Chancroid

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D. Nate Michalak, B.A. Yazan Daaboul, M.D.

Chancroid is a sexually transmitted disease caused by Haemophilus ducreyi, a fastidious Gram-negative coccobacillus. There are 3 classes of this bacteria, 2 of which cause genital ulcer disease and 1 that may be the cause of cutaneous limb ulcers. Pathogenesis involves secretion of 2 virulence factors: fimbrialike proteins (Flp) responsible for adhesion and H. ducreyi cytolethal distending toxin (HdCDT) which cause DNA double-stranded breaks that lead to cell cycle arrest and apoptosis in epithelial cells, fibroblasts, and lymphocytes. Chancroid must be differentiated from other diseases that cause genital ulcers and lymphadenopathy including syphilis, herpes simplex, dermatologic aspects of Behçet’s disease, dermatologic manifestations of Lymphogranuloma venereum, donovanosis, and fixed drug eruption. The characteristic manifestation of chancroid is a painful, nonindurated ulcer. The ulcer looks similar to a syphilitic chancre. Approximately 50% of patients (predominantly in males) develop painful inguinal lymphadenopathy, known as buboes. Chancroid can be classified according to its clinical variants identified during a physical examination. Such variants include: dwarf, giant, follicular, transient, serpiginous, mixed, and phagedenic. Chancroid symptoms typically develop 4 to 10 days after infection. Lack of rapid and reliable laboratory tests make diagnosis and treatment decisions based on microbiologic findings difficult. Available laboratory tests involve acquiring a sample of ulcer exudate and include: Gram stain, culture, and multiplex Polymerase Chain Reaction (M-PCR). UNAIDS and the World Health Organization estimate the global incidence of chancroid to be approximately 6 million cases per year. Chancroid is a common cause of genital ulcer disease in developing countries, and is also prevalent in areas of crack cocaine use and prostitution in developed countries. The mainstay of therapy for chancroid is antimicrobial therapy with a single dose of Azithromycin or Ceftriaxone. Special considerations must be taken with patients who are HIV positive or with women who are pregnant or breastfeeding. Methods of primary prevention include: limiting the number of sexual partners, especially those who are prostitutes, using a barrier method of contraception, avoiding traveling to endemic areas of chancroid and prophylaxis with azithromycin. The goal of secondary prevention is to stop the spread of disease. Therefore infection individuals should abstain from sexual intercourse until symptoms reside.

Chancoid has been known to humans since the time of the ancient Greeks. Chancroid was first differentiated from syphilis by Leon Bassereau in 1852. Augusto Ducrey identified Haemophilus ducreyi as the causative organism for chancroid in the 1890s.

Chancroid may develop after transmission of Haemophilus ducreyi through breaks in human epithelium, most commonly through sexual contact. Fimbrialike proteins, Flp1, Flp2, Flp3, are suspected to form pili that assist in adhesion and microcolony formation. H. ducreyi induces secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), which causes inflammatory cells to form abscesses, leading to the formation of papules that may progress into pustules. H. ducreyi cytolethal distending toxin (HdCDT) is a major virulence factor that contributes to necrosis of myeloid and epithelial cells, causing ulceration. Associated conditions include: coinfection with Human Immunodeficiency Virus (HIV), since HIV and H. ducreyi facilitate each others infection, and coinfection with Treponema pallidum, since syphilis is shown to commonly occur with chancroid. On microscopic examination, a three-zone structure is typical.

Haemophilus ducreyi is a fastidious Gram-negative coccobacillus causing chancroid, a gential ulcer disease. A genetically distinct non-sexually transmitted strain may also cause cutaneous limb ulcers.

Chancroid may be classified according to its clinical variants identified during a physical examination. Such variants include: dwarf, giant, follicular, transient, serpiginous, mixed, and phagedenic.

Chancroid must be differentiated from other diseases that cause genital ulcers and lymphadenopathy including syphilis, herpes simplex, Behçet’s disease, lymphogranuloma venereum, donovanosis, and fixed drug eruption.

