tion of yaws are finally to be re alized.
F ro m th e C e n te r f o r G lo b a l H e a lth a n d D is eases, C ase W e s te rn
R eserve U n iv e rs ity ,
C le v e la n d . 1. M itjei O , A s ie d u K, M a b e y D. Yaws. L a n ce t 2013;381:763-73.
2 . E ra d ic a tio n o f yaw s — th e M o rg e s s tra te gy. W k ly E p id e m io l Rec 2012;87:189-94.
3 . M itj& O , H ays R, Ip a i A , e t al. S in g le -d o s e a z ith ro m y c in v e rs u s b e n z a th in e b e n z y lp e n ic illin fo r tre a tm e n t o f yaw s in c h ild re n in P apua N e w G u in e a : an o p e n -la b e l, n o n - in fe rio rity , ra n d o m is e d tr ia l. L a n c e t 2012;379: 342-7.
4 . M a rk s M , G o n c a lv e s A , V ahi V, e t al. Eval u a tio n o f a ra p id d ia g n o s tic te s t fo r yaw s in fe c tio n in a c o m m u n ity s u rv e illa n c e s e ttin g .
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
PLoS N e g l T ro p D is 2014;8(9):e3156. D O I: 10.1056/N EJM p l4 1 5346 C opyright © 2 015 M assachusetts M e d ical Society.
Healthcare.gov 3.0 — Behavioral Economics and Insurance Exchanges Peter A. Ubel, M.D., David A. Comerford, Ph.D., and Ericjohnson, Ph.D.
n October 2013, the Afford able Care Act introduced a new insurance market — state and federal exchanges where people can purchase health in surance for themselves or their families. Although the rollout of the exchanges was disastrous,
I
around-the-clock efforts fixed many of the biggest technical problems, and nearly 7 million people purchased insurance in the new market. The second round of enrollment exposed some new problems with the ex change websites — for example,
N ENG LJ
M E D 3 7 2 |8
N E J M .O R G
FEBRUARY 1 9 , 2 0 1 5
Colorado’s website had difficul ty determining whether people were eligible for tax credits — but these problems paled in comparison with those encoun tered when the exchanges were first rolled out. In short, we have a largely glitch-free system
695
Copyright © Massachusetts Medical Society 2015.
NEW ENGLAND JOURNAL
MEDICINE
Perspective FEBRUARY 19, 2015
Yaws Eradication — A Goal Finally within Reach Jam es
W.
Kazura,
M.D. Related article, p. 703
aws is a chronic infectious disease caused by Treponem a pallidum subspecies pertenue, a gram negative bacterium that is genetically closely re lated to the less common nonvenereal endemic
Y
treponematoses, bejel and pinta, and T. pallidum subspecies pallidum, the causative agent of syphilis. As one o f the 17 neglected tropi cal diseases that the World Health Organization (WHO) has classi fied as disproportionately affect ing economically disadvantaged populations, yaws was added to the list o f those endorsed for global eradication by a 2013 reso lution of the World Health Assem bly (WHA66.12). Transmission of T. pallidum per tenue occurs by the direct contact of minor abrasions o f the skin of an uninfected person with conta gious skin lesions of an infected person. The median period be tween inoculation and the appear ance o f a primary yaws lesion is
21 days (range, 9 to 90). Primary yaws manifests as a papule, pap illoma, and ulcer of the skin that can range in diameter from 2 to 5 cm (see photo). The lesions most commonly involve the skin o f the lower leg and ankle, and less frequently the arm, hand, or buttocks. Primary yaws resolves over the course of 3 to 6 months, but if it is not treated with anti biotics, hematogenous and lym phatic dissemination of the bac teria may occur and lead to the development o f secondary yaws, a condition characterized by con tagious, superficial patchy scal ing o f the skin and plaques of the palms and soles accompa nied by arthralgia and malaise. If untreated, yaws may become a
N EN G LJ
M E D 3 7 2 |8
N E J M .O R G
F E B R U A R Y 19> 2 0 1 5
chronic, relapsing disease mani fested in periostitis, dactylitis, destructive ulceration of the pal ate and nasopharynx, and defor mities o f long bones of the ex tremities.1 As of 2013, the presence of symptomatic yaws was document ed in 13 countries in Africa, Southeast Asia, and the Western Pacific region (see map), although such documentation probably rep resents an underestimate o f the global distribution of yaws, given the lack o f systematic mapping. From an epidemiologic perspec tive, yaws primarily affects chil dren living in rural areas of the tropics, where rainfall and hu midity are high and poverty and poor hygiene favor person-to-person transmission. Periods of high seasonal rainfall in tropical rain forests are known to be associat ed with increased rates of trans mission. There is not thought to be a zoonotic reservoir for yaws,
693
YAWS
Yaws Cutaneous Ulcer Involving the Lower Leg o f a 10-Year-O id Child in Papua N e w G uinea.
