1415CHAPTER 183 Endemic Treponematoses

Indonesia, Papua New Guinea, the Solomon Islands, East Timor, and

Vanuatu. India actively renewed its focus on yaws control in 1996,

achieved zero-case status in 2003, declared elimination in 2006, and

was declared yaws-free in 2016. In the Americas, suspected yaws cases

have been reported in Haiti, Colombia, and Ecuador, with insufficient

recent data for Peru, Brazil, Guyana, Surinam, and many Caribbean

islands. Pinta is thought to be limited to Central America and northern South America, where it is found rarely and only in very remote

villages. Evidence of yaws-like and genital lesions, with treponemal

seroreactivity, has been found in several species of wild nonhuman

primates (NHPs) in sub-Saharan Africa and has led to speculation

that there may be an animal reservoir for yaws. Organisms very closely

related at the genomic level to known T. pallidum subspecies pertenue

isolates have been identified in lesions from affected NHPs, although

direct NHP-human transmission has not been confirmed.

■ MICROBIOLOGY

The etiologic agents of the endemic treponematoses are listed in

Table 183-1. These little-studied organisms are morphologically

identical to T. pallidum subspecies pallidum (the agent of venereal

syphilis), and no definitive antigenic differences among them have been

identified to date. A controversy has existed about whether the pathogenic

treponemes are truly separate organisms, as genome sequencing indicates

that yaws, bejel, and syphilis treponemes are 99.8% identical, and several

studies support the ability of these pathogens to exchange DNA between

subspecies. Three of the four etiologic agents are classified as subspecies

of T. pallidum; the fourth (T. carateum) remains a separate species simply

because no organisms have been available for genetic studies. Based on

analysis of a limited number of strains and clinical samples available for

genomic studies, molecular signatures—assessed using approaches ranging from restriction fragment length polymorphism to whole genome

sequencing—have been identified that can differentiate the T. pallidum

subspecies. Whether these minor genetic differences are related to distinct

clinical characteristics of these diseases has not been determined. Full

genome sequencing of a previously unclassified Treponema strain (Fribourg-Blanc), which was isolated from a baboon in 1966 and can cause

experimental infection in humans, shows a very high degree of homology

with available strains of T. pallidum subspecies pertenue. Recent genomic

analyses of additional samples from nonhuman primates indicate a very

close genetic relationship with known yaws isolates, but the importance of

the nonhuman primate reservoir for human infection is not yet known.

■ CLINICAL FEATURES

All of the treponemal infections, including syphilis, are chronic and are

characterized by defined disease stages, with a localized primary lesion,

disseminated secondary lesions, periods of latency, and possible late

lesions. Primary and secondary stages are more frequently overlapping

in yaws and endemic syphilis than in venereal syphilis, and the late manifestations of pinta are very mild relative to the destructive lesions of the

other treponematoses. The current preference is to divide the clinical

course of the endemic treponematoses into “early” and “late” stages.

Historically, the major clinical distinctions made between venereal syphilis and the nonvenereal infections are the apparent lack of

congenital transmission and of central nervous system (CNS) involvement in the nonvenereal infections. It is not known whether these

distinctions are entirely accurate. Because of the high degree of genetic

relatedness among the organisms, there is little biological reason to

think that T. pallidum subspecies endemicum and T. pallidum subspecies pertenue would be unable to cross the blood-brain barrier or to

invade the placenta. These organisms are like T. pallidum subspecies

pallidum in that they obviously disseminate from the site of initial

infection and can persist for decades. The lack of recognized congenital

infection may be due to the fact that childhood infections often reach

the latent stage (low bacterial load) before girls reach sexual maturity,

thus reducing the likelihood of fetal infection. Neurologic involvement

may go unrecognized because of the lack of trained medical personnel

in endemic regions, the delay of many years between infection and possible CNS manifestations, or a low rate of symptomatic CNS disease.

Some published evidence supports congenital transmission as well as

cardiovascular, ophthalmologic, and CNS involvement in yaws and

endemic syphilis. Although the reported studies have been small, have

failed to control for other causes of CNS abnormalities, and in some

instances have not included serologic confirmation, it may be erroneous to accept unquestioningly the frequently repeated belief that these

organisms fail to cause such manifestations.