UNAIDS and the World Health Organization estimate the global incidence of chancroid to be approximately 6 million cases per year. Chancroid is uncommon in developed countries but may be prevalent in areas of crack cocaine use and prostitution. Chancroid is a common cause of genital ulcer disease in developing countries. Lack of diagnostic testing and difficulty of culturing H. ducreyi make true incidence difficult to determine, therefore potentially leading to under-diagnosis of chancroid in both developed and developing countries. The male to female ratio of patients with chancroid ranges from 3:1 in endemic areas to 25:1 during outbreak situations. Chancroid is common in areas with high rates of Human Immunodeficiency Virus (HIV) infection because HIV infection is a risk factor for acquiring H. ducreyi.

Risk factors for chancroid include: multiple sex partners, unprotected sexual intercourse, travel to endemic areas in developing countries, lack of circumcision in males, and infection with Human Immunodeficiency Virus (HIV).

Chancroid symptoms typically develop 4 to 10 days after infection. Initial indication of infection involves formation of erythematous papules which develop into pustules after several days. Approximately 1-2 weeks after pustule formation, the lesions may ulcerate. Patients typically develop 1 to 4 ulcers. Lymphadenopathy develops in approximately half of patients, predominantly in males, 1 to 2 weeks after appearance of the primary ulcer. In approximately 25% of patients with lymphadenopathy, lymph nodes may swell to form fluctuant buboes which may rupture and form giant ulcers. Prognosis is poor without treatment. Complications from chancroid include: superinfection of lesions, extensive adenitis, development of inguinal abscesses, and nonhealing ulcers.

The characteristic manifestation of chancroid is a painful, nonindurated ulcer. The ulcer may range from 1/8 to 2 inches in diameter and has irregular and sharp borders. Ulcers may discharge a grey/yellow exudate. Other symptoms include painful inguinal lymphadenitis (predominantly in males), known as buboes, and dysuria and dyspareunia in females. Probable cause of chancroid also includes negative tests for Treponema pallidum or syphilis and Herpes Simplex Virus (HSV).

Patients may present with erythematous papules, pustules, or ulcers depending the stage of the chancroid. Ulcers are soft with irregular but sharp margins, and looks similar to a syphilitic chancre. Males typically have 1 ulcer while females typically have multiple. The most common location in males is the foreskin (prepuce). The most common location in females in the labia majora. Approximately 50% of patients may present with swollen inguinal lymph nodes.

Lack of rapid and reliable laboratory tests make diagnosis and treatment decisions based on microbiologic findings difficult. Available laboratory tests involve acquiring a sample of ulcer exudate and include: Gram stain, culture, and multiplex Polymerase Chain Reaction (M-PCR).

There are no other diagnostic studies associated with chancroid.

The mainstay of therapy for chancroid is antimicrobial therapy. Azithromycin and Ceftriaxone are preferred because these agents offer the advantage of single dose therapy. Ceftriaxone is the drug of choice for pregnant women. Patients with HIV may require longer and repeated courses of therapy.

Since there is no vaccine for chancroid, methods of primary prevention include: limiting the number of sexual partners, especially those who are sex workers, using a barrier method of contraception, avoiding traveling to endemic areas of chancroid and prophylaxis with azithromycin. The goal of secondary prevention is to stop the spread of disease. Therefore infected individuals should abstain from sexual intercourse until symptoms reside.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Chancoid has been known to humans since the time of the ancient Greeks. Chancroid was first differentiated from syphilis by Leon Bassereau in 1852. Augusto Ducrey identified Haemophilus ducreyi as the causative organism for chancroid in the 1890s.

• Chancroid has been known to humans since the time of ancient Greeks.
• 1852 – Leon Bassereau distinguished chancroid from syphilis (i.e. soft chancre from hard chancre).
• 1890s – Augusto Ducrey identified the causative agent of chancroid to be the be the bacterium Haemophilus ducreyi.
• 1900 – Benzacon and colleagues isolated H. ducreyi.
• 1970s – Hammond and colleagues developed selective media for H. ducreyi.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Chancroid may develop after transmission of Haemophilus ducreyi through breaks in human epithelium, most commonly through sexual contact. Fimbrialike proteins, Flp1, Flp2, Flp3, are suspected to form pili that assist in adhesion and microcolony formation. H. ducreyi induces secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), which causes inflammatory cells to form abscesses, leading to the formation of papules that may progress into pustules. H. ducreyi cytolethal distending toxin (HdCDT) is a major virulence factor that contributes to necrosis of myeloid and epithelial cells, causing ulceration. Associated conditions include: coinfection with Human Immunodeficiency Virus (HIV), since HIV and H. ducreyi facilitate each others infection, and coinfection with Treponema pallidum, since syphilis is shown to commonly occur with chancroid. On microscopic examination, a three-zone structure is typical.

