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Review article

International Journal of STD & AIDS


2015, Vol. 26(10) 696–703
! The Author(s) 2014
Yaws Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0956462414549036
std.sagepub.com
Michael Marks1,2, Dornubari Lebari3, Anthony W Solomon1,2
and Stephen P Higgins3

Abstract
Yaws is a non-venereal endemic treponemal infection caused by Treponema pallidum sub-species pertenue, a spirochaete
bacterium closely related to Treponema pallidum ssp. pallidum, the agent of venereal syphilis. Yaws is a chronic, relapsing
disease predominantly affecting children living in certain tropical regions. It spreads by skin-to-skin contact and, like
syphilis, occurs in distinct clinical stages. It causes lesions of the skin, mucous membranes and bones which, without
treatment, can become chronic and destructive. Treponema pallidum ssp. pertenue, like its sexually-transmitted counter-
part, is exquisitely sensitive to penicillin. Infection with yaws or syphilis results in reactive treponemal serology and there
is no widely available test to distinguish between these infections. Thus, migration of people from yaws-endemic areas to
developed countries may present clinicians with diagnostic dilemmas. We review the epidemiology, clinical presentation
and treatment of yaws.

Keywords
Syphilis, Yaws, Treponema pallidum pertenue, non-venereal endemic syphilis, neglected tropical diseases

Date received: 7 June 2014; accepted: 29 July 2014

Yaws cool and dryness and may explain why skin lesions are
Yaws is a non-venereal endemic treponemal infection seen more often in the rainy season.4
caused by Treponema pallidum sub-species pertenue,1 a In the 1950s it was estimated that 50 million people
bacterium closely related to Treponema pallidum ssp. were infected with yaws. The World Health
pallidum, the agent of venereal syphilis. Yaws predom- Organization (WHO) tried to eliminate the disease
inantly affects children living in tropical regions of the through a mass treatment campaign using benzylpeni-
world. It causes lesions of the skin, mucous membranes cillin.2,5 Consequently, the number of infections world-
and bones which, without treatment, can become wide dropped significantly but yaws then fell off the
chronic and destructive. There is no widely available public health agenda. The next 30 years saw a resur-
test to distinguish yaws from syphilis. Thus, migration gence of cases and the disease is, again, a public health
of people from yaws-endemic areas to developed coun- problem in Africa,6 South-East Asia, the Pacific7,8 and
tries may present clinicians with diagnostic dilemmas. South America.9 The WHO estimates that 2.5 million
The other endemic treponemal infections are bejel individuals may currently be infected.2 A failure to
(endemic syphilis) caused by Treponema pallidum ssp.
endemicum and pinta caused by Treponema carateum.
1
Clinical Research Department, Faculty of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine, London, UK
Epidemiology 2
The Hospital for Tropical Diseases, Mortimer Market Centre, Mortimer
Market, London, UK
Yaws is currently thought to be endemic in at least 12 3
Department of Sexual Health and HIV, North Manchester General
countries2,3 (Table 1). The number of notified yaws Hospital, Manchester, UK
cases is almost certainly an underestimate of true dis-
ease incidence. Yaws primarily affects children living in Corresponding author:
Michael Marks, Clinical Research Department, Faculty of Infectious and
poor, densely-populated rural areas. The concentration Tropical Diseases, London School of Hygiene and Tropical Medicine,
of yaws in warm, humid climates is thought to be Keppel Street, London, UK.
explained by the sensitivity of T p pertenue to relative Email: michael.marks@lshtm.ac.uk
Marks et al. 697

Table 1. Countries in which yaws is currently endemic.


