Affection of the oral mucosa at diphtheria, tuberculosis, syphilis, gonorrhea.
Diphtheria is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is characterized by sore throat, low fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity. A milder form of diphtheria can be restricted to the skin. Less common consequences include myocarditis (about 20% of cases) and peripheral neuropathy (about 10% of cases).
Diphtheria is a contagious disease spread by direct physical contact or breathing the aerosolized secretions of infected individuals. Historically quite common, diphtheria has largely been eradicated in industrialized nations through widespread vaccination.
Transmition
Diphtheria is transmitted to close contacts via airborne respiratory droplets or by direct contact with nasopharyngeal secretions or skin lesions. Rarely, it can be spread by objects contaminated by an infected person. Overcrowding and poor living conditions can further contribute to the spread of diphtheria.
Humans are the only known reservoir of Corynebacterium diphtheriae. Infected individuals may develop symptoms of diphtheria, or they may become carriers of the bacteria with no symptoms (asymptomatic carriers). These asymptomatic carriers can serve as reservoirs for active infection and may transmit the disease to other individuals.
Signs and symptoms
The symptoms of respiratory diphtheria usually begin after a two- to five-day incubation period. Symptoms of respiratory diphtheria may include the following:
1. sore throat,
2. fever,
3. malaise,
4. hoarseness,
5. difficulty swallowing, or
6. difficulty breathing.
With the progression of respiratory diphtheria, the infected individual may also develop an adherent gray membrane (pseudomembrane) forming over the lining tissues of the tonsils and/or nasopharynx. Individuals with severe disease may also develop neck swelling and enlarged neck lymph nodes, leading to a “bull-neck” appearance. Extension of the pseudomembrane into the larynx and trachea can lead to obstruction of the airway with subsequent suffocation and death.
The dissemination of diphtheria toxin can also lead to systemic disease, causing complications such as inflammation of the heart (myocarditis) and neurologic problems such as paralysis of the soft palate, vision problems, and muscle weakness.
Cutaneous diphtheria is characterized by a non-healing skin ulcer covered by a gray-brown membrane. It is typically a localized infection that is rarely associated with systemic complications.
Mechanism
Diphtheria toxin is produced by C. diphtheriae only when infected with a bacteriophage that integrates the toxin-encoding genetic elements into the bacteria.
Diphtheria toxin is a single, 60,000 molecular weight protein composed of two peptide chains, fragment A and fragment B, held together by a disulfide bond. Fragment B is a recognition subunit that gains the toxin entry into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor (HB-EGF) on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, the toxin is split by a trypsin-like protease into its individual A and B fragments. The acidity of the endosome causes fragment B to create pores in the endosome membrane, thereby catalyzing the release of fragment A into the cell’s cytoplasm.
Fragment A inhibits the synthesis of new proteins in the affected cell. It does this by catalyzing ADP-ribosylation of elongation factor EF-2—a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis.
ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction’s end-products, and high amounts will drive the reaction in the opposite direction.
Diagnosis
The current definition of diphtheria is based on both laboratory and clinical criteria.
Laboratory criteria
Isolation of Corynebacterium diphtheriae from a gram stain or throat culture from a clinical specimen, or
Histopathologic diagnosis of diphtheria by a stain called “Albert’s Stain”.
Clinical criteria
Upper respiratory tract illness with sore throat
Low-grade fever (>102 °F (39 °C) is rare)
An adherent, dense, grey pseudomembrane covering the posterior aspect of the pharynx. In severe cases, it can extend to cover the entire tracheobronchial tree.
Case classification
Probable: a clinically compatible case that is not laboratory-confirmed and is not epidemiologically linked to a laboratory-confirmed case
Confirmed: a clinically compatible case that is either laboratory-confirmed or epidemiologically linked to a laboratory-confirmed case
Empirical treatment should generally be started in a patient in whom suspicion of diphtheria is high.
Treatment
The disease may remain manageable, but in more severe cases, lymph nodes in the neck may swell, and breathing and swallowing will be more difficult. People in this stage should seek immediate medical attention, as obstruction in the throat may require intubation or a tracheotomy. Abnormal cardiac rhythms can occur early in the course of the illness or weeks later, and can lead to heart failure. Diphtheria can also cause paralysis in the eye, neck, throat, or respiratory muscles. Patients with severe cases will be put in a hospital intensive care unit and be given a diphtheria antitoxin. Since antitoxin does not neutralize toxin that is already bound to tissues, delaying its administration is associated with an increase in mortality risk. Therefore, the decision to administer diphtheria antitoxin is based on clinical diagnosis, and should not await laboratory confirmation.