• Chancroid may develop after transmission of class I or class II of the bacterium Haemophilus ducreyi through sexual contact.^[1]
• A class I genetically distinct subclade strain of H. ducreyi may serve as the etiologic agent of non-sexually transmitted skin ulcers.^[2][3]
• H. ducreyi is an obligate human pathogen.

• H. ducreyi enters the skin through breaks in the epithelium.
• H. ducreyi produces 3 fimbrialike proteins (Flp), Flp1, Flp2, and Flp3 that help the bacteria adhere to subcutaneous epithelial cells and fibroblasts.^[4][5]
• H. ducreyi recruits inflammatory cells to the infected area and induces secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8) from epithelial cells. IL-8 induces neutrophils and macrophages to form abscesses, which may cause the presentation of erythematous papules which progress into intradermal pustules.^[5][6][7]
• Ulcers develop after secretion of the virulence factor H. ducreyi cytolethal distending toxin (HdCDT), which causes necrosis of myeloid and epithelial cells.^[7]
• It is presumed that iron plays an essential role in chancroid pathogenesis.^[5]
• H. ducreyi has the ability to avoid phagocytosis.^[7]

• H. Ducreyi produces and secretes 2 major virulence factors: fimbrialike protein (Flp) and H. ducreyi cytolethal distending toxin (HdCDT).

Flp:

• A 12.8 kb Flp operon regulates the expression of 3 fimbrialike proteins, Flp1, Flp2, and Flp3 in a type IV secretion system. These proteins have been demonstrated to play an important role in adherence to fibroblasts and pathogenesis of chancroid.^[4]

HdCDT:^[8][9]

• HdCDT is a tripartite protein complex consisting of CdtA, CdtB, and CdtC subunits, all of which are required to produce the active form of the toxin.
• HdCDT induces DNA double-stranded breaks that result in cellular responses similar to that of ionizing radiation.
• The effect of HdCDT is cell type-specific.
• In epithelial cells and fibroblasts, DNA damage activates ATM kinases, which activate RhoA GTPase leading to induction of actin stress fibers and cell distention.
• RhoA activation is not detected in lymphocytes.

• Other virulence factors that have been isolated include the following:^[10]

• Lipooligosaccharide
• Hemolysin
• Copper-zinc superoxide dismutase
• Outer membrane proteins (OMP) DsrA, PAL, and hemoglobin-binding OMP

• The tadA gene is though to be an important regulator for expression of the flp gene cluster.
• Flp1, Flp2, and Flp3 are suspected to play a role in forming pili on the cellular surface of H. ducreyi.
• In vitro, animal, and human models demonstrate that Flps are necessary for H. ducreyi to form microcolonies, which enables pathogenesis.^[4]

• H. ducreyi and Human Immunodeficiency Virus (HIV) facilitate each other’s transmission.^[11]

• HIV transmission may be enhanced by the following mechanisms:

• H. ducreyi’s ability to cause cell cycle arrest and apoptosis in lymphocytes.
• The chancroidal ulcer’s promotion of viral shedding into blood and semen.^[12]
• Establishment of an entry point for HIV via an ulcer.

• Presence of HIV may result in atypical manifestations of chancroid including: increased number of lesions, extragenital lesions, extended therapy.^[13][14]

• Coinfection with Treponema pallidum:

• Syphilis has been shown to commonly occur with chancroid^[15]

On microscopic pathology, the following characteristic features may be present in chancroid:^[5]

• Three-zone structure:

• Narrow superficial zone – contains necrotic tissue, erythrocytes, fibrin, and degenerated leucocytes
• Middle zone – contains edematous inflamed tissue
• Deep zone – contains plasma cells and lymphocytes

• Granulomatous base
• Purulent exudates

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Haemophilus ducreyi is a fastidious gram-negative coccobacillus causing chancroid, a gential ulcer disease. A genetically distinct non-sexually transmitted strain may also cause cutaneous limb ulcers.

