Hepatitis (plural hepatitides) implies injury to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar (ηπαρ) or hepato- (ηπατο-), meaning liver, and suffix -itis, meaning "inflammation" . The condition can be self-limiting, healing on its own, or can progress to scarring of the liver. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of liver damage worldwide. Hepatitis can also be due to toxins (notably alcohol), other infections or from autoimmune process. It may run a subclinical course when the affected person may not feel ill. The patient becomes unwell and symptomatic when the disease impairs liver functions that include, among other things, removal of harmful substances, regulation of blood composition, and production of bile to help digestion.
Causes
Acute hepatitis
* Viral Hepatitis: Hepatitis A through E (more than 95% of viral cause), Herpes simplex, Cytomegalovirus, Epstein-Barr, yellow fever virus, adenoviruses.
* Non viral infection: toxoplasma, Leptospira, Q fever,[2] rocky mountain spotted fever[3]
* Alcohol
* Toxins: Amanita toxin in mushrooms, carbon tetrachloride, asafetida
* Drugs: Paracetamol, amoxycillin, antituberculosis medicines, minocycline and many others (see longer list below).
* Ischemic hepatitis (circulatory insufficiency)
* Pregnancy
* Auto immune conditions, e.g. Systemic Lupus Erythematosus (SLE)
* Metabolic diseases, e.g. Wilson's disease
Chronic hepatitis
* Viral hepatitis: Hepatitis B with or without hepatitis D, hepatitis C (Hepatitis A and E do not lead to chronic disease)
* Autoimmune: Autoimmune hepatitis
* Alcohol
* Drugs: methyldopa, nitrofurantoin, isoniazid, ketoconazole
* Non-alcoholic steatohepatitis
* Heredity: Wilson's disease, alpha 1-antitrypsin deficiency
* Primary biliary cirrhosis and primary sclerosing cholangitis occasionally mimic chronic hepatitis[4]
Signs and symptoms
Acute hepatitis
Clinically, the course of acute hepatitis varies widely from mild symptoms requiring no treatment to fulminant hepatic failure needing liver transplantation. Acute viral hepatitis is more likely to be asymptomatic in younger people. Symptomatic individuals may present after convalescent stage of 7 to 10 days, with the total illness lasting 2 to 6 weeks.[4]
Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice (33%) and tender hepatomegaly (10%). There can be occasional lymphadenopathy (5%) or splenomegaly (5%).[5]
Chronic Hepatitis
Majority of patients will remain asymptomatic or mildly symptomatic, abnormal blood tests being the only manifestation. Features may be related to the extent of liver damage or the cause of hepatitis. Many experience return of symptoms related to acute hepatitis. Jaundice can be a late feature and may indicate extensive damage. Other features include abdominal fullness from enlarged liver or spleen, low grade fever and fluid retention (ascites). Extensive damage and scarring of liver (i.e., cirrhosis) leads to weight loss, easy bruising and bleeding tendencies. Acne, abnormal menstruation, lung scarring, inflammation of the thyroid gland and kidneys may be present in women with autoimmune hepatitis.[6]
Findings on clinical examination are usually those of cirrhosis or are related to aetiology.
Types of hepatitis
Please see the respective articles for more detailed information.
See also: Infectious canine hepatitis
Viral
Most cases of acute hepatitis are due to viral infections:
* Hepatitis A
* Hepatitis B
* Hepatitis C
* Hepatitis B with D
* Hepatitis E
* Hepatitis F virus (existence unknown)
* Hepatitis G, or GBV-C
* In addition to the hepatitis viruses (please note that the hepatitis viruses are not all related), other viruses can also cause hepatitis, including cytomegalovirus, Epstein-Barr virus, yellow fever, etc.
Hepatitis A
Hepatitis A or infectious jaundice is caused by a picornavirus transmitted by the fecal-oral route, often associated with ingestion of contaminated food or with anal/oral sex. It causes an acute form of hepatitis and does not have a chronic stage. The patient's immune system makes antibodies against hepatitis A that confer immunity against future infection. People with hepatitis A are advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent infection from hepatitis A for up to 10 years. Hepatitis A can be spread through personal contact, consumption of raw sea food or drinking contaminated water. This occurs primarily in third world countries. Strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection. Infected people excrete the hepatitis A virus with their feces two weeks before and one week after the appearance of jaundice. The time between the infection and the start of the illness averages 28 days (ranging from 15 to 50 days),[7] and most recover fully within 2 months, although approximately 15% of sufferers may experience continuous or relapsing symptoms from six months to a year following initial diagnosis.[8]
Hepatitis B
Hepatitis B is caused by a hepadnavirus, which can cause both acute and chronic hepatitis. Chronic hepatitis develops in the 15% of patients who are unable to eliminate the virus after an initial infection. Identified methods of transmission include blood (blood transfusion, now rare), tattoos (both amateur and professionally done), sexually (through sexual intercourse or through contact with blood or bodily fluids), or via mother to child by breast feeding (minimal evidence of transplacental crossing). However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention.