Antibiotics have not been demonstrated to affect healing of local infection in diphtheria patients treated with antitoxin. Antibiotics are used in patients or carriers to eradicate C. diphtheriae and prevent its transmission to others.
– Metronidazole
– Erythromycin (orally or by injection) for 14 days (40 mg/kg per day with a maximum of 2 g/d), or
– Procaine penicillin G given intramuscularly for 14 days (300,000 U/d for patients weighing <10 kg and 600,000 U/d for those weighing >10 kg). Patients with allergies to penicillin G or erythromycin can use rifampin or clindamycin.
In cases that progress beyond a throat infection, diphtheria toxin spreads through the blood and can lead to potentially life-threatening complications that affect other organs, such as the heart and kidneys. The toxin can cause damage to the heart that affects its ability to pump blood or the kidneys’ ability to clear wastes. It can also cause nerve damage, eventually leading to paralysis. About 40% to 50% of those left untreated can die.
Epidemiology
Diphtheria is fatal in between 5% and 10% of cases. In children under five years and adults over 40 years, the fatality rate may be as much as 20%. As of 2010 it caused about 2,900 deaths down from 6,300 in 1990.
Outbreaks, though very rare, still occur worldwide, including in developed nations, such as Germany and Canada. After the breakup of the former Soviet Union in the late 1980s, vaccination rates in its constituent countries fell so low that there was an explosion of diphtheria cases. In 1991, there were 2,000 cases of diphtheria in the USSR. By 1998, according to Red Cross estimates, there were as many as 200,000 cases in the Commonwealth of Independent States, with 5,000 deaths. This was so great an increase that diphtheria was cited in the Guinness Book of World Records as “most resurgent disease”
Tuberculosis
Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people who have an active TB infection cough, sneeze, or otherwise transmit respiratory fluids through the air. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected.
The classic symptoms of active TB infection are a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss (the latter giving rise to the formerly prevalent term “consumption”). Infection of other organs causes a wide range of symptoms. Diagnosis of active TB relies on radiology (commonly chest X-rays), as well as microscopic examination and microbiological culture of body fluids. Diagnosis of latent TB relies on the tuberculin skin test (TST) and/or blood tests. Treatment is difficult and requires administration of multiple antibiotics over a long period of time. Social contacts are also screened and treated if necessary. Antibiotic resistance is a growing problem in multiple drug-resistant tuberculosis (MDR-TB) infections. Prevention relies on screening programs and vaccination with the bacillus Calmette–Guérin vaccine.
One third of the world’s population is thought to have been infected with M. tuberculosis, with new infections occurring in about 1% of the population each year. In 2007, there were an estimated 13.7 million chronic active cases globally, while in 2010, there were an estimated 8.8 millioew cases and 1.5 million associated deaths, mostly occurring in developing countries. The absolute number of tuberculosis cases has been decreasing since 2006, and new cases have decreased since 2002. The distribution of tuberculosis is not uniform across the globe; about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5–10% of the United States population tests positive. More people in the developing world contract tuberculosis because of compromised immunity, largely due to high rates of HIV infection and the corresponding development of AIDS.
Signs and symptoms
The main symptoms of variants and stages of tuberculosis are given, with many symptoms overlapping with other variants, while others are more (but not entirely) specific for certain variants. Multiple variants may be present simultaneously.
About 5–10% of those without HIV, infected with tuberculosis, develop active disease during their lifetimes. In contrast, 30% of those coinfected with HIV develop active disease. Tuberculosis may infect any part of the body, but most commonly occurs in the lungs (known as pulmonary tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the lungs. Extrapulmonary TB may coexist with pulmonary TB as well. General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue, and significant finger clubbing may also occur.
Pulmonary
If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases). Symptoms may include chest pain and a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e. they remain “asymptomatic”). Occasionally, people may cough up blood in small amounts, and in very rare cases, the infection may erode into the pulmonary artery, resulting in massive bleeding (Rasmussen’s aneurysm). Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs. The upper lung lobes are more frequently affected by tuberculosis than the lower ones. The reason for this difference is not entirely clear. It may be due either to better air flow, or to poor lymph drainage within the upper lungs.
Extrapulmonary
In 15–20% of active cases, the infection spreads outside the respiratory organs, causing other kinds of TB. These are collectively denoted as “extrapulmonary tuberculosis”. Extrapulmonary TB occurs more commonly in immunosuppressed persons and young children. In those with HIV, this occurs in more than 50% of cases. Notable extrapulmonary infection sites include the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints (in Pott’s disease of the spine), among others. When it spreads to the bones, it is also known as “osseous tuberculosis” a form of osteomyelitis. Sometimes, bursting of a tubercular abscess through skin results in tuberculous ulcer. An ulcer originating from nearby infected lymph nodes is painless, slowly enlarging and has an appearance of “wash leather”. A potentially more serious, widespread form of TB is called “disseminated” TB, commonly known as miliary tuberculosis. Miliary TB makes up about 10% of extrapulmonary cases.