The ulcer resolved after the administration o f intram uscular penicillin G benzathine.
although wild gorillas in central Africa have been found to be in fected with T. pallidum pertenue. The current WHO strategy for eradicating yaws was formulated at an international meeting of experts held in Morges, Switzer land, in 2012.2 Key concepts of the strategy include total com munity treatment — treatment o f all eligible members of com munities in which yaws is en demic with oral azithromycin (or intramuscular penicillin G ben zathine if azithromycin is contra indicated). Azithromycin is a macrolide antibiotic that has been shown to be noninferior to the previous standard treatment reg imen, intramuscular injection of long-acting penicillin.3 The use o f an oral antibiotic is a major advantage, since it obviates the need for, and the additional cost of, administering intramuscular injections on a community-wide basis.
694
E R A D IC A T IO N
A second important element of the strategy is to follow mass treatment with active surveillance and targeted treatment of symp tomatic as well as latent (asymp tomatic) yaws at approximately 6-month intervals, particularly in children, who represent the ma jor reservoir of contagious cases required for continuing transmis sion. An effort promulgated by the WHO and the United Nations Children’s Fund from 1952 to 1964 to eliminate yaws in 46 countries by mass treatment with injectable long-acting penicillin did not succeed, largely because of a failure to focus on treating children with latent yaws (al though the number of active yaws cases in the world was re duced by an estimated 95%). The article by Mitja and col leagues in this issue o f the Jour nal (pages 703-710) provides strong empirical evidence that the Morges strategy should result in the eradication of yaws, if it is implemented and sustained long enough. A total of 83% o f 16,092 residents o f rural villages on Lihir Island, Papua New Guinea, were given mass treatment con sisting of single-dose azithromycin and were monitored for 1 year for active infectious yaws and clinically silent latent yaws in children (as determined by seropositivity on rapid plasma reagin [RPR] testing). The prevalence of active yaws in the community de creased from 2.4% before treat ment to 0.3% a year after treat ment. Latent yaws with high-titer seroreactivity (RPR, >1:16) was observed in 18.9% o f 874 chil dren 6 to 15 years of age on pre treatment testing and in 7.3% of 796 children on testing 1 year after treatment. The reduction in the prevalence of high-titer latent yaws cases among children 1 to
N EN G LJ
M E D 3 7 2 ,8
N E J M .O R G
FEBRUARY 19, 2015
------ A G O A L
F IN A L L Y
W IT H IN
REACH
5 years of age was even more dramatic. Molecular analyses to detect T. pallidum pertenue and Hae m ophilus ducreyi DNA showed that both organisms caused cutaneous ulcers. The proportion of ulcers containing T. pallidum species DNA but not H. ducreyi DNA decreased after treatment. There was no evidence of the emergence of ge netic markers of macrolide resis tance in T. pallidum species after the administration of azithromy cin. Collectively, these findings indicate that the benefit o f mass treatment with azithromycin to eliminate yaws far outweighs the risks o f side effects of such treat ment and of the emergence of anti microbial resistance beyond yaws. There are clear challenges ahead if yaws eradication — de fined as the absence o f active yaws and latent yaws (serologic negativity for T. pallidum pertenue infection in children younger than 5 years of age) for 3 consecutive years with active surveillance — is to be achieved by the stated goal of 2020. First, mass treat ment and targeted treatment pro grams with high-quality, regular monitoring for both active and latent yaws need to be main tained for a minimum of 3 years. Second, yaws elimination efi forts will be conducted by local health systems that must place high priority on other infectiousdisease control programs, such as deworming in children and malaria and filariasis elimination efforts. Many yaws control pro grams will be executed in areas where the public health infra structure is weak and constrained by limited human and financial resources. Third, since yaws is highly focal and heterogeneous in its geograph ic distribution, better mapping will be needed in order to prioritize
A rle n e D e n t, M .D ., P h.D .