Clinical presentation
Country Local name
The clinical presentation of yaws bears similarities to
Benin Not Known that of syphilis (Table 2). Like syphilis, yaws can be
Cameroon Not Known staged as early (primary and secondary) and late, or
Central African Republic Not Known tertiary. Though clinically useful, this classification is
Democratic Republic Not Known artificial and patients may present with a mixture of
of the Congo clinical signs.
Congo Not Known
Côte d’Ivoire* Goundou Primary yaws
Ghana Gyator
A papule appears at the inoculation site after about
Togo Gbodo, Gbodokui,
21 days (range 9–90).1,10 This ‘Mother Yaw’ may
Indonesia Frambusia evolve either into an exudative papilloma, 2–5 cm in
Timor-Leste Not Known size or degenerate to form a single, non-tender ulcer
Papua New Guinea Not Known (Figures 1–3) covered by a yellow crust. The legs and
Solomon Islands Yaws ankles are the commonest sites affected, but lesions may
Vanuatu  50 vatu soa occur on the face, buttocks, arms or hands.14 ‘Split-
 bigfella soa papules’ may occur at the angle of the mouth.1
*Endemic status unclear.
Regional lymphadenopathy is common. In contrast to
syphilis, genital lesions are rare. Primary lesions are
indolent and take 3–6 months to heal, more often leav-
identify contacts of infected individuals, inadequate ing a pigmented scar.15 As in syphilis,16 the primary
treatment of latent yaws as well as a failure to integrate lesion is still present when signs of secondary yaws
control efforts into primary health care are thought to develop in about 9–15% of patients.17
have led to the eventual failure of the WHO elimination
strategy.5
Secondary yaws
Haematogenous and lymphatic spread of treponemes
Transmission
produces secondary lesions, most commonly one to
Bacteria from infectious lesions enter via a breach in two months (but up to 24 months) after the primary
the skin. Lesions of early yaws are most infectious as lesion. General malaise and lymphadenopathy may
they carry a higher bacterial load, whilst late yaws occur. The most florid manifestations of secondary
lesions are not infectious. It is estimated that infectivity yaws occur in skin and bone.14
lasts for 12–18 months after primary infection1 but
relapsing disease can extend this period (see ‘latency’
Skin
below). It has been postulated that infection might be
spread by flies10 but there is no evidence to support this The rash begins as pinhead-size papules, which develop
mode of transmission in humans. Transplacental a pustular or crusted appearance and may persist for
spread of T p pertenue is said not to occur, but this weeks. If the crust is removed a raspberry-like appear-
view is disputed.11 ance may be revealed. Sometimes papules enlarge and
coalesce into cauliflower-like lesions, most frequently
on the face, trunk, genitalia and buttocks. Scaly mac-
Bacteriology
ules may be seen (Figures 4 and 5). Lesions in warm,
T p pertenue is a Gram-negative spirochaete which moist areas may resemble condylomata lata of syphilis.
cannot be cultured in vitro.1 Five strains have been The skin lesions of early yaws are often itchy and the
cultured in rabbits and golden hamsters.12 The organ- Koebner phenomenon has been observed. Mixed papu-
ism is closely related to T p pallidum with a genome that lar and macular lesions are often seen in individual
differs by approximately 0.2%. These differences are patients. Secondary skin lesions may heal even without
restricted to a small number of genes including tpr treatment, with or without scarring.
and TP0136. The role of these genes is uncertain but Squamous macular or plantar yaws can resemble
they have been implicated in pathogenesis.12 The phylo- secondary syphilis.1 Lesions on the soles of the feet
genetic relationship of yaws and syphilis remains may become hyperkeratotic, cracked, discoloured or
unclear and there is evidence that recombination secondarily infected. This can result in pain and a
between the two organisms can occur.13 crab-like gait.18 Mucous membrane involvement, most
698 International Journal of STD & AIDS 26(10)

Table 2. Comparison of clinical features and timing of yaws and syphilis.


Syphilis Yaws

Primary Incubation 9–90 days Incubation 10–90 days


Morphology Chancre. Usually solitary, Morphology Mother yaw. Usually solitary.
often multiple. Non-tender.
Non-tender. Scarring usual.
Scarring very unusual.
Site Ano-genital Site Legs, ankles
Secondary Incubation Weeks-24 months Incubation Weeks-24 months
Clinical presentation Skin rash Clinical presentation Arthralgia
Lymphadenopathy Malaise
Mucosal lesions Skin lesions
Polyosteitis of fingers, feet
or long bones
Latency Yes Yes
Infectious relapses Commonest within the first two years, Up to 5 years,
rarely thereafter Rarely up to 10 years.
Tertiary Clinical Clinical
Cardiovascular (10%) Decades ??Cardiovascular
Neurosyphilis (10%) Weeks (meningitis, ??Neuroyaws
cranial neuritis)
Decades: tabes, GPI 5 þ years
Gummata 10–15 years Gummatous nodules.
Scarring, contractures.
Gangosa. Tibial bowing.
Goundou
Congenital Yes No evidence
infection

Figure 1. Ulcer of primary yaws. Copyright Michael Marks.


