Tropical STIs (excluding LGV)

TROPICAL STIS

Tropical STIs (excluding LGV)

What’s new?

Nigel O’Farrell C

C

Abstract Chancroid and donovanosis are causes of genital ulceration found mainly in tropical areas. Chancroid ulcers are painful with a ragged edge and whitish base. Donovanosis ulcers are classically beefy-red and bleed to the touch. Chancroid was identified early on as a risk factor for HIV transmission amongst heterosexuals and this led to a renewed interest in genital ulcers. The incidence of both conditions has recently decreased significantly, while the incidence of genital herpes has increased. Improved control of all causes of genital ulceration should be a priority in countries where HIV and genital ulcers are prevalent. The nonvenereal treponemal diseases include yaws, endemic syphilis and pinta. All three have similarities with venereal syphilis. A global eradication programme in the 1950s and 1960s was successful at the time but there appears to have been a recent resurgence of yaws and endemic syphilis in some isolated communities.

The global burden of chancroid and donovanosis continues to decrease Despite eradication efforts, the endemic treponematoses are still prevalent in some countries. Further efforts are required to eliminate these curable and preventable neglected tropical diseases

and glans in men, and the labia minora and fourchette in women. Ulcers of the vaginal wall and cervix may occur. Extragenital lesions are rare. In men, lesions are associated with absence of circumcision. Painful unilateral or bilateral enlargement of the inguinal lymph glands may progress to bubo formation and require aspiration. Sequelae include phimosis and phagedenic ulceration causing tissue destruction following secondary infection. Buboes that rupture may take a long time to heal.

Keywords bejel; chancroid; donovanosis; genital ulcers; non-venereal treponematoses; pinta; yaws

Diagnosis Nucleic acid amplification tests (NAATs) are now the most sensitive method for diagnosing H. ducreyi, but their availability remains limited. Primers have been developed to amplify sequences from the H. ducreyi 16S ribosomal RNA gene, the rrs (16S)errl (23S) ribosomal intergenic spacer region and the groEL gene. Antigen detection using fluorescent techniques may be useful, but is expensive. Serological tests are unable to distinguish between old and new infections. Culture was the usual method of diagnosis of chancroid, but has been overtaken by NAATs. Culture media must be fresh and may need fine adjustment, depending on the characteristics of local strains of H. ducreyi. Two culture media are required to achieve reasonable sensitivity. Media used include gonococcal agar base and Muller Hinton, with various additives and supplements. Thioglycolate haemin-based transport medium may allow storage of viable organisms at 4  C for 24 h or possibly longer. Most strains are beta-lactamase producers. Gram-staining of material from ulcers may show characteristic Gram-negative coccobacilli in a ‘school of fish’ or ‘railroad track’ appearance. Histology shows superficial necrosis with large numbers of neutrophils, endothelial proliferation, and infiltration with plasma cells, lymphocytes and fibroblasts.

Chancroid Chancroid is an STI causing painful genital sores. Inguinal lymphadenopathy is common. The causative organism is a Gram-negative bacterium, Haemophilus ducreyi. Epidemiology Chancroid now has limited endemicity in some developing countries. The highest prevalences are reported in southern Africa. Small outbreaks have been reported in the USA. Chancroid is associated with sex work, poor standards of genital hygiene and low socioeconomic status. Asymptomatic carriage of H. ducreyi has been reported in female sex-workers. Pathogenesis Abrasions are necessary for H. ducreyi to penetrate the epidermis and cause infection. The organisms are found in macrophages and neutrophils, and free in the interstitium. Clinical features The incubation period of chancroid is usually 4e7 days. Lesions usually start as a tender papule that develops into a pustule and then an ulcer. Vesicles are not seen. The classical ulcer has a ragged, undermined edge with a grey or yellow base that bleeds when touched. Lesions may be single or multiple (Figure 1). The usual sites of infection are the prepuce, coronal sulcus, frenulum

Differential diagnoses Differential diagnoses include genital herpes, syphilis, donovanosis and lymphogranuloma venereum (LGV). Mixed infections with other causes of genital ulceration should always be suspected.

Nigel O’Farrell MSc MD FRCP is Consultant in HIV/Genitourinary Medicine at Ealing Hospital, London, UK. He qualified from the University of Birmingham, and trained in HIV/genitourinary medicine in London and in Durban, South Africa. Competing interests: none declared.

