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Epidemiology of Haemophilus ducreyi infections.

The global epidemiology of Haemophilus ducreyi infections is poorly documented because of difficulties in confirming microbiological diagnoses. We evaluated published data on the proportion of genital and nongenital skin ulcers caused by H. ducreyi before and after introduction of syndromic management for genital ulcer disease (GUD). Before 2000, the proportion of GUD caused by H. ducreyi ranged from 0.0% to 69.0% (35 studies in 25 countries). After 2000, the proportion ranged from 0.0% to 15.0% (14 studies in 13 countries). In contrast, H. ducreyi has been recently identified as a causative agent of skin ulcers in children in the tropical regions; proportions ranged from 9.0% to 60.0% (6 studies in 4 countries). We conclude that, although there has been a sustained reduction in the proportion of GUD caused by H. ducreyi, this bacterium is increasingly recognized as a major cause of nongenital cutaneous ulcers.

Haemophilus ducreyi, a fastidious gram-negative bacterium, is the causative agent of chancroid, a genital ulcer disease (GUD). The organism is usually spread during sexual intercourse through microabrasions, and the disease usually manifests as multiple painful superficial ulcers associated with inguinal lymphadenitis (1). As a result of the painful nature of the lesions, patients usually seek immediate treatment, and asymptomatic carriage is therefore uncommon (2). In addition to causing GUD, H. ducreyi has been found in several recent studies to be a major cause of chronic skin ulceration in children from developing countries (3-5).

The global epidemiology of chancroid is poorly documented, and it is not included in World Health Organization estimates of the global incidence of curable sexually transmitted infections (STIs). There are some key challenges in interpreting data on the epidemiology of H. ducreyi as a causative agent of GUD. First, genital herpes cases are easily misdiagnosed as chancroid on clinical examination. Thus, reports based only on clinical diagnosis can be erroneous. Second, laboratory culture is technically difficult, and the highly sensitive and specific nucleic acid amplification tests, such as PCR, are rarely available outside national reference laboratories or specialized STI research settings, which makes it difficult to confirm clinical diagnoses.

Determination of the true global incidence of chancroid is made more difficult by widespread adoption of syndromic management for bacterial GUD (i.e., treatment with antimicrobial drugs effective against syphilis and chancroid) without microbiological confirmation in many countries. Therefore, countries often report only the total number of GUD cases. In addition, identification of GUD etiology is rarely conducted in resource-poor countries to validate syndromic management for which chancroid could also be common.

Earlier studies of tropical skin ulcers did not generally test for H. ducreyi, with the exception of a small number of case reports. There are major limitations in describing the prevalence of causative agents in tropical skin lesions that typically occur in children in rural areas where there is no access to laboratory facilities. Pathogens such as Fusobacterium fusiforme, Staphylococcus aureus, and Streptococcus pyogenes have been reported from Gram staining of exudative material collected from tropical ulcers (6). However, cultures or PCR testing for definitive identification of fastidious pathogens involved has not been traditionally conducted. The purpose of this study was to improve our understanding of the epidemiology of H. ducreyi infection through a systematic review of published data on the proportion of genital and skin ulcers caused by this bacterium.

Methods

Search Strategy and Selection Criteria

A systematic review was conducted to identify all relevant studies that examined the etiology of GUD and nongenital skin ulcers involving H. ducreyi. We searched the National Library of Medicine through PubMed for "H. ducreyi," "chancroid," "genital ulcer," OR "skin ulceration" AND "proportion" OR "prevalence." The search was limited to studies published during January 1, 1980-December 31, 2014. In addition, we searched references of identified articles and other databases for other articles, and we reviewed abstracts, titles, and selected studies potentially containing information on chancroid epidemiology. We contacted researchers who were working with H. ducreyi to identify unpublished literature for inclusion. No language restrictions were set for searches.