Causes
Mycobacteria
The main cause of TB is Mycobacterium tuberculosis, a small, aerobic, nonmotile bacillus. The high lipid content of this pathogen accounts for many of its unique clinical characteristics. It divides every 16 to 20 hours, which is an extremely slow rate compared with other bacteria, which usually divide in less than an hour. Mycobacteria have an outer membrane lipid bilayer. If a Gram stain is performed, MTB either stains very weakly “Gram-positive” or does not retain dye as a result of the high lipid and mycolic acid content of its cell wall. MTB can withstand weak disinfectants and survive in a dry state for weeks. Iature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in the laboratory.
Using histological stains on expectorated samples from phlegm (also called “sputum”), scientists can identify MTB under a regular (light) microscope. Since MTB retains certain stains even after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB). The most common acid-fast staining techniques are the Ziehl–Neelsen stain, which dyes AFBs a bright red that stands out clearly against a blue background, and the auramine-rhodamine stain followed by fluorescence microscopy.
The M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti. M. africanum is not widespread, but it is a significant cause of tuberculosis in parts of Africa. M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries. M. canetti is rare and seems to be limited to the Horn of Africa, although a few cases have been seen in African emigrants. M. microti is also rare and is mostly seen in immunodeficient people, although the prevalence of this pathogen has possibly been significantly underestimated.
Other known pathogenic mycobacteria include M. leprae, M. avium, and M. kansasii. The latter two species are classified as “nontuberculous mycobacteria” (NTM). NTM cause neither TB nor leprosy, but they do cause pulmonary diseases that resemble TB.
Risk factors
A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all TB cases are infected by the virus. This is a particular problem in sub-Saharan Africa, where rates of HIV are high. Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty. Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource-poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health care providers serving these patients. Chronic lung disease is another significant risk factor – with silicosis increasing the risk about 30-fold. Those who smoke cigarettes have nearly twice the risk of TB thaonsmokers. Other disease states can also increase the risk of developing tuberculosis, including alcoholism and diabetes mellitus (threefold increase). Certain medications, such as corticosteroids and infliximab (an anti-αTNF monoclonal antibody) are becoming increasingly important risk factors, especially in the developed world. There is also a genetic susceptibility, for which overall importance remains undefined.
Transmission
When people with active pulmonary TB cough, sneeze, speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to 40,000 droplets. Each one of these droplets may transmit the disease, since the infectious dose of tuberculosis is very low (the inhalation of fewer than 10 bacteria may cause an infection).
People with prolonged, frequent, or close contact with people with TB are at particularly high risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis may infect 10–15 (or more) other people per year. Transmission should only occur from people with active TB – those with latent infection are not thought to be contagious. The probability of transmission from one person to another depends upon several factors, including the number of infectious droplets expelled by the carrier, the effectiveness of ventilation, the duration of exposure, the virulence of the M. tuberculosis strain, the level of immunity in the uninfected person, and others. The cascade of person-to-person spread can be circumvented by effectively segregating those with active (“overt”) TB and putting them on anti-TB drug regimens. After about two weeks of effective treatment, subjects with nonresistant active infections generally do not remain contagious to others. If someone does become infected, it typically takes three to four weeks before the newly infected person becomes infectious enough to transmit the disease to others.
Pathogenesis
About 90% of those infected with M. tuberculosis have asymptomatic, latent TB infections (sometimes called LTBI), with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous disease. In those with HIV, the risk of developing active TB increases to nearly 10% a year. If effective treatment is not given, the death rate for active TB cases is up to 66%.
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within endosomes of alveolar macrophages. The primary site of infection in the lungs, known as the “Ghon focus”, is generally located in either the upper part of the lower lobe, or the lower part of the upper lobe. Tuberculosis of the lungs may also occur via infection from the blood stream. This is known as a Simon focus and is typically found in the top of the lung. This hematogenous transmission can also spread infection to more distant sites, such as peripheral lymph nodes, the kidneys, the brain, and the bones. All parts of the body can be affected by the disease, though for unknown reasons it rarely affects the heart, skeletal muscles, pancreas, or thyroid.
Tuberculosis is classified as one of the granulomatous inflammatory diseases. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts are among the cells that aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. Bacteria inside the granuloma can become dormant, resulting in latent infection. Another feature of the granulomas is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye, this has the texture of soft, white cheese and is termed caseous necrosis.