Figure 2. Ulcer of primary yaws. Copyright Michael Marks.
Marks et al. 699

commonly nasal, was reported in less than 0.5% of


cases in American Samoa.19
There is some evidence that the manifestations of
yaws in the modern era are less florid than previously
reported. It has been postulated that use of penicillins
to treat other conditions may be responsible for this.
The differential diagnosis of yaws lesions is wide and
includes syphilis, leishmaniasis, leprosy and Buruli
ulcer, as well as non-infectious causes. Discussion
with a physician with expertise in tropical medicine is
recommended as the differential diagnosis and choice of
investigations will vary depending on the patient’s
country of origin.

Figure 3. Papilloma of primary yaws. Copyright Oriol Mitjà.


Bones
Secondary yaws typically causes osteoperiostitis of mul-
tiple bones. Involvement of long bones may cause noc-
turnal pain and visible periosteal thickening (Figures 6
and 7). Involvement of the proximal phalanges of the
fingers manifests as polydactylitis. This contrasts with
late yaws in which mono-dactylitis is typical. One study
from Papua New Guinea14 reported joint pains in 75%
of children with secondary yaws.

Latent yaws
Individuals with latent yaws have reactive serological
tests but no clinical signs. It is not known how many
patients are infected without developing clinical dis-
ease. Patients with primary and secondary yaws may
pass into a period of latency after resolution of clinical
signs. As in syphilis, infectious relapses can occur, most
Figure 4. Secondary yaws: multiple small ulcerative lesions. commonly up to five years (rarely up to 10 years) after
Copyright Michael Marks. infection.1,20 Relapsing lesions tend to occur around the
axillae, anus and mouth.

Figure 5. Secondary yaws: maculo-papular lesions with scaling.


Copyright Oriol Mitjà. Figure 6. Secondary yaws: dactylitis. Copyright Oriol Mitjà.
700 International Journal of STD & AIDS 26(10)

anecdotal reports.11 Most were published when sero-


diagnosis relied on non-treponemal tests and before
treponemal IgM testing of neonates was feasible.19

Yaws and HIV


There are no published data on the interaction between
HIV and yaws. It is possible that patients with latent yaws
might develop relapsing disease with increasing immune
damage.25 There are also no data on the impact on other
STIs, although given the low rates of genital lesions and
that the disease predominantly occurs in children it might
be anticipated that any effect would be minimal.

Figure 7. Secondary yaws: radiographic evidence of osteoper- Diagnosis


iostitis. Copyright Oriol Mitjà.
Syphilis or yaws?
Physicians working in endemic areas usually make a pre-
Tertiary yaws
sumptive diagnosis of yaws based on clinical and epi-
Tertiary yaws is thought to occur in about 10% of demiological features, with or without confirmatory
untreated patients, although its manifestations are rare blood tests. However, because syphilis and yaws co-exist
in the modern era. The skin is most commonly affected. in many tropical regions, and serology cannot distinguish
Hyperkeratosis of palms and soles and plaques may between treponemal sub-species, it may be impossible to
occur. Nodules may form near joints and ulcerate, caus- identify with certainty the causative organism. There are
ing tissue necrosis.4 ‘Sabre tibia’ results from chronic reports of yaws presenting in non-endemic countries.26,27
osteo-periostitis. Gangosa or rhinopharyngitis mutilans
denotes mutilating facial ulceration of the palate and
nasopharynx secondary to osteitis. Goundou was a rare Laboratory diagnosis
complication even when yaws was hyperendemic and is
characterised by exostoses of the maxillary bones.21
Dark ground microscopy
Spirochaetes were first observed in yaws ulcers in 1905,28
the year in which T pallidum ssp. pallidum was identified in
Cardiovascular yaws a lymph gland of a patient with syphilis. T pallidum ssp.
Although the consensus is that yaws does not cause pertenue is morphologically identical to T pallidum ssp.
cardiovascular disease, this view has been challenged. pallidum. As T pallidum spp. are only 0.3 mm wide and
Post-mortem studies have found evidence of aortitis in 6–20 mm in length, dark ground microscopy is required
patients with yaws.22 Histologically these lesions are for visualisation. Samples from primary and secondary
similar to those found in tertiary syphilis. Despite yaws lesions are obtained as described for syphilis.
these studies, definitive evidence of cardiovascular dis-
ease in yaws is lacking.
Polymerase chain reaction
Polymerase chain reaction (PCR) testing of samples can
Neurological yaws
identify T pallidum but current PCR protocols do not
The consensus that yaws does not cause neurological distinguish between sub-species.14,29 T pallidum ssp.
disease1 has also been challenged by studies that found pertenue has been identified to sub-species level using
neuro-ophthalmic23 and CSF abnormalities24 in real-time PCR and DNA sequencing in a child from
patients with yaws. As with cardiovascular disease Congo with a pruritic skin eruption,27 but few clinicians
definitive evidence for a causal role of yaws in neuro- have access to such techniques.
logical disease remains absent.
Serology
Yaws and pregnancy
While serological tests are the bedrock of yaws diagno-
While there is no laboratory evidence that T pallidum sis they cannot distinguish between sub-species of
ssp. pertenue can cause congenital yaws, there are T pallidum.30
Marks et al. 701