The decision tree for inclusion or exclusion of articles is shown in Figure 1. We included studies if the proportion of etiologic agents in genital ulcers and nongenital skin ulcers, including H. ducreyi, was confirmed by laboratory techniques. Clinical diagnosis of chancroid is often based on the appearance of the ulcer, which is characteristically painful, purulent, and deep with ragged, undermined edges (Figure 2). However, because the appearance of these ulcers is similar to ulcers caused by other bacteria, clinical diagnosis can be nonspecific or insensitive and often requires laboratory confirmation (1). In addition, microscopy identification of typical morphologic features and serologic detection lack sensitivity and specificity (7,8). Thus, we only considered the following diagnostic methods as providing acceptable evidence of H. ducreyi infection: 1) isolation and identification by culture; or 2) PCR/real-time PCR.

Data Extraction and Synthesis

For all qualifying studies, extracted data included study country, year of study, diagnostic test used for confirmation, total number of H. ducreyi--positive cases, and sample size. Descriptive analyses of extracted data were conducted, and the number of H. ducreyi---confirmed cases was divided by the total number of cases to calculate the proportion of cases caused by H. ducreyi. Studies qualifying for data extraction were grouped into 2 categories: studies conducted before 2000 and studies after 2000. This date separates studies before and after widespread implementation of syndromic management of GUD. Study sites were also plotted by geographic region. No quantitative metaanalysis was undertaken.

Results

We identified 277 records in which we found 46 articles describing 49 studies on GUD that met our inclusion criteria (Tables 1, 2; online Technical Appendix, http://wwwnc.cdc.gov/EID/artide/21/1/15-0425-TechappLpdf). All identified studies were based on cohorts of patients attending STI clinics, including 3 studies that enrolled only commercial sex workers. The age group for all cases was adults >18 years of age, except for 3 studies in Zambia, South Africa, and China, which included patients >16 years of age, and 1 study in Madagascar, which included patients >14 years of age. A total of 9 published studies and 2 unpublished reports that described nongenital skin ulcers caused by H. ducreyi were also included in our systematic review.

Laboratory confirmation of chancroid by PCR or culture was reported in 33 (67%) and 16 (32%) of the 49 studies, respectively. Of 16 studies that used culture, 7 (43%) used Mueller-Hinton agar with a nutritional supplement (e.g., Iso-Vitalex; Becton Dickinson, Franklin Lakes, NJ, USA), 1% used hemoglobin, and 5 (31%) used chocolate agar-based media; the remaining studies used other culture media. Five (31%) of 16 studies incubated agar plates at low temperatures (33[degrees]C-35[degrees]C), and 2 (12%) incubated plates at 36[degrees]C. Remaining articles did not specify incubating temperature.

Different PCR primer targets were used to amplify DNA sequences, including the 16S rRNA gene, the groEL gene, and the hemolysin gene. In addition to herpes simplex virus (HSV) PCR, 23 studies used a multiplex PCR that could simultaneously detect the 3 major causes of GUD (H. ducreyi, Treponema pallidum, and HSV types 1 and 2) (9). Studies encompassed 33 countries: 17 in Africa, 4 in Southeast Asia, 3 in Europe, 2 in the Middle East, 3 in South America, and 2 in the Caribbean, 1 in the United States, and 1 in Australia.

Incidence of Chancroid

Of 49 studies on chancroid analyzed, 35 were published during 1980-1999 (Table 1) and 14 during 2000-2014 (Table 2). In general, data showed a clear decrease in the proportion of chancroid during 1980-2014 in all areas analyzed (Figure 3).

During 1980-1999, the proportion of genital ulcers caused by H. ducreyi in these studies ranged from 0.0% in Thailand and China to 68.9% in South Africa (Table 1). Eleven (31.4%) studies reported high proportions (>40%) of cases of infection with H. ducreyi. All of these studies were conducted in countries in Africa (Cote d'Ivoire, Gambia, Kenya, Lesotho, Senegal, South Africa, and Swaziland). Slightly lower proportions (20%-40% of cases) were observed in 15 (42%) studies: 10 in countries in Africa, 2 in the United States during localized outbreaks, 1 in Jamaica, 1 in the Dominican Republic, and 1 in India.