If TB bacteria gain entry to the bloodstream from an area of damaged tissue, they can spread throughout the body and set up many foci of infection, all appearing as tiny, white tubercles in the tissues. This severe form of TB disease, most common in young children and those with HIV, is called miliary tuberculosis. People with this disseminated TB have a high fatality rate even with treatment (about 30%).
In many people, the infection waxes and wanes. Tissue destruction and necrosis are often balanced by healing and fibrosis. Affected tissue is replaced by scarring and cavities filled with caseous necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria, and so can spread the infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.
Diagnosis
Active tuberculosis
Diagnosing active tuberculosis based merely on signs and symptoms is difficult, as is diagnosing the disease in those who are immunosuppressed. A diagnosis of TB should, however, be considered in those with signs of lung disease or constitutional symptoms lasting longer than two weeks. A chest X-ray and multiple sputum cultures for acid-fast bacilli are typically part of the initial evaluation. Interferon-γ release assays and tuberculin skin tests are of little use in the developing world. IGRA have similar limitations in those with HIV.
A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g. sputum, pus, or a tissue biopsy). However, the difficult culture process for this slow-growing organism can take two to six weeks for blood or sputum culture. Thus, treatment is often begun before cultures are confirmed.
Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB. These tests, however, are not routinely recommended, as they rarely alter how a person is treated. Blood tests to detect antibodies are not specific or sensitive, so they are not recommended.
Latent tuberculosis
The Mantoux tuberculin skin test is often used to screen people at high risk for TB. Those who have been previously immunized may have a false-positive test result. The test may be falsely negative in those with sarcoidosis, Hodgkin’s lymphoma, malnutrition, or most notably, in those who truly do have active tuberculosis. Interferon gamma release assays (IGRAs), on a blood sample, are recommended in those who are positive to the Mantoux test. These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results. However they are affected by M. szulgai, M. marinum and M. kansasii. IGRAs may increase sensitivity when used in addition to the skin test but may be less sensitive than the skin test when used alone.
Prevention
Tuberculosis prevention and control efforts primarily rely on the vaccination of infants and the detection and appropriate treatment of active cases. The World Health Organization has achieved some success with improved treatment regimens, and a small decrease in case numbers.
Vaccines
The only currently available vaccine as of 2011 is bacillus Calmette–Guérin (BCG) which, while it is effective against disseminated disease in childhood, confers inconsistent protection against contracting pulmonary TB. Nevertheless, it is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.However, the immunity it induces decreases after about ten years. As tuberculosis is uncommon in most of Canada, the United Kingdom, and the United States, BCG is only administered to people at high risk. Part of the reasoning arguing against the use of the vaccine is that it makes the tuberculin skin test falsely positive, and therefore, of no use in screening. A number of new vaccines are currently in development.
Public health
The World Health Organization declared TB a “global health emergency” in 1993, and in 2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis that aims to save 14 million lives between its launch and 2015. A number of targets they have set are not likely to be achieved by 2015, mostly due to the increase in HIV-associated tuberculosis and the emergence of multiple drug-resistant tuberculosis (MDR-TB). A tuberculosis classification system developed by the American Thoracic Society is used primarily in public health programs.
Prognosis
Progression from TB infection to overt TB disease occurs when the bacilli overcome the immune system defenses and begin to multiply. In primary TB disease (some 1–5% of cases), this occurs soon after the initial infection. However, in the majority of cases, a latent infection occurs with no obvious symptoms. These dormant bacilli produce active tuberculosis in 5–10% of these latent cases, often many years after infection.
The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In people coinfected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year. Studies using DNA fingerprinting of M. tuberculosis strains have shown reinfection contributes more substantially to recurrent TB than previously thought, with estimates that it might account for more than 50% of reactivated cases in areas where TB is common. The chance of death from a case of tuberculosis is about 4% as of 2008, down from 8% in 1995.
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis. Other human diseases caused by related Treponema pallidum include yaws (subspecies pertenue), pinta (subspecies carateum), and bejel (subspecies endemicum).
The signs and symptoms of syphilis vary depending in which of the four stages it presents (primary, secondary, latent, and tertiary). The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration), secondary syphilis with a diffuse rash which frequently involves the palms of the hands and soles of the feet, latent syphilis with little to no symptoms, and tertiary syphilis with gummas, neurological, or cardiac symptoms. It has, however, been known as “the great imitator” due to its frequent atypical presentations. Diagnosis is usually via blood tests; however, the bacteria can also be detected using dark field microscopy. Syphilis can be effectively treated with antibiotics, specifically the preferred intramuscular penicillin G (given intravenously for neurosyphilis), or else ceftriaxone, and in those who have a severe penicillin allergy, oral doxycycline or azithromycin.