PERSPECTIVE
PERSPECTIVE
YAWS
E R A D IC A T IO N
—
A G O AL
F IN A L L Y W IT H IN
REACH
C am eroon Benin
Central A frican R epublic Papua N ew G uinea
/ lvor>' Coast
Togp Ghana
D em ocratic
S olom on Islands
R epublic o f Congo
’Indonesia East T im o rVanuatu
Congo
C o u n t r ie s W h e r e Y a w s Is C u r r e n t l y K n o w n t o B e E n d e m i c .
areas for the initiation of elimi nation programs. Initial mapping of areas of high endemicity could be based on surveys conducted by local field teams using picto rial guides of clinical manifesta tions of yaws. Progress toward the elimination of transmission could be monitored by means of point-of-care serologic surveys for latent yaws in children.4 Finally, as with mass drugadministration programs for con trolling and eliminating other infectious diseases, maintaining
high levels of community partici pation in treatment and monitor ing will be essential. Azithromy cin uptake by 80% or more of eligible community participants, as Mitja et al. report in Papua New Guinea, with continued tar geted community treatment will be critical if local elimination and, ultimately, global eradica tion of yaws are finally to be re alized.
F ro m th e C e n te r f o r G lo b a l H e a lth a n d D is eases, C ase W e s te rn
R eserve U n iv e rs ity ,
C le v e la n d . 1. M itjei O , A s ie d u K, M a b e y D. Yaws. L a n ce t 2013;381:763-73.
2 . E ra d ic a tio n o f yaw s — th e M o rg e s s tra te gy. W k ly E p id e m io l Rec 2012;87:189-94.
3 . M itj& O , H ays R, Ip a i A , e t al. S in g le -d o s e a z ith ro m y c in v e rs u s b e n z a th in e b e n z y lp e n ic illin fo r tre a tm e n t o f yaw s in c h ild re n in P apua N e w G u in e a : an o p e n -la b e l, n o n - in fe rio rity , ra n d o m is e d tr ia l. L a n c e t 2012;379: 342-7.
4 . M a rk s M , G o n c a lv e s A , V ahi V, e t al. Eval u a tio n o f a ra p id d ia g n o s tic te s t fo r yaw s in fe c tio n in a c o m m u n ity s u rv e illa n c e s e ttin g .
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
PLoS N e g l T ro p D is 2014;8(9):e3156. D O I: 10.1056/N EJM p l4 1 5346 C opyright © 2 015 M assachusetts M e d ical Society.
Healthcare.gov 3.0 — Behavioral Economics and Insurance Exchanges Peter A. Ubel, M.D., David A. Comerford, Ph.D., and Ericjohnson, Ph.D.
n October 2013, the Afford able Care Act introduced a new insurance market — state and federal exchanges where people can purchase health in surance for themselves or their families. Although the rollout of the exchanges was disastrous,
I
around-the-clock efforts fixed many of the biggest technical problems, and nearly 7 million people purchased insurance in the new market. The second round of enrollment exposed some new problems with the ex change websites — for example,
N ENG LJ
M E D 3 7 2 |8
N E J M .O R G
FEBRUARY 1 9 , 2 0 1 5
Colorado’s website had difficul ty determining whether people were eligible for tax credits — but these problems paled in comparison with those encoun tered when the exchanges were first rolled out. In short, we have a largely glitch-free system
695
Copyright © Massachusetts Medical Society 2015.