Only a few countries reported low proportions (<10%) of genital ulcers infected with H. ducreyi, including Singapore (8.3%), Peru (5%), Greece (4.6%), the Netherlands (0.9%), United States (3.1%), and Saudi Arabia (2.1%). The study in Saudi Arabia was conducted during 1995-1999; a total of 27,490 patients were examined for STIs. Chancroid was diagnosed by culture and was reported as the least common STI during this survey. The only studies that reported no cases of chancroid were conducted in Thailand in 1996 and China in 1999; both studies used multiplex PCR for detection of GUD cases.

During 2000-2014, the proportion of H. ducreyi infections was low (<10%) in all studies analyzed, except for 1 study in Malawi (15%) (Table 2). Studies in 5 countries (Kenya, Namibia, Zambia, Brazil, and Australia) did not report any cases of infection with H. ducreyi. Other studies reporting proportions of infections <10% were conducted in Botswana, Mozambique, South Africa, Uganda, Pakistan, and France. No reports were found for studies in North America, Southeast Asia, or the Caribbean.

Nongenital Skin Infections with H. ducreyi

During 1988-2010, several case reports described 4 children and 4 adults with nonsexually transmitted infections with H. ducreyi that manifested as lower leg lesions but no genital lesions. The reported case-patients were travelers who had been to Fiji (reference 55 in online Technical Appendix), Samoa (reference 56 in online Technical Appendix), Vanuatu (reference 57 in online Technical Appendix), or Papua New Guinea (reference 58 in online Technical Appendix) (Table 3). Outside the south Pacific region, a 5-year-old refugee from Sudan who had lower leg ulceration was also given a diagnosis of infection with H. ducreyi (reference 59 in online Technical Appendix).

A cohort study conducted in Papua New Guinea in 2014 showed evidence that H. ducreyi is a major cause of chronic skin ulceration; H. ducreyi DNA was identified by PCR in 60.0% of skin lesions in children (3). Similar studies in other areas reported laboratory-confirmed skin ulcers in children caused by H. ducreyi in Papua New Guinea (reference 60 in online Technical Appendix), Solomon Islands (4), Vanuatu (C.Y. Chen, pers. comm.), and Ghana (5) (Table 3).

Discussion

Our review confirmed 2 major findings. First, reduction in the proportion of genital ulcers caused by H. ducreyi has been sustained for the past decade and a half. Second, there is increasing evidence that H. ducreyi is a common and newly recognized causative agent of chronic skin ulceration in children from developing countries.

In the 1990s, the global prevalence of chancroid was estimated to be 7 million (11). Chancroid was one of the most prevalent GUDs, particularly in resource-poor countries in Africa, Asia, Latin America, and the Caribbean (1; reference 45 in online Technical Appendix). Recommendations to introduce syndromic management for treatment of GUD caused by bacteria were published by the World Health Organization in 1991 and fully implemented by 2000 (reference 61 in online Technical Appendix). Since that time, global incidence of GUDs, particularly chancroid, has decreased substantially, and genital herpes viruses (HSV-1 and HSV-2) have become the predominant cause of GUD (reference 47 in online Technical Appendix). Currently in Europe and the United States, chancroid is restricted to rare sporadic cases. Transmission of H. ducreyi remains ongoing in only a few countries that have limited access to health services (2; reference 60 in online Technical Appendix).