Syphilis is thought to have infected 12 million people worldwide in 1999, with greater than 90% of cases in the developing world. After decreasing dramatically since the widespread availability of penicillin in the 1940s, rates of infection have increased since the turn of the millennium in many countries, often in combination with human immunodeficiency virus (HIV). This has been attributed partly to unsafe sexual practices among men who have sex with men, increased promiscuity, prostitution, and decreasing use of condoms.
Signs and symptoms
Syphilis can present in one of four different stages: primary, secondary, latent, and tertiary, and may also occur congenitally. It was referred to as “the great imitator” by Sir William Osler due to its varied presentations.
Primary
Primary syphilis is typically acquired by direct sexual contact with the infectious lesions of another person. Approximately 3 to 90 days after the initial exposure (average 21 days) a skin lesion, called a chancre, appears at the point of contact. This is classically (40% of the time) a single, firm, painless, non-itchy skin ulceration with a clean base and sharp borders between 0.3 and 3.0 cm in size. The lesion, however, may take on almost any form. In the classic form, it evolves from a macule to a papule and finally to an erosion or ulcer. Occasionally, multiple lesions may be present (~40%), with multiple lesions more common when coinfected with HIV. Lesions may be painful or tender (30%), and they may occur outside of the genitals (2–7%). The most common location in women is the cervix (44%), the penis in heterosexual men (99%), and anally and rectally relatively commonly in men who have sex with men (34%). Lymph node enlargement frequently (80%) occurs around the area of infection, occurring seven to 10 days after chancre formation. The lesion may persist for three to six weeks without treatment.
Secondary
Reddish papules and nodules over much of the body due to secondary syphilis
Secondary syphilis occurs approximately four to ten weeks after the primary infection. While secondary disease is known for the many different ways it can manifest, symptoms most commonly involve the skin, mucous membranes, and lymph nodes. There may be a symmetrical, reddish-pink, non-itchy rash on the trunk and extremities, including the palms and soles. The rash may become maculopapular or pustular. It may form flat, broad, whitish, wart-like lesions known as condyloma latum on mucous membranes. All of these lesions harbor bacteria and are infectious. Other symptoms may include fever, sore throat, malaise, weight loss, hair loss, and headache. Rare manifestations include hepatitis, kidney disease, arthritis, periostitis, optic neuritis, uveitis, and interstitial keratitis. The acute symptoms usually resolve after three to six weeks; however, about 25% of people may present with a recurrence of secondary symptoms. Many people who present with secondary syphilis (40–85% of women, 20–65% of men) do not report previously having had the classic chancre of primary syphilis.
Latent
Latent syphilis is defined as having serologic proof of infection without symptoms of disease. It is further described as either early (less than 1 year after secondary syphilis) or late (more than 1 year after secondary syphilis) in the United States. The United Kingdom uses a cut-off of two years for early and late latent syphilis. Early latent syphilis may have a relapse of symptoms. Late latent syphilis is asymptomatic, and not as contagious as early latent syphilis.
Tertiary
Tertiary syphilis may occur approximately 3 to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%). Without treatment, a third of infected people develop tertiary disease. People with tertiary syphilis are not infectious.
Gummatous syphilis or late benign syphilis usually occurs 1 to 46 years after the initial infection, with an average of 15 years. This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size. They typically affect the skin, bone, and liver, but can occur anywhere.
Neurosyphilis refers to an infection involving the central nervous system. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis, which is associated with poor balance and lightning pains in the lower extremities. Late neurosyphilis typically occurs 4 to 25 years after the initial infection. Meningovascular syphilis typically presents with apathy and seizure, and general paresis with dementia and tabes dorsalis. Also, there may be Argyll Robertson pupils, which are bilateral small pupils that constrict when the person focuses oear objects, but do not constrict when exposed to bright light.
Cardiovascular syphilis usually occurs 10–30 years after the initial infection. The most common complication is syphilitic aortitis, which may result in aneurysm formation.
Congenital
Congenital syphilis may occur during pregnancy or during birth. Two-thirds of syphilitic infants are born without symptoms. Common symptoms that then develop over the first couple years of life include: hepatosplenomegaly (70%), rash (70%), fever (40%), neurosyphilis (20%), and pneumonitis (20%). If untreated, late congenital syphilis may occur in 40%, including: saddle nose deformation, Higoumenakis sign, saber shin, or Clutton’s joints among others.
Bacteriology
Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium. Three other human diseases are caused by related Treponema pallidum, including yaws (subspecies pertenue), pinta (subspecies carateum) and bejel (subspecies endemicum). Unlike subtype pallidum, they do not cause neurological disease. Humans are the only knowatural reservoir for subspecies pallidum. It is unable to survive without a host for more than a few days. This is due to its small genome (1.14 MDa) failing to encode the metabolic pathways necessary to make most of its macronutrients. It has a slow doubling time of greater than 30 hours.