Yaws Also known as pian, framboesia, or bouba, yaws is characterized by the development of one or several primary lesions (“mother

yaw”) followed by multiple disseminated skin lesions. All early skin

lesions are infectious and may persist for many months; cutaneous

relapses are common during the first 5 years. Late manifestations,

affecting ~10% of untreated persons, are destructive lesions of skin,

bone, and joints.

The infection is transmitted by direct contact with infectious

lesions, often during play or group sleeping, and may be enhanced by

disruption of the skin by insect bites or abrasions. While T. pallidum

subspecies pertenue DNA has been detected on flies and fomites from

endemic regions, there is not yet convincing evidence of insect or

fomite transmission of infection. After an average of 3–4 weeks, the

first lesion begins as a papule—usually on an extremity—and then

enlarges (particularly during moist warm weather) to become ulcerated (Fig 183-2A) or papillomatous (“raspberry-like”—thus the name

“framboesia”). Notably, recent data indicate that a large proportion

of ulcerative lesions in yaws-endemic regions contain Haemophilus

ducreyi, either as the sole etiologic agent or in combination with T.

pallidum subspecies pertenue. (H. ducreyi DNA has also been detected

on flies and fomites, as described above for T. pallidum subspecies

pertenue.) Regional lymphadenopathy develops, and the lesion usually

heals within 6 months; dissemination is thought to occur during the

early weeks of infection. A generalized secondary eruption, accompanied by generalized lymphadenopathy, appears either concurrent with

or after the primary lesion; may take several forms—macular, papular,

or papillomatous (Fig. 183-2B); and may become secondarily infected

with other bacteria, including H. ducreyi. Painful papillomatous lesions

on the soles of the feet result in a crablike gait (“crab yaws”), and periostitis (Fig. 183-2C) may result in nocturnal bone pain and polydactylitis

A B C D

FIGURE 183-2 Clinical manifestations of early yaws. A. Primary ulcer. B. Secondary papillomata. C. Periostitis, D. Polydactylitis. (Photos were taken during a yaws

elimination trial in Papua New Guinea and are published with permission from Dr. Oriol Mitjà.)

1416 PART 5 Infectious Diseases

(Fig. 183-2D). Late yaws is manifested by gummas of the skin and long

bones, hyperkeratoses of the palms and soles, osteitis and periostitis,

and hydrarthrosis. The late gummatous lesions are characteristically

extensive. Destruction of the nose, maxilla, palate, and pharynx is

termed gangosa and is similar to the destructive lesions seen in leprosy

and leishmaniasis.

Endemic Syphilis The early lesions of endemic syphilis (bejel, siti,

dichuchwa, njovera, skerljevo) are localized primarily to mucocutaneous

and mucosal surfaces. The infection is reportedly transmitted by direct

contact, by kissing, by premastication of food, or by sharing of drinking

and eating utensils. Recently, however, T. pallidum subspecies endemicum has been identified in genital lesions (assumed to be chancres) and

in secondary lesions in several settings (Paris, Cuba, Japan), suggesting

sexual transmission. The initial lesion, usually an intraoral papule, may

go unrecognized and is followed by mucous patches on the oral mucosa

(Fig. 183-3A) and mucocutaneous lesions resembling the condylomata

lata of secondary syphilis. This eruption may last for months or even

years, and treponemes can readily be demonstrated in early lesions.

Periostitis and regional lymphadenopathy are common. After a variable

period of latency, late manifestations may appear, including osseous

and cutaneous gummas. Destructive gummas, osteitis, and gangosa are

more common in endemic syphilis than in yaws.

Pinta Pinta (mal del pinto, carate, azul, purupuru) is the most

benign of the treponemal infections. This disease has three stages

that are characterized by marked changes in skin color (Fig. 183-3B),

but pinta does not appear to cause destructive lesions or to involve

tissues other than the skin. The initial papule is most often located

on the extremities or face and is pruritic. After 1 to many months of

infection, numerous disseminated secondary lesions (pintides) appear.

These lesions are initially red but become deeply pigmented, ultimately

turning a dark slate blue. The secondary lesions are infectious and

highly pruritic and may persist for years. Late pigmented lesions are

called dyschromic macules and contain treponemes. Over time, most

pigmented lesions show varying degrees of depigmentation, becoming

brown and eventually white and giving the skin a mottled appearance.

White achromic lesions are characteristic of the late stage.