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Management Treatment of chancroid comprises one of the following:  ciprofloxacin, 500 mg orally 12 hourly for 3 days

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TROPICAL STIS

Figure 1 Multiple ulcers of chancroid on the coronal sulcus. (By courtesy of O P Arya.) Figure 2 Typical lesions of subpreputial ulcerogranulomatous donovanosis.

 erythromycin, 500 mg orally 8 hourly for 7 days (in pregnant women)  azithromycin, 1 g orally as a single dose  ceftriaxone, 250 mg i.m. as a single dose Co-trimoxazole is no longer recommended. Many H. ducreyi isolates have plasmid-mediated resistance to ampicillin, chloramphenicol, tetracycline and sulphonamides. Healing of ulcers is usually achieved after 7e14 days. Longer courses of treatment are sometimes required in HIV-positive patients, who should be followed up until healing is complete.

Clinical features The classical lesion (ulcerogranulomatous, Figure 2) is a beefy, red ulcer that bleeds readily to the touch. Other types include hypertrophic, necrotic and sclerotic (uncommon) variants. The genitals are affected in 90% of patients and the inguinal region in 10%. The common sites of infection are the prepuce, coronal sulcus, frenulum and glans in men, and the labia minora

Prevention Sexual contacts of index cases should be offered epidemiological treatment. Uncircumcised men should ensure adequate genital hygiene.

Donovanosis (granuloma inguinale) Donovanosis is a chronic, progressive bacterial infection that usually involves the genital region. The causative organism has been reclassified as Klebsiella granulomatis comb nov based on phylogenetic analysis,1 though there is debate about this; some authorities consider the original nomenclature, Calymmatobacterium granulomatis, to be more appropriate.2 Epidemiology Donovanosis is endemic in Papua New Guinea, parts of southern Africa and India, and Brazil. A programme targeting aboriginal communities has succeeded in almost eliminating the condition in Australia.3 Donovanosis is associated with poor hygiene, and is more common in lower socioeconomic groups and in men compared with women. Donovanosis is a risk factor for HIV infection.4 Pathogenesis Lesions start as a papule or a subcutaneous nodule that later ulcerates after trauma. The incubation period is about 50 days.

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Figure 3 Tissue smear stained using a rapid Giemsa (RapiDiff ) technique, showing numerous Donovan bodies in monocytes.

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Management of genital ulcers in resource-poor settings Patient complains of genital sore or ulcer

Examine

Depending on counselling capabilities, HIV testing should be offered to all patients

No Sore/ulcer/vesicle present? Yes Vesicles or small ulcers with history of recurrent small ulcers/vesicles

Yes

Educate, counsel, condom promotion

Management of herpes, educate, counsel, consider treatment for syphilis and chancroid with single-dose therapy if no history of ulcers

No Treat for syphilis and chancroid (depending on local disease prevalence), educate, counsel, condom promotion, partner management, advise to return in 7 days

Clinical deterioration or no improvement after 7 days? Yes Consider HIV infection

Figure 4

and fourchette in women. In men, lesions are associated with absence of circumcision. Extragenital lesions may involve the lip, gums, cheek, palate, pharynx, larynx and chest, and the number of case reports of these is increasing. Haematogenous spread to liver and bone is reported. Lymphadenitis is uncommon. During pregnancy, lesions tend to develop more quickly and respond more slowly to treatment. Complications include carcinoma, pseudo-elephantiasis and stenosis of the urethra, vagina or anus.

Culture of the organism has been reported in peripheral blood monocytes and in Hep-2 cells. Polymerase chain reaction analysis using a colorimetric detection system can now be used in routine diagnostic laboratories. A genital ulcer multiplex PCR that includes C. granulomatis has been developed.5 Serological tests have poor specificity. Differential diagnoses Differential diagnoses include syphilis, chancroid, LGV, genital herpes, neoplasm and amoebiasis. Mixed infections are common.

Diagnosis A clinical diagnosis of donovanosis made by an experienced practitioner is usually of high positive predictive value. The diagnosis is confirmed by microscopic identification of Donovan bodies (Figure 3) in tissue smears. Preparation of a good-quality smear is important. A swab should be rolled firmly over an ulcer previously cleaned with a dry swab to remove debris. Smears can be examined in a clinic setting by direct microscopy using a rapid Giemsa or Wright’s stain. Alternatively, a piece of granulation tissue crushed and spread between two slides can be used. Donovan bodies can be seen in large, mononuclear cells as Gram-negative, intracytoplasmic cysts filled with deeply staining bodies that may have a safety-pin appearance. Histological changes include chronic inflammation with infiltration of plasma cells and neutrophils. Epithelial changes include ulceration, micro-abscesses and elongation of the rete ridges.