Transmission
Syphilis is transmitted primarily by sexual contact or during pregnancy from a mother to her fetus; the spirochaete is able to pass through intact mucous membranes or compromised skin. It is thus transmissible by kissing near a lesion, as well as oral, vaginal, and anal sex. Approximately 30 to 60% of those exposed to primary or secondary syphilis will get the disease. Its infectivity is exemplified by the fact that an individual inoculated with only 57 organisms has a 50% chance of being infected. Most (60%) of new cases in the United States occur in men who have sex with men. It can be transmitted via blood products. However, it is tested for in many countries and thus the risk is low. The risk of transmission from sharing needles appears limited. Syphilis cannot be contracted through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.
Diagnosis
Syphilis is difficult to diagnose clinically early in its presentation. Confirmation is either via blood tests or direct visual inspection using microscopy. Blood tests are more commonly used, as they are easier to perform. Diagnostic tests are, however, unable to distinguish between the stages of the disease.
Blood tests
Blood tests are divided into nontreponemal and treponemal tests. Nontreponemal tests are used initially, and include venereal disease research laboratory (VDRL) and rapid plasma reagin tests. However, as these tests are occasionally false positives, confirmation is required with a treponemal test, such as treponemal pallidum particle agglutination (TPHA) or fluorescent treponemal antibody absorption test (FTA-Abs). False positives on the nontreponemal tests can occur with some viral infections such as varicella and measles, as well as with lymphoma, tuberculosis, malaria, endocarditis, connective tissue disease, and pregnancy. Treponemal antibody tests usually become positive two to five weeks after the initial infection. Neurosyphilis is diagnosed by finding high numbers of leukocytes (predominately lymphocytes) and high protein levels in the cerebrospinal fluid in the setting of a known syphilis infection.
Direct testing
Dark ground microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. However, hospitals do not always have equipment or experienced staff members, whereas testing must be done within 10 minutes of acquiring the sample. Sensitivity has been reported to be nearly 80%, thus can only be used to confirm a diagnosis but not rule one out. Two other tests can be carried out on a sample from the chancre: direct fluorescent antibody testing and nucleic acid amplification tests. Direct fluorescent testing uses antibodies tagged with fluorescein, which attach to specific syphilis proteins, while nucleic acid amplification uses techniques, such as the polymerase chain reaction, to detect the presence of specific syphilis genes. These tests are not as time-sensitive, as they do not require living bacteria to make the diagnosis.
Prevention
As of 2010, there is no vaccine effective for prevention. Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis, as is the proper use of a latex condom. Condom use, however, does not completely eliminate the risk. Thus, the Centers for Disease Control and Prevention recommends a long-term, mutually monogamous relationship with an uninfected partner and the avoidance of substances such as alcohol and other drugs that increase risky sexual behavior.
Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. The United States Preventive Services Task Force (USPSTF) strongly recommends universal screening of all pregnant women, while the World Health Organization recommends all women be tested at their first antenatal visit and again in the third trimester. If they are positive, they recommend their partners also be treated. Congenital syphilis is, however, still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others do receive does not include screening, and it still occasionally occurs in the developed world, as those most likely to acquire syphilis (through drug use, etc.) are least likely to receive care during pregnancy. A number of measures to increase access to testing appear effective at reducing rates of congenital syphilis in low- to middle-income countries.
Syphilis is a notifiable disease in many countries, including Canada, the European Union, and the United States. This means health care providers are required to notify public health authorities, which will then ideally provide partner notification to the person’s partners. Physicians may also encourage patients to send their partners to seek care. The CDC recommends sexually active men who have sex with men are tested at least yearly.
Treatment
Early infections
The first-choice treatment for uncomplicated syphilis remains a single dose of intramuscular penicillin G or a single dose of oral azithromycin. Doxycycline and tetracycline are alternative choices; however, due to the risk of birth defects these are not recommended for pregnant women. Antibiotic resistance has developed to a number of agents, including macrolides, clindamycin, and rifampin. Ceftriaxone, a third-generation cephalosporin antibiotic, may be as effective as penicillin-based treatment.
Late infections
For neurosyphilis, due to the poor penetration of penicillin G into the central nervous system, those affected are recommended to be given large doses of intravenous penicillin for a minimum of 10 days. If a person is allergic, ceftriaxone may be used or penicillin desensitization attempted. Other late presentations may be treated with once-weekly intramuscular penicillin G for three weeks. If allergic, as in the case of early disease, doxycycline or tetracycline may be used, albeit for a longer duration. Treatment at this stage limits further progression, but has only slight effect on damage which has already occurred.