■ DIAGNOSIS

Diagnosis of the endemic treponematoses is based on clinical manifestations and, when available, dark-field microscopy and serologic testing.

The same serologic tests that are used for venereal syphilis (Chap. 182)

become reactive during all treponemal infections. To date there is no

antibody test that can discriminate among the treponemal infections.

The nonvenereal treponemal infections should be considered in the

evaluation of a reactive syphilis serology in any person who has emigrated from an endemic area. Sensitive polymerase chain reaction

assays can be used to confirm treponemal infection and identify the

etiologic agent in research laboratories.

TREATMENT

Endemic Treponematoses

The current WHO-recommended therapy for patients and their contacts includes either azithromycin (30 mg/kg, up to a maximum of 2 g)

or benzathine penicillin G (1.2 million units IM for adults; 600,000

units for children <10 years old); these two drugs have been shown to

be equivalent in a recent study. The recommended dose of benzathine

penicillin G is half of that recommended for early venereal syphilis,

yet no controlled efficacy studies have been conducted. Evidence of

genetic resistance to penicillin is lacking, although relapsing lesions

have been reported after penicillin treatment in Papua New Guinea.

The efficacy of single-dose azithromycin provided the WHO’s

revitalized yaws eradication program with a much easier regimen

for use in mass treatment. Macrolide resistance has become common in circulating strains of T. pallidum subspecies pallidum in

many parts of the world, and analysis of yaws samples from Papua

New Guinea has yielded evidence of mutations for resistance to

macrolide antibiotics, including azithromycin, in a small number

of patients. Further surveillance is essential. Limited data suggest

the efficacy of tetracycline for treatment of yaws, but no data exist

for other endemic treponematoses. Based solely on experience

with venereal syphilis, it is thought that doxycycline or tetracycline

(at doses appropriate for syphilis; Chap. 182) are alternatives,

in addition to azithromycin, for patients allergic to penicillin. A

Jarisch-Herxheimer reaction (Chap. 182) may follow treatment of

endemic treponematoses. Nontreponemal serologic titers (in the

Venereal Disease Research Laboratory [VDRL] slide test or the

rapid plasma reagin [RPR] test) usually decline after effective therapy, but patients may not become seronegative.

■ CONTROL

Buoyed by the successful elimination of yaws in India and the availability of an inexpensive, single-dose oral drug for treatment, in 2012,

the WHO renewed its efforts to eradicate yaws globally by 2020. Based

on the results of several pilot programs of MDA, however, the target

year for eradication will likely be extended. Initial enthusiasm has been

dampened by several factors: (1) Pilot studies have indicated that a very

high level of MDA coverage must be achieved and that multiple rounds

of MDA are needed in the affected areas. Treatment must be followed

by careful case detection and targeted treatment of cases and contacts.

(2) Azithromycin resistance has emerged during the pilot study in

Papua New Guinea. Although subsequent treatment with benzathine

penicillin G was able to contain the spread of resistant organisms, such

evidence suggests that there may be only a short window of time during

which countries can successfully use azithromycin for yaws eradication. Antibiotic resistance is of particular concern if multiple rounds

of MDA are required. Further, given the ongoing campaigns against

trachoma using low-dose azithromycin MDA, often in populations

also at high risk for yaws, more widespread macrolide resistance seems

inevitable. (3) Lastly, the possible animal reservoir needs be evaluated,

particularly in Africa. Yaws elimination will require rapid implementation and scale-up of high-level drug coverage in endemic areas and

continued careful surveillance by local health centers will be essential

for success of this timely and important effort.

■ FURTHER READING

Giacani L, Lukehart SA: The endemic treponematoses. Clin Microbiol Rev 27:89, 2014.

Knauf S et al: Nonhuman primates across sub-Saharan Africa are

infected with the yaws bacterium Treponema pallidum subsp. pertenue. Emerg Microbes Infect 7:157, 2018.

Mitjà O et al: Re-emergence of yaws after a single mass azithromycin

treatment followed by targeted treatment: A longitudinal study. Lancet 391:1599, 2018.

A B

FIGURE 183-3 Clinical manifestations of endemic syphilis and pinta. A.

Mucous patches of early endemic syphilis. B. Pigmented macules of early pinta.

(Photos reprinted with permission from PL Perine et al: Handbook of Endemic

Treponematoses. Geneva, World Health Organization, Color Plates 54, 60; 1984.)