Our data show marked decreases in the proportion of GUD caused by H. ducreyi in several countries. Spinola et al. reported similar conclusions obtained from 25 PCR-based studies (reference 62 in online Technical Appendix). For example, in Botswana (10), Kenya, (14), and South Africa (23), the proportion of GUD caused by H. ducreyi decreased from 25%-69% to negligible (0.0%-1.2%) levels (10; references 42, 46 in online Technical Appendix). Studies in Zambia (reference 50 in online Technical Appendix), Namibia (reference 45 in online Technical Appendix), Brazil (reference 51 in online Technical Appendix), and China (30) did not report any cases of chancroid during 2000-2009. A study in Thailand reported elimination of chancroid by introduction of a condom use program in the 1990s (reference 63 in online Technical Appendix). Similar decreases have been reported from Cambodia and Sri Lanka, with rapid elimination of chancroid and congenital syphilis in most settings (reference 63 in online Technical Appendix). However, these findings should be interpreted with caution because, given the short duration of infectivity, even a low prevalence of H. ducreyi in a population with GUD implies that a reservoir of infected persons with a high rate of sex partners is present.

Recent research has identified H. ducreyi as a previously unrecognized cause of nongenital skin ulcers in tropical areas. In 2013-2015, six studies in Papua New Guinea (3; reference 60 in online Technical Appendix), the Solomon Islands (4), Vanuatu (C.Y. Chen et al., pers. comm.), and Ghana (5; C.Y. Chen et al., pers. comm.) showed that a high proportion of laboratory-confirmed skin ulcers were caused by H. ducreyi. Nearly half of the 690 enrolled patients with ulcers in these 6 studies had H. ducreyi detectable by PCR, whereas other bacteria, such as T. pallidum subsp. pertenue, the causative agent of yaws, were detected in 25% of patients.

These cases of infection with H. ducreyi confirmed by molecular analysis suggest that clinicians should be more aware of this newly recognized bacterium in skin ulcers of persons in tropical areas. In the context of new efforts to eradicate yaws, mass treatment with azithromycin in Papua New Guinea reduced the absolute prevalence of ulcers not caused by yaws, which were mainly caused by H. ducreyi, from 2.7% to 0.6% (prevalence ratio 0.23, 95% CI 0.18-0.29) at 12 months after treatment (6). However, persistence of H. ducreyi at low levels after mass treatment in Papua New Guinea (3) and Ghana (5) suggest that 1 round of mass treatment might not be successful in eradicating H. ducreyi skin ulcers.

Our review has several limitations. First, the increase in HSV-related GUD as a result of immunosuppression by HIV infection would result in a decrease in the proportion of chancroid among all GUD case-patients. Second, the lack of sequential studies performed in similar clinical settings at multiple time points precludes an optimal interpretation of the apparent decrease. Third, results might be affected by poor-quality data from many developing countries and might be inflated by publication bias. Fourth, PCR is more sensitive than culture. Therefore, increasing diagnostic yield might have partially masked the scale of the decrease in H. ducreyi as a cause of GUD.

In summary, we observed a quantitative and sustained reduction in cases of chancroid as a result of antimicrobial drug syndromic management and major social changes. In addition, data from several research groups indicate that H. ducreyi can cause nongenital skin lesions in persons residing in different regions. Further studies of this newly described pathogen skin disease association are required, and appropriate policies are needed that include the routine practice of managing tropical skin ulcers.

M.M. is supported by a Wellcome Trust Clinical Research Fellowship (WT102807).

Ms. Gonzalez-Beiras is a predoctoral fellow at Instituto de Higiene e Medicina Tropical, Lisbon, Portugal. Her primary research interests are strategies for elimination of neglected tropical diseases.

Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medscape, LLC and Emerging Infectious Diseases. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)[TM]. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/eid; (4) view/print certificate.

Release date: December 17, 2015; Expiration date: December 17, 2016 Learning Objectives

Upon completion of this activity, participants will be able to:

* Distinguish the clinical presentation of genital ulcer disease with Haemophilus ducreyi

* Assess the means used to diagnose H. ducreyi infection

* Identify global areas disproportionately affected by H. ducreyi-related genital ulcer disease

* Assess worldwide trends in the epidemiology of infection with H. ducreyi

CME Editor

Thomas J. Gryczan, MS, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Thomas J. Gryczan, MS, has disclosed no relevant financial relationships.