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Management Treatment of donovanosis requires one of the following:  azithromycin, 1 g orally on day 1 then 500 mg daily for 7 days or 1 g weekly for 4 weeks. If available, this is the drug of choice.  co-trimoxazole, 960 mg orally 12 hourly for 14 days  doxycycline, 100 mg orally 12 hourly for 14 days  erythromycin, 500 mg orally 6 hourly for 14 days (in pregnant women)  tetracycline, 500 mg orally 6 hourly for 14 days. Ceftriaxone, chloramphenicol and norfloxacin are also effective. Gentamicin can be added for slow responders. Patients treated for 14 days should be followed-up until the lesions have healed completely. Those treated with azithromycin probably do not need such rigorous follow-up.

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Geographical distribution of the endemic treponematoses in the early 1990sa

Pinta Yaws Endemic syphilis

a

Source: WHO, with permission.

Figure 5

Syndromic management

Control and prevention It is important to use an adequate dose and duration of antibiotics when treating donovanosis. Epidemiological treatment of sexual partners is recommended, and advice should be given about how to improve genital hygiene.

Syndromic management involves the identification of a syndrome (e.g. genital ulceration, inguinal bubo) comprising symptoms and signs that are associated with several infections. A clinical flow chart (Figure 4) is used to facilitate step-by-step management. Treatment is usually prescribed for the most likely causes of the syndrome. Syndromic management is suitable for resource-poor settings and enables treatment to be given at the first attendance without the need for specialized skills or expensive laboratory tests. The degree of over-treatment resulting from this approach to the management of genital ulcers is generally regarded as acceptable. It should be noted that genital herpes has emerged as a significant cause of genital ulceration in areas with a high prevalence of HIV. Treatment for donovanosis and LGV should be given in areas where these conditions are prevalent. Inguinal buboes should be managed by treating for chancroid and LGV with ciprofloxacin, 500 mg orally 12 hourly for 3 days and doxycycline, 100 mg orally 12 hourly for 14e21 days. Syndromic management should also include the basic components of comprehensive case management of STIs, including:     

Figure 6 Early yaws. Papillomata at various stages of development.

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health education promotion of condom use contact tracing reinforcing the importance of compliance with treatment voluntary testing and counselling for HIV.

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TROPICAL STIS

Endemic non-venereal treponematoses

used to be endemic in the Middle East, Bosnia and Bulgaria and is still found in the Sahelian region of Africa. Primary lesions are rare but involve the skin. Secondary lesions including condylomata lata may involve the mucous membranes and moist areas of the body and painful bone lesions occur. Late-stage disease is characterized by severe tissue destruction involving skin, bone and cartilage.

Yaws, pinta and endemic syphilis are non-venereal treponemal infections with many similarities to sexually transmitted syphilis (Figure 5). Immune responses are similar, making the interpretation of serological tests difficult. There is no congenital transmission. Yaws Yaws (also known as framboesia, pian and buba) is caused by Treponema pallidum subspecies pertenue. The organism has been cultured in rabbits but not on artificial culture media.

Management WHO recommends benzathine penicillin 1.2 MU i.m. for the endemic treponematoses for patients and their contacts and half this dose for children under 10 years. Reduced effectiveness of penicillin has been reported in yaws.7 Tetracycline, doxycycline and erythromycin are alternatives in patients allergic to penicillin. A

Epidemiology Transmission occurs through direct contact with infected yaws lesions usually in children. Yaws has occurred in tropical climates in some parts of Africa, South America, the Caribbean, and SouthEast Asia. Nowadays a few foci are found in South-East Asia (Indonesia, Timor-Leste, Papua New Guinea) and Africa (Ghana, Republic of the Congo).6 In Europe most patients with yaws have inactive disease and are identified during screening. In the UK most patients with a history of yaws are originally from the West Indies. Extensive use of arsenicals and then penicillin mass treatment campaigns in the 1950s and 1960s led to a dramatic decline in yaws in most regions.