1417CHAPTER 184 Leptospirosis

Leptospirosis is a globally important zoonotic disease whose apparent

reemergence is illustrated by recent outbreaks on virtually all continents. The disease is caused by pathogenic Leptospira species and is

characterized by a broad spectrum of clinical manifestations, varying

from asymptomatic infection to fulminant, fatal disease. In its mild

form, leptospirosis may present as nonspecific symptoms such as fever,

headache, and myalgia. Severe leptospirosis, characterized by jaundice,

renal dysfunction, and hemorrhagic diathesis, is often referred to as

Weil’s syndrome. With or without jaundice, severe pulmonary hemorrhage is increasingly recognized as an important presentation of severe

disease.

■ ETIOLOGIC AGENT

Leptospira species are spirochetes belonging to the order Spirochaetales

and the family Leptospiraceae. Traditionally, the genus Leptospira comprised two species: the pathogenic L. interrogans and the free-living L.

biflexa, now designated L. interrogans sensu lato and L. biflexa sensu

lato, respectively. Sixty-four Leptospira species with pathogenic (17

species), intermediate (21 species), and nonpathogenic (26 species)

status have now been described on the basis of phylogenetic analyses

(Fig. 184-1). Genome sequences of all Leptospira species have been

published, and this will undoubtedly lead to a better understanding

of the pathogenesis of leptospirosis. However, classification based on

serologic differences better serves clinical, diagnostic, and epidemiologic purposes. Pathogenic Leptospira species are divided into serovars

according to their antigenic composition. There are more than 260

known pathogenic serovars, which are arranged in 26 serogroups.

Leptospires are coiled, thin, highly motile organisms that have

hooked ends and two periplasmic flagella, with polar extrusions from

the cytoplasmic membrane that are responsible for motility (Fig. 184-2).

These organisms are 6–20 μm long and ~0.1 μm in diameter; they stain

poorly but can be seen microscopically by dark-field examination and

after silver impregnation staining of tissues. Leptospires require special

media and conditions for growth; it may take weeks to months for

cultures to become positive.

■ EPIDEMIOLOGY

Leptospirosis has a worldwide distribution but occurs most commonly

in the tropics and subtropics because the climate and occasionally poor

hygienic conditions favor the pathogen’s survival and distribution. In

most countries, leptospirosis is an underappreciated problem. Most

cases occur in men, with a peak incidence during the summer and fall

in both the Northern and Southern Hemispheres and during the rainy

season in the tropics.

Reliable data on morbidity and mortality from leptospirosis have

gradually started to appear. Current information on global human

leptospirosis varies but indicates that ~1 million severe cases occur per

year, with a mean case–fatality rate of nearly 10%.

As a zoonosis, leptospirosis affects almost all mammalian species

and represents a significant veterinary burden. Rodents, especially

rats, are the most important reservoir, although other wild mammals

as well as domestic and farm animals may also harbor these microorganisms. Leptospires establish a symbiotic relationship with their host

and can persist in the urogenital tract for years. Some serovars are generally associated with particular animals—e.g., Icterohaemorrhagiae

and Copenhageni with rats, Grippotyphosa with voles, Hardjo with

cattle, Canicola with dogs, and Pomona with pigs—but may occur in

other animals as well.

Leptospirosis presents as both an endemic and an epidemic disease.

Transmission of leptospires may follow direct contact with urine,

blood, or tissue from an infected animal or, more commonly, exposure

to environmental contamination. The dogma that human-to-human

transmission is very rare is challenged by recent findings on household

184

clustering, asymptomatic renal colonization, and prolonged excretion

of leptospires. (Both of the latter features imply human infection

sources that are not recognized.) Because leptospires can survive in a

humid environment for many months, water is an important vehicle in

their transmission. Epidemics of leptospirosis are not well understood.

Leptospirosis

Jiři F. P. Wagenaar, Marga G.A. Goris

FIGURE 184-1 Differentiation of pathogenic, intermediate, and nonpathogenic

(saprophytic) Leptospira species by molecular phylogenetic analysis using core

genomes comparison (CgMLST). (Reproduced with permission from Dr. A Ahmed,

Leptospirosis Reference Center, Academic Medical Center, Medical Microbiology,

Amsterdam, The Netherlands.)