CME Author

Charles P. Vega, MD, Clinical Professor of Family Medicine, University of California, Irvine. Disclosure: Charles P. Vega, MD, has disclosed the following financial relationships: served as an advisor or consultant for Lundbeck, Inc.; McNeil Pharmaceuticals; Takeda Pharmaceuticals North America, Inc.

Authors

Disclosures: Camila Gonzalez-Beiras, BSc, MSC; Michael Marks, MBBS; Cheng-Yen Chen, PhD; Sally Roberts, MBChB, FRACP, FRCPA; and Oriol Mitja, MD, PhD, have disclosed no relevant financial relationships.

Camila Gonzalez-Beiras, Michael Marks, Cheng Y. Chen, Sally Roberts, Oriol Mitja

Author affiliations: Nova University of Lisbon, Lisbon, Portugal (C. Gonzalez-Beiras); Barcelona Institute for Global Health, Barcelona, Spain (C. Gonzalez-Beiras, O. Mitja); London School of Hygiene and Tropical Medicine, London, UK (M. Marks); Hospital for Tropical Diseases, London (M. Marks); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (C.Y. Chen); Auckland District Health Board, Auckland, New Zealand (S. Roberts); Lihir Medical Centre, Lihir Island, Papua New Guinea (O. Mitja)

DOI: http://dx.doi.org/10.3201/eid2201.150425

CME Questions

1. You are seeing a 21-year-old woman who recently emigrated from rural South Africa. She complains of genital ulcers. You consider whether Haemophilus ducreyi may be responsible for her symptoms. Which of the following statements regarding genital ulcer disease and H. ducreyi is most accurate?

A. H. ducreyi is a gram-positive organism

B. H. ducreyi promotes painless genital ulcers

C. Many patients with genital ulcer disease stemming from H. ducreyi have inguinal lymphadenitis

D. Most carriers of H. ducreyi are asymptomatic and are unaware of their infection

2. You perform an evaluation for genital ulcer disease in this patient. Which of the following statements regarding the diagnosis of H. ducreyi infection in the current study is most accurate?

A. Most cases of H. ducreyi were confirmed by PCR

B. All culture studies used low temperatures to grow H. ducreyi

C. All PCR studies used the hemolysin gene as a target

D. Multiplex studies that can detect H. ducreyi, Treponema pallidum, and herpes viruses were not used

3. Which of the following continents featured nations with the highest proportions of cases of H. ducreyi from 1980-1999?

A. South America

B. Australia and the South Pacific

C. Africa

D. Asia

4. Which of the following statements regarding trends in the diagnosis of chancroid in the current study is most accurate?

A. No study found a proportion of H. ducreyi genital ulcers above 10%

B. No African country reported rates of H. ducreyi below 10% between 2000 and 2014

C. More recent studies found that H. ducreyi was an emerging cause of chronic skin ulceration

D. The proportion of H. ducreyi found in genital ulcer disease remained relatively stable between 1980 and 2014

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(46.) Kyriakis KP, Hadjivassiliou M, Paparizos VA, Flemetakis A, Stavrianeas N, Katsambas A. Incidence determinants of gonorrhea, chlamydial genital infection, syphilis and chancroid in attendees at a sexually transmitted disease clinic in Athens, Greece. Int J Dermatol. 2003;42:876-81. http://dx.doi.org/10.1046/j.1365-4362.2003.01737.x

Address for correspondence: Oriol Mitja, Department of Community Health, Lihir Medical Center Post Office Box 34, Lihir Island, New Ireland Province, Lihir 00, Papua New Guinea; email: oriol.mitja@isglobal.org

Table 1. Characteristics of 35 studies of genital
ulcers caused by Haemophilus ducreyi, 1980-1999 *