• Haemophilus ducreyi, also known as H. ducreyi, is a fastidious, Gram-negative, coccobacillus that causes the sexually transmitted disease chancroid, characterized as a genital ulcer disease.^[1]
• H. ducreyi can range from short to relatively long bacilli with rounded ends, and typically grow in chains, known as a “school of fish.”
• H. ducreyi was originally classified as a Haemophilus species due to its growth requirements and antigentic relatedness to other species in the genus. However, rRNA analysis indicates H. ducreyi is not a true Haemophilus but is more closely related to the Pasteurellaceae family.^[2]
• Due to its complex growth requirements H. ducreyi is difficult to culture.^[1]
• The genome of H. ducreyi is a single 1.7-Mb chromosome.

• H. ducreyi is an obligate human pathogen.
• H. ducreyi is typically transmitted through sexual intercourse but certain strains my also cause non-sexually transmitted cutaneous limb ulcers (CLU).
• H. ducreyi causes chancroid by secreting several virulence factors, the most well-characterized being fimbrialike protein (Flp) and H. ducreyi cytolethal distending toxin (HdCDT). Three Flps, Flp1, Flp2, and Flp3, are suspected to form pili that enable adhesion to fibroblasts and epithelial cells.^[3] Active HdCDT is composed of 3 subunits and is homologous to DNase1, causing DNA double stranded breaks, which results in cell cycle arrest and apoptosis human epithelial cells, lymphocytes and fibroblasts.^[4]

• Multi Locus Sequence Analysis (MLSA) of several virulence factors and housekeeping genes has identified class I and class II strains of H. ducreyi causing chancroid, a sexually transmitted genital ulcer disease.^[5]
• Such analysis has identified a class I genetically distinct subclade strain of H. ducreyi that may cause non-sexually transmitted (CLU).^[5]

• 
  Direct smear microscopic exam revealed the presence of Haemophilus ducreyi indicative of a chancroid infection. From Public Health Image Library (PHIL). ^[6]
• 
  Photomicrograph of a rabbit blood culture showing Haemophilus ducreyi bacteria using Gram-stain technique. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria, which had been extracted from a culture. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria, which had been extracted from a culture. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria (1200x mag). From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria arranged in parallel rows. From Public Health Image Library (PHIL). ^[6]
• 
  Gram-negative Haemophilus ducreyi bacteria arranged in parallel rows. From Public Health Image Library (PHIL). ^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Chancroid may be classified according to its clinical variants identified during a physical examination. Such variants include: dwarf, giant, follicular, transient, serpiginous, mixed, and phagedenic.

The table below outlines the variations of chancroid clinical presentation:^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Chancroid must be differentiated from other diseases that cause genital ulcers and lymphadenopathy including syphilis, herpes simplex, Behçet’s disease, lymphogranuloma venereum, donovanosis, and fixed drug eruption.

Chancroid must be differentiated from other diseases that cause genital ulcers and lymphadenopathy:

• Syphilis
• Herpes simplex
• Behçet’s disease
• Lymphogranuloma venereum
• Donovanosis
• Fixed drug eruption
• Psoriasis

Syphilitic chancres most closely resemble chancroid lesions. A comparison is found below:^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

UNAIDS and the World Health Organization estimate the global incidence of chancroid to be approximately 6 million cases per year. Chancroid is uncommon in developed countries but may be prevalent in areas of crack cocaine use and prostitution. Chancroid is a common cause of genital ulcer disease in developing countries. Lack of diagnostic testing and difficulty of culturing H. ducreyi make true incidence difficult to determine, therefore potentially leading to under-diagnosis of chancroid in both developed and developing countries. The male to female ratio of patients with chancroid ranges from 3:1 in endemic areas to 25:1 during outbreak situations. Chancroid is common in areas with high rates of Human Immunodeficiency Virus (HIV) infection because HIV infection is a risk factor for acquiring H. ducreyi.