Non-treponemal (cardiolipin) tests primary and secondary yaws, with a cure rate of
The venereal disease research laboratory (VDRL) and approximately 95%.38 No other treatment strategies
rapid plasma reagin (RPR) tests use an antigen of car- are supported by randomised controlled trials although
diolipin, lecithin and cholesterol. Patient-derived anti- data from case series suggest oral penicillin can be
bodies produced against lipid in the cell surface of successful.9
T pallidum react with antigen to cause visible floccula- Based on these findings, azithromycin is now central
tion. The VDRL is read microscopically whereas the to the WHO eradication plan for yaws, which aims to
RPR can be read with the naked eye. Although non- employ community mass treatment in endemic regions.
specific, VDRL/RPR titres best reflect disease activity. WHO plan to have no further cases of active yaws
Titres fall after treatment and may become zero, espe- worldwide by 2017 and to confirm eradication by
cially after treatment of early infection.31 RPR titres are 2020.39,40 Despite this optimism there are several bar-
generally higher in primary than secondary yaws.1 riers to a successful eradication programme including a
lack of accurate epidemiological data from many coun-
tries where yaws is reported, the absence of dedicated
Treponemal tests funding for eradication efforts and a concern that
These include the T pallidum haemagglutination resistance to azithromycin, well described in syphilis,41
(TPHA) and the T pallidum particle agglutination will emerge in yaws. Monitoring for this during the
(TPPA) tests. They are more specific than cardiolipin eradication programme will be essential. This ambi-
tests and usually remain positive after treatment. tious plan will require considerable input from NGOs,
Point-of-care tests have proved useful in syphilis and academic institutions and policy makers.
results of an initial study in Papua New Guinea suggest
they may also be of value in the diagnosis of yaws with
good sensitivity and specificity.32 Further studies of
Response to treatment
these tests in yaws are in progress. Treponemes disappear from lesions within 8–10 hours
of treatment with penicillin. Skin lesions begin to heal
within 2–4 weeks (Figure 8). In patients with secondary
Histology yaws, joint pains may begin to improve within as little
In early yaws there is marked epidermal hyperplasia as 48 hours.42 Bone changes are reversible if treated
and papillomatosis, often with focal spongiosis.33
Neutrophils accumulate in the epidermis, causing
microabscesses. A dense dermal infiltrate of plasma
cells is seen.34 In contrast with syphilis, there is little
endothelial cell proliferation or vascular obliteration.34
T pallidum can be identified in tissue sections using
Warthin-Starry or Levaditi silver stains. While T palli-
dum ssp. pertenue is found mainly in the epidermis, T
pallidum ssp. pallidum is identified more in the dermis.35
Direct and indirect immunofluorescence and immuno-
peroxidase tests using specific polyclonal antibodies to
T pallidum can also be used with histology specimens.36

Radiology
Bone involvement may be revealed by radiographs even
when clinical signs are absent (Figure 7).37

Treatment
Benzathine penicillin-G has been the mainstay of treat-
ment for yaws for over 60 years. Lower doses are used
compared to syphilis with a recommended dose of 0.6
MU for children (under 10) and 1.2 MU for older chil-
dren and adults. In a recent single-centre randomised
controlled trial, one dose of azithromycin 30 mg/kg was Figure 8. Primary yaws: healed Lesion. Copyright Michael
shown to be equivalent to penicillin in patients with Marks.
702 International Journal of STD & AIDS 26(10)

early enough. Following successful treatment the RPR this article: MM is supported by a Wellcome Trust Clinical
declines and at 12 months up to 90% of individuals Research Fellowship - WT102807. AWS is a Wellcome Trust
have either a four-fold reduction in RPR or become Intermediate Clinical Fellow (098521) at the London School
seronegative.43 Failure of skin lesions to heal or the of Hygiene & Tropical Medicine.
RPR to drop should be considered treatment failure
and an indication for repeat treatment. In endemic set-
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