                                                Year of
Area, reference ([dagger])       Country         study


Africa
  Paz-Bailey et al. (16)         Botswana         1993
  Steen (17)                  Cote d'Ivoire       1996
  Mabey et al. (18)               Gambia          1987
  Hawkes et al. (19)              Gambia          1995
  Nsanze et al. (20)              Kenya           1980
  Kaul et al. (21)                Kenya           1997
  Morse et al. (22)              Lesotho          1994
  Harms et al. (23)             Madagascar        1992
  Behets et al. (24)            Madagascar        1997
  Behets et al. (25)              Malawi          1995
  Hoyo et al. (26)                Malawi          1999
  Bogaerts et al. (27)            Rwanda          1992
  Totten et al. (28)             Senegal          1992
  Crewe-Brown et al. (29)      South Africa       1981
  Dangor et al. (30)           South Africa       1989
  Chen et al. (31)             South Africa       1994
  Lai et al. (32)              South Africa       1994
                               South Africa       1998
  Meheus et al. (33)            Swaziland         1979
  Ahmed et al. (34)              Tanzania         1999
  Le Bacq et al. (35)            Zimbabwe         1991

Asia
  Wang et al. (36)                China           1999
  Risbud et al. (37)              India           1994
  Rajan et al. (38)             Singapore         1983
  Beyrer et al. (15)             Thailand         1996

North America
  Dillon et al. (39)          United States       1990
  Mertz et al. (40)           United States       1995
  Mertz et al. (41)           United States       1996

South America
  Sanchez et al. (42)              Peru           1995

Caribbean
  Sanchez et al. (42)           Dominican         1996
                                 Republic
  Behets et al. (43)             Jamaica          1996
  Bauwens et al. (44)            Bahamas          1992

Middle East
  Madani et al. (45)           Saudi Arabia       1999

Europe
  Kyriakis et al. (46)            Greece          1996
  Bruisten et al. (47)       The Netherlands      1996

                             Diagnostic   No. patients
Area, reference ([dagger])     method       with GUD

Africa
  Paz-Bailey et al. (16)      Culture         108
  Steen (17)                    PCR            NA
  Mabey et al. (18)           Culture         104
  Hawkes et al. (19)           M-PCR           18
  Nsanze et al. (20)          Culture          97
  Kaul et al. (21)            Culture         189
  Morse et al. (22)            M-PCR          105
  Harms et al. (23)           Culture          12
  Behets et al. (24)           M-PCR          196
  Behets et al. (25)           M-PCR          778
  Hoyo et al. (26)             M-PCR          137
  Bogaerts et al. (27)        Culture         395
  Totten et al. (28)            PCR            39
  Crewe-Brown et al. (29)     Culture         100
  Dangor et al. (30)          Culture         240
  Chen et al. (31)             M-PCR          538
  Lai et al. (32)              M-PCR          160
                               M-PCR           94
  Meheus et al. (33)          Culture         155
  Ahmed et al. (34)             PCR           102
  Le Bacq et al. (35)         Culture          90

Asia
  Wang et al. (36)             M-PCR           96
  Risbud et al. (37)           M-PCR          302
  Rajan et al. (38)           Culture         670
  Beyrer et al. (15)           M-PCR           38

North America
  Dillon et al. (39)          Culture          82
  Mertz et al. (40)            M-PCR          143
  Mertz et al. (41)            M-PCR          516

South America
  Sanchez et al. (42)          M-PCR           61

Caribbean
  Sanchez et al. (42)          M-PCR           81

  Behets et al. (43)           M-PCR          304
  Bauwens et al. (44)           PCR            47

Middle East
  Madani et al. (45)          Culture        3,679

Europe
  Kyriakis et al. (46)        Culture         695
  Bruisten et al. (47)         M-PCR          368

                             No. cases
                             H. ducreyi
Area, reference ([dagger])   infection        % (95% CI)