• UNAIDS and the World Health Organization estimate the global incidence of chancroid to be approximately 6 million cases per year.^[1]
• A true incidence is difficult to determine due to lack of readily available diagnostic testing. H. ducreyi is difficult to culture so chancroid may be under-diagnosed.^[2]
• Since 1987, reported cases of chancroid declined steadily until 2001. Since then, the number of cases reported has fluctuated, but still appearing to decline overall.^[2]

• Chancroid may develop in individuals of any age but is typically found in sexually active individuals with a mean patient age of 30 years.

• The male-to-female ratio of patients with chancroid ranges from 3:1 in endemic areas to 25:1 during outbreak situations.^[1]
• Female sex workers with either symptomatic chancroid or as asymptomatic carriers serve as a reservoir for H. ducreyi.^[1]

• Although race is not a risk factor, chancroid is seen more commonly in African Americans and Hispanics in the United States.^[3]

• Chancroid is uncommon in the United States and other developed countries, but can been present in endemic areas associated with the use of crack cocaine and prostitution.
• In the United States, the Centers for Disease Control and Prevention reported 6 cases of chancroid in 2014.^[4]
• The majority of cases in developed countries occur in individuals who have returned from chancroid-endemic areas in the world.

• Chancroid is a major cause of genital ulcer disease in Africa, southeast Asia and parts of Latin America.^[5]
• Acquiring epidemiological data is more difficult in developing countries due to greater lack of resources to test for H. ducreyi.
• Chancroid is common in countries that have high rates of Human Immunodeficiency Virus (HIV) infection, because HIV facilitates acquisition of H. ducreyi and vice versa.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Risk factors for chancroid include: multiple sex partners, unprotected sexual intercourse, travel to endemic areas in developing countries, lack of circumcision in males, and infection with Human Immunodeficiency Virus (HIV).

• Multiple sex partners
• Unprotected sexual intercourse
• Travel to endemic areas in Africa, southeast Asia and parts of Latin America^[1]
• Living in areas with high crack cocaine use and prostitution^[2]
• Lack of circumcision in males^[3]
• Human Immunodeficiency Virus (HIV) infection^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Nate Michalak, B.A.; Serge Korjian M.D.

Chancroid symptoms typically develop 4 to 10 days after infection. Initial indication of infection involves formation of erythematous papules which develop into pustules after several days. Approximately 1-2 weeks after pustule formation, the lesions may ulcerate. Patients typically develop 1 to 4 ulcers. Lymphadenopathy develops in approximately half of patients, predominantly in males, 1 to 2 weeks after appearance of the primary ulcer. In approximately 25% of patients with lymphadenopathy, lymph nodes may swell to form fluctuant buboes which may rupture and form giant ulcers. Prognosis is poor without treatment. Complications from chancroid include: superinfection of lesions, extensive adenitis, development of inguinal abscesses, and nonhealing ulcers.

• The incubation period for H. ducreyi is typically 4 to 10 days, after which erythematous papules arise.
• Approximately 2 to 3 days after symptom onset, papules evolve into pustules.^[1]
• Pustules may resolve spontaneously or ulcerate in approximately 1-2 weeks since formation. Patients typically develop between 1 to 4 ulcers.
• Inguinal lymphadenitis develops in approximately half of patients, usually unilaterally and more commonly in males than females, 1 to 2 weeks after appearance of primary ulcer.^[2]
• In approximately 25% of patients with lymphadenitis, lymph nodes may swell to form fluctuant buboes. Untreated buboes may rupture, discharge exudate, and ulcerate.^[2]

• Superinfection of lesions by other anaerobic bacteria such as Fusobacterium and Bacteroides^[3][4]
• Phimosis in men^[2]
• Extensive adenitis in the absence of treatment
• Development of inguinal abscesses which may rupture to form a draining sinus or giant ulcer
• Nonhealing ulcers

• Chancroid is not lethal.
• Prognosis is poor without treatment. Indications of poor prognosis include:

Nonhealing ulcers

Lymphadenopathy, especially with the formation and/or rupture of buboes

Superinfection of lesions (phagedenic chancroid)

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