REFERENCES 1 Carter J, Bowden FJ, Bastian I, Myers GM, Sriprakash KS, Kemp DJ. Phylogenetic evidence for reclassification of Calymmatobacterium granulomatis as Klebsiella granulomatis comb nov. Int J Syst Bacteriol 1999; 49: 1695e700. 2 Kharsany AB, Hoosen AA, Kiepala P, Kirby R, Sturm AW. Phylogenetic analysis of Calymmatobacterium granulomatis based on 16S sequences. J Med Microbiol 1999; 48: 841e7. 3 Bowden FJ. Donovanosis in Australia: going, going.. Sex Transm Infect 2005; 81: 365e6. 4 O’Farrell N, Windsor I, Becker P. Risk factors for HIV-1 in heterosexual attenders at a sexually transmitted diseases clinic in Durban, South Africa. S Afr Med J 1991; 80: 17e20. 5 Mackay IM, Harnett G, Jeoffreys N, et al. Detection and discrimination of herpes simplex viruses, Haemophilus ducreyi, Treponema pallidum, and Calymmatobacterium (Klebsiella) granulomatis from genital ulcers. Clin Infect Dis 2006; 42: 1431e8. 6 Rinaldi A. Yaws: a second (and maybe last?) chance for eradication. PLoS Negl Trop Dis 2008; 2: e275. 7 Backhouse JL, Hudson BJ, Hamilton PA, Nesteroff SI. Failure of penicillin treatment of yaws on Karkar Island, Papua New Guinea. Am J Trop Med Hyg 1998; 59: 388e92.

Clinical features These can be divided into early-stage disease, involving skin and bone, and late-stage disease. The first sign of infection is usually a small papule that progresses over a few weeks to a proliferative papilloma. Ulceration may occur leaving a scar. Secondary lesions may appear usually after 1e2 years, characterized by large raised papillomas and papules that are highly infectious (Figure 6). Lesions may also be found on the skin, in the mouth and on the soles of the feet. Relapses may occur during the first 5 years of infection. Bone pain may result from osteoperiostitis involving the long bones and the bones of the hands and feet. Hypertrophic osteitis of the nasal process of the maxilla (goundou) may occur. Late-stage disease occurs in about 10% of individuals 5e10 years after the initial infection, and involves the skin, subcutaneous tissues, bones and joints. Tissue destruction and ulceration are common. A not uncommon diagnostic dilemma in the UK is whether or not to do a lumbar puncture to exclude neurosyphilis in patients with dementia that give a history of yaws as a child in the Caribbean. Patients with positive syphilis tests that include a non-specific test should probably have a lumbar puncture.

FURTHER READING Antal GM, Lukehart SA, Meheus AZ. The endemic treponematoses e review. Microbes Infect 2002; 4: 83e94. Asiedu K, Amouzou B, Dhariwal A, et al. Yaws eradication: past efforts and future perspectives. Bull World Health Organ 2008; 86: 49e50. Clinical Effectiveness Group (British Association for Sexual Health and HIV). National guideline for the management of chancroid, www. bashh.org/documents/85/85.pdf; 2007. Meheus A, Ndowa FJ. Endemic treponematoses. In: Holmes KK, Sparling PF, Stamm WE, et al., eds. Sexually transmitted diseases. McGraw-Hill, 2008: 685e8. O’Farrell N. Donovanosis. In: Holmes KK, Sparling PF, Stamm WE, et al., eds. Sexually transmitted diseases. McGraw-Hill, 2008: 701e8. Rajam RV, Rangiah PN. Donovanosis, granuloma inguinale, granuloma venereum. Geneva: WHO, 1954. Spinola SM. Chancroid and Haemophilus ducreyi. In: Holmes KK, Sparling PF, Stamm WE, et al., eds. Sexually transmitted diseases. McGraw-Hill, 2008: 689e99. World Health Organisation. Yaws: a forgotten disease, www.who.int/ neglected_diseases/diseases/yaws/en/index; 2007.

Pinta (also known as azul, carate and mal de pinto) Pinta is caused by T. carateum. Transmission occurs through direct skin contact usually in childhood. The condition is confined to natives in remote areas in Central and South America. Early lesions are confined to the skin and start as itchy red papules. Secondary lesions develop months later involving the skin with papule formation. Late disease is characterized by pigmentary changes and marked pruritus. Endemic syphilis Endemic syphilis (also known as bejel, dichuchwa and sklerjevo) is caused by T. pallidum subspecies endemicum. The condition

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