Africa
  Paz-Bailey et al. (16)         27        25.0 (17.7-33.9)
  Steen (17)                     NA               47
  Mabey et al. (18)              54        51.9 (42.4-61.2)
  Hawkes et al. (19)             8         44.4 (24.5-66.2)
  Nsanze et al. (20)             60        61.8 (51.9-70.9)
  Kaul et al. (21)               54        28.5 (22.6-35.3)
  Morse et al. (22)              55        53.3 (43.8-62.6)
  Harms et al. (23)              61        19.6 (11.6-31.3)
  Behets et al. (24)             64        32.6 (26.4-39.5)
  Behets et al. (25)            204        26.2 (23.2-29.4)
  Hoyo et al. (26)               41        29.0 (22.8-38.0)
  Bogaerts et al. (27)          115        29.1 (24.8-33.7)
  Totten et al. (28)             22        56.4 (40.9-70.7)
  Crewe-Brown et al. (29)        45         45 (35.5-54.7)
  Dangor et al. (30)            164        68.3 (62.2-73.8)
  Chen et al. (31)              171        31.7 (27.9-35.8)
  Lai et al. (32)               232        68.9 (62.7-74.5)
                                186        50.5 (43.4-57.6)
  Meheus et al. (33)             68        43.8 (36.3-51.7)
  Ahmed et al. (34)              12        11.7 (6.8-19.4)
  Le Bacq et al. (35)            22        24.4 (16.7-34.2)

Asia
  Wang et al. (36)               0          0.0 (0.0-3.8)
  Risbud et al. (37)             84        27.8 (23.0-33.1)
  Rajan et al. (38)              56          83 (64-107)
  Beyrer et al. (15)             0          0.0 (0.0-9.1)

North America
  Dillon et al. (39)             27        32.9 (23.7-43.6)
  Mertz et al. (40)              56       39.1 (231.5-47.3)
  Mertz et al. (41)              16         3.1 (1.9-4.9)

South America
  Sanchez et al. (42)            3          4.9 (1.6-13.4)

Caribbean
  Sanchez et al. (42)            21        25.9 (17.6-36.4)

  Behets et al. (43)             72        236 (19.2-28.7)
  Bauwens et al. (44)            7          148 (7.4-27.6)

Middle East
  Madani et al. (45)             78         2.1 (1.7-2.5)

Europe
  Kyriakis et al. (46)           32         4.6 (3.2-6.4)
  Bruisten et al. (47)           3          0.8 (0.2-2.3)

* GUD, genital ulcer disease; NA, not available;
M-PCR, multiplex PCR.

([dagger]) References 41-47 provided in
the online Technical Appendix
(http://wwwnc.cdc.gov/EID/article/22/1/15-0425-Techapp1.pdf).

Table 2. Characteristics of 14 studies of genital ulcers
caused by Haemophilus ducreyi, 2001-2014 *

Area, reference                              Year of
([dagger])                      Country       study

Africa
  Paz-Bailey et al. (16)        Botswana      2002
  Mehta et al. (48)              Kenya        2007
  Phiri et al. (49)              Malawi       2006
  Zimba et al. (50)            Mozambique     2005
  Tobias et al. (51)            Namibia       2007
  O'Farrell et al. (52)       South Africa    2004
  Lewis et al. (53)           South Africa    2006
  Nilsen et al. (54)            Tanzania      2001
  Suntoke et al. (55)            Uganda       2006
  Makasa et al. (56)             Zambia       2010

South America
  Gomes Naveca et al. (57)       Brazil       2009

Middle East
  Maan et al. (58)              Pakistan      2009

Europe
  Hope-Rapp et al. (59)          France       2005

Oceania
  Mackay et al. (60)           Australia      2002

Area, reference               Diagnostic   No. patients
([dagger])                      method       with GUD

Africa
  Paz-Bailey et al. (16)         PCR            137
  Mehta et al. (48)             M-PCR           59
  Phiri et al. (49)             M-PCR           398
  Zimba et al. (50)              PCR            79
  Tobias et al. (51)             PCR            199
  O'Farrell et al. (52)         M-PCR           162
  Lewis et al. (53)             M-PCR           613
  Nilsen et al. (54)             PCR            232
  Suntoke et al. (55)           M-PCR           100
  Makasa et al. (56)             PCR            200