Jarisch-Herxheimer reaction
One of the potential side effects of treatment is the Jarisch-Herxheimer reaction. It frequently starts within one hour and lasts for 24 hours, with symptoms of fever, muscles pains, headache, and tachycardia. It is caused by cytokines released by the immune system in response to lipoproteins released from rupturing syphilis bacteria.
Epidemiology
Syphilis is believed to have infected 12 million people in 1999, with greater than 90% of cases in the developing world. It affects between 700,000 and 1.6 million pregnancies a year, resulting in spontaneous abortions, stillbirths, and congenital syphilis. During 2010 it caused about 113,000 deaths down from 202,000 in 1990. In sub-Saharan Africa, syphilis contributes to approximately 20% of perinatal deaths. Rates are proportionally higher among intravenous drug users, those who are infected with HIV, and men who have sex with men. In the United States, rates of syphilis as of 2007 were six times greater in men than women, while they were nearly equal in 1997. African Americans accounted for almost half of all cases in 2010.
Syphilis was very common in Europe during the 18th and 19th centuries. In the developed world during the early 20th century, infections declined rapidly with the widespread use of antibiotics, until the 1980s and 1990s. Since the year 2000, rates of syphilis have been increasing in the USA, Canada, the UK, Australia and Europe, primarily among men who have sex with men. Rates of syphilis among American women have, however, remained stable during this time, and rates among UK women have increased, but at a rate less than that of men. Increased rates among heterosexuals have occurred in China and Russia since the 1990s. This has been attributed to unsafe sexual practices, such as sexual promiscuity, prostitution, and decreasing use of barrier protection.
Untreated, it has a mortality of 8% to 58%, with a greater death rate in males. The symptoms of syphilis have become less severe over the 19th and 20th centuries, in part due to widespread availability of effective treatment and partly due to decreasing virulence of the spirochaete. With early treatment, few complications result. Syphilis increases the risk of HIV transmission by two to five times, and coinfection is common (30–60% in a number of urban centers).
Gonorrhea
Gonorrhea (colloquially known as the clap) is a common human sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. The usual symptoms in men are burning with urination and penile discharge. Women, on the other hand, are asymptomatic half the time or have vaginal discharge and pelvic pain. In both men and women if gonorrhea is left untreated, it may spread locally causing epididymitis or pelvic inflammatory disease or throughout the body, affecting joints and heart valves.
Treatment is commonly with ceftriaxone as antibiotic resistance has developed to many previously used medications. This is typically given in combination with either azithromycin or doxycycline, as gonorrhea infections may occur along with chlamydia, an infection which ceftriaxone does not cover. Some strains of gonorrhea have begun showing resistance to this treatment, which will make infection more difficult to treat.
Signs and symptoms
Symptoms of gonorrhoea usually show up within one week of being infected. But sometimes symptoms may not appear until many months later, or until the infection has spread to other parts of your body.
About one in 10 infected men and half of infected women will not experience any obvious symptoms after contracting gonorrhoea, which means it can go untreated for some time.
Women
In women, symptoms of gonorrhoea can include:
an unusual discharge from the vagina, which may be thick and green or yellow in colour
pain when passing urine
pain or tenderness in the lower abdominal area (this is less common)
bleeding between periods or heavier periods (this is less common)
Men
Nine out of 10 men who contract gonorrhoea experience symptoms after they are infected, which can include:
an unusual discharge from the tip of the penis, which may be white, yellow or green
pain or a burning sensation when urinating
inflammation (swelling) of the foreskin
pain or tenderness in the testicles or prostate gland (this is rare)
Men and women
Both men and women can also catch gonorrhoea at other sites of the body. These include infection in the:
rectum, which may cause pain, discomfort or discharge
throat, which does not usually have any symptoms
eyes, which can cause pain, swelling, irritation and discharge (conjunctivitis)
Babies
Gonorrhoea can be passed from a mother to her baby during childbirth. Newborn babies normally show symptoms in their eyes during the first two weeks. The eyes become red and swollen, and have a thick pus-like discharge (conjunctivitis).
Gonorrhoea can be treated with antibiotics when you are pregnant or when you are breastfeeding. The antibiotics will not harm your baby.
Cause
Gonorrhea is caused by the bacterium Neisseria gonorrhoeae. The infection is transmitted from one person to another through vaginal, oral, or anal sex. Men have a 20% risk of getting the infection from a single act of vaginal intercourse with an infected woman. The risk for men who have sex with men is higher. Women have a 60–80% risk of getting the infection from a single act of vaginal intercourse with an infected man. A mother may transmit gonorrhea to her newborn during childbirth; when affecting the infant’s eyes, it is referred to as ophthalmia neonatorum. It cannot be spread by toilets or bathrooms.