South America
  Gomes Naveca et al. (57)       PCR            434

Middle East
  Maan et al. (58)             Culture          521

Europe
  Hope-Rapp et al. (59)        Culture          278

Oceania
  Mackay et al. (60)            M-PCR           64

Area, reference                 No. cases H.
([dagger])                    ducreyi infection      % (95% CI)

Africa
  Paz-Bailey et al. (16)              1            0.7 (0.1-4.0)
  Mehta et al. (48)                   0            0.0 (0.0-6.1)
  Phiri et al. (49)                  60           15.0 (11.8-18.9)
  Zimba et al. (50)                   3            3.8 (1.3-10.9)
  Tobias et al. (51)                  0            0.0 (0.0-1.8)
  O'Farrell et al. (52)               2            1.2 (0.3-4.6)
  Lewis et al. (53)                  10            1.6 (0.9-2.9)
  Nilsen et al. (54)                 12            5.1 (2.9-8.8)
  Suntoke et al. (55)                 2            2.0 (0.5-7.0)
  Makasa et al. (56)                  0             0 (0.0-1.8)

South America
  Gomes Naveca et al. (57)            0             0 (0.0-0.8)

Middle East
  Maan et al. (58)                   20            3.8 (2.5-5.8)

Europe
  Hope-Rapp et al. (59)               8            2.8 (1.4-5.5)

Oceania
  Mackay et al. (60)                  0            0.0 (0.0-5.6)

* GUD, genital ulcer disease; M-PCR, multiplex PCR.

([dagger]) References 48-60 provided
in the online Technical Appendix
(http://wwwnc.cdc.gov/EID/article/22/1/15-0425-Techapp1.pdf).

Table 3. Characteristics of 11 studies on skin ulcers
caused by Haemophilus ducreyi, 1988-2014 *

                                                Year
Reference                      Country        of study

Marckmann et al. (7)        Fiji Islands        1988
Ussher et al. (8)               Samoa           2005
McBride et al. (9)             Vanuatu          2007
Peel et al. (10)          Vanuatu and Papua     2010
                             New Guinea
Humphrey et al. (11)            Sudan           2007
Mitja et al. (3)          Papua New Guinea      2013
Mitja et al. (6)          Papua New Guinea      2014
Marks et al. (4)           Solomon Islands      2013
Chen et al. ([dagger])         Vanuatu          2013
Chen et al. ([dagger])          Ghana           2013
Ghinai et al. (5)               Ghana           2014

                                        No. patients
                          Diagnostic      with skin
Reference                   method         ulcers

Marckmann et al. (7)        Culture         1 man
Ussher et al. (8)             PCR        3 girls <10
                                          y of age
McBride et al. (9)            PCR          1 woman
Peel et al. (10)              PCR           2 men
Humphrey et al. (11)          PCR           1 boy
Mitja et al. (3)              PCR            90
Mitja et al. (6)              PCR            114
Marks et al. (4)              PCR            41
Chen et al. ([dagger])        PCR            176
Chen et al. ([dagger])        PCR            179
Ghinai et al. (5)             PCR            90

                          No cases H.
                            ducreyi
Reference                  infection        % (95% CI)

Marckmann et al. (7)           1                NA
Ussher et al. (8)              3                NA
McBride et al. (9)             1                NA
Peel et al. (10)               2                NA
Humphrey et al. (11)           1                NA
Mitja et al. (3)               54        60.0 (49.6-69.5)
Mitja et al. (6)               60        60.1 (54.3-65.5)
Marks et al. (4)               13        31.7 (19.5-46.9)
Chen et al. ([dagger])         68        38.6 (31.7-46.0)
Chen et al. ([dagger])         49        27.3 (21.3-34.3)
Ghinai et al. (5)              8          8.8 (4.5-16.5)

* NA, not applicable.

([dagger]) Pers. comm.
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Title Annotation:SYNOPSIS
Author:Gonzalez-Beiras, Camila; Marks, Michael; Chen, Cheng Y.; Roberts, Sally; Mitja, Oriol
Publication:Emerging Infectious Diseases
Geographic Code:6SOUT
Date:Jan 1, 2016
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