Diagnosis
Traditionally, gonorrhea was diagnosed with gram stain and culture; however, newer polymerase chain reaction (PCR) based testing methods are becoming more common. In those who fail initial treatment culture should be done to determine sensitivity to antibiotics. All people who test positive for gonorrhea should be tested for other sexually transmitted diseases such as chlamydia, syphilis and human immunodeficiency virus.
Treatment
It is important to receive treatment for gonorrhoea quickly. It is unlikely the infection will go away without treatment and, if you delay treatment, you risk the infection causing complications and more serious health problems. You may also pass the infection onto someone else.
Gonorrhoea is treated with a single dose of antibiotics, usually one of the following:
– ceftriaxone
– cefixime
– spectinomycin
The antibiotics are usually given as an injection but sometimes a pill can be used, which is taken orally.
Recently, it has become apparent that some strains of gonorrhoea are becoming resistant to some antibiotics, particularly antibiotics that have been used heavily in the past, like penicillin, so these tend not to be used.
If there is a high chance that you have gonorrhoea, you may be given treatment before you get your results back. You will usually be offered treatment if your partner is found to have gonorrhoea.
You should avoid sexual intercourse and intimate contact with other partners until you (and your partner) have both finished the course of treatment. This is to prevent reinfection or passing the infection onto anyone else.
Babies who display signs of a gonorrhoea infection at birth, such as inflammation of the eyes (conjunctivitis), or who are at increased risk of infection because the mother has gonorrhoea, will usually be given antibiotics immediately after birth. This is to prevent blindness and other complications of gonorrhoea developing and does not harm the baby.
Prevention
The risk of infection can be reduced significantly by using condoms correctly and by having a mutually monogamous relationship with an uninfected person. It may also be reduced by avoiding sexual intercourse.
Prognosis
If not treated gonococcal ophthalmia neonatorum will develop in 28% of infants born to women with gonorrhea.
Gonorrhea if left untreated may last for weeks or months with higher risks of complications. One of the complications of gonorrhea is systemic dissemination resulting in skin pustules or petechia, septic arthritis, meningitis or endocarditis. This occurs in between 0.6 and 3.0% of women and 0.4 and 0.7% of men.
In men, inflammation of the epididymis (epididymitis); prostate gland (prostatitis) and urethral stricture (urethritis) can result from untreated gonorrhea. In women, the most common result of untreated gonorrhea is pelvic inflammatory disease. Other complications include perihepatitis, a rare complication associated with Fitz-Hugh-Curtis syndrome; septic arthritis in the fingers, wrists, toes, and ankles; septic abortion; chorioamnionitis during pregnancy; neonatal or adult blindness from conjunctivitis; and infertility.
Neonates coming through the birth canal are given erythromycin ointment in the eyes to prevent blindness from infection. The underlying gonorrhea should be treated; if this is done then usually a good prognosis will follow.
References:
1. Danilevskiy M.F. et al. “ Diseases of the mucous membrane of the mouth.” – K.: “Medytsyna”, 2010.
2. Bruch J.M. Clinical oral medicine and pathology/ J.M. Bruch, N.S. Treister// London.:Humana Press, 2010
3. Cawson R. E. Cawson’s essentials of oral pathology and oral medicine. Seventh edition/ Cawson R. E. et. al. //Elsevier science limited, 2002.
4. Slootweg P. Dental pathology – a practical introduction/ P.J. Slootweg// Berlin.: Springer, 2007.
5. Da Silva J.D. Oxford American Handbook of Clinical Dentistry (Oxford American Handbooks in Medicine) / J.D. Da Silva et al.// Oxford University Press, 2007.
6. http://en.wikipedia.org/wiki/Gonorrhea
7. http://www.fpa.org.uk/sexually-transmitted-infections-stis-help/gonorrhoea
8. http://www.nhs.uk/Conditions/Gonorrhoea/Pages/Introduction.aspx
9. http://www.onhealth.com/diphtheria/article.htm
10. http://www.nlm.nih.gov/medlineplus/ency/article/001608.htm
11. http://emedicine.medscape.com/article/782051-overview
12. http://www.onhealth.com/tuberculosis/article.htm
13. http://www.medicalnewstoday.com/articles/8856.php
14. http://en.wikipedia.org/wiki/Tuberculosis
16. http://www.cdc.gov/std/syphilis/
17. http://www.webmd.com/sexual-conditions/guide/syphilis
18. http://en.wikipedia.org/wiki/Syphilis
Information was prepared by Sukhovolets I.O.