Patients with chronic hepatitis B have antibodies against hepatitis B, but these antibodies are not enough to clear the infection that establishes itself in the DNA of the affected liver cells. The continued production of virus combined with antibodies is a likely cause of the immune complex disease seen in these patients. A vaccine is available that will prevent infection from hepatitis B for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are six FDA-approved treatment options available for persons with a chronic hepatitis B infection: alpha-interferon, pegylated interferon adefovir, entecavir, telbivudine and lamivudine. About 65% of persons on treatment achieve a sustained response.
Hepatitis B is the most infectious bloodborne pathogen known.
Hepatitis C
Hepatitis C (originally "non-A non-B hepatitis") is caused by a virus with an RNA genome that is a member of the Flaviviridae family. It can be transmitted through contact with blood (including through sexual contact if the two parties' blood is mixed) and can also cross the placenta. Hepatitis C may lead to a chronic form of hepatitis, culminating in cirrhosis. It can remain asymptomatic for 10-20 years. Patients with hepatitis C are susceptible to severe hepatitis if they contract either hepatitis A or B, so all hepatitis C patients should be immunized against hepatitis A and hepatitis B if they are not already immune, and avoid alcohol. The virus can cause cirrhosis of the liver. HCV viral levels can be reduced to undetectable levels by a combination of interferon and the antiviral drug ribavirin. The genotype of the virus determines the rate of response to this treatment regimen. Genotype 1 is more resistant to interferon therapy than other HCV genotypes.
Hepatitis D
Hepatitis D is caused by hepatitis delta agent, which is similar to a viroid as it can only propagate in the presence of the Hepatitis B virus.
Hepatitis E
Hepatitis E produces symptoms similar to hepatitis A, although it can take a fulminant course in some patients, particularly pregnant women; it is more prevalent in the Indian subcontinent.
Hepatitis F virus
Hepatitis F virus is a hypothetical virus linked to hepatitis. Several hepatitis F virus candidates emerged in the 1990s; none of these reports have been substantiated.
Hepatitis G, now called GB virus C
Another potential viral cause of hepatitis, initially identified as hepatitis G virus,[9] is probably spread by blood and sexual contact.[10] There is very little evidence that this virus causes hepatitis, as it does not appear to replicate primarily in the liver.[11] It is now classified as GB virus C[2].
Other viral causes of hepatitis
Other viral infections can cause hepatitis (inflammation of the liver):
* Mumps virus
* Rubella virus
* Cytomegalovirus
* Epstein-Barr virus
* Other herpes viruses
Alcoholic hepatitis
Main article: Alcoholic hepatitis
Ethanol, mostly in alcoholic beverages, is a significant cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption. Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset.
Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C.[citation needed] The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis.
Drug induced hepatitis
A large number of drugs can cause hepatitis:[12]
* Allopurinol
* Amitriptyline (antidepressant)
* Amiodarone (antiarrhythmic)
* Atomoxetine [13]
* Azathioprine[14]
* Halothane (a specific type of anesthetic gas)
* Hormonal contraceptives
* Ibuprofen and indomethacin (NSAIDs)
* Isoniazid (INH), rifampicin, and pyrazinamide (tuberculosis-specific antibiotics)
* Ketoconazole (antifungal)
* Methotrexate (immune suppressant)
* Methyldopa (antihypertensive)
* Minocycline (tetracycline antibiotic)
* Nifedipine (antihypertensive)
* Nitrofurantoin (antibiotic)
* Phenytoin and valproic acid (antiepileptics)
* Troglitazone (antidiabetic, withdrawn in 2000 for causing hepatitis)
* Zidovudine (antiretroviral i.e. against HIV)
* Some herbs and nutritional supplements[15]
The clinical course of drug-induced hepatitis is quite variable, depending on the drug and the patient's tendency to react to the drug. For example, halothane hepatitis can range from mild to fatal as can INH-induced hepatitis. Hormonal contraception can cause structural changes in the liver. Amiodarone hepatitis can be untreatable since the long half life of the drug (up to 60 days) means that there is no effective way to stop exposure to the drug. Statins can cause elevations of liver function blood tests normally without indicating an underlying hepatitis. Lastly, human variability is such that any drug can be a cause of hepatitis.
Other toxins that cause hepatitis
Toxins and drugs can cause hepatitis:
* Amatoxin-containing mushrooms, including the Death Cap (Amanita phalloides), the Destroying Angel (Amanita ocreata), and some species of Galerina. A portion of a single mushroom can be enough to be lethal (10 mg or less of α-amanitin).
* White phosphorus, an industrial toxin and war chemical.
* Paracetamol (acetaminophen in the United States) can cause hepatitis when taken in an overdose. The severity of liver damage may be limited by prompt administration of acetylcysteine.
* Carbon tetrachloride ("tetra", a dry cleaning agent), chloroform, and trichloroethylene, all chlorinated hydrocarbons, cause steatohepatitis (hepatitis with fatty liver).
* Cylindrospermopsin, a toxin from the cyanobacterium Cylindrospermopsis raciborskii and other cyanobacteria.
Metabolic disorders
Some metabolic disorders cause different forms of hepatitis. Hemochromatosis (due to iron accumulation) and Wilson's disease (copper accumulation) can cause liver inflammation and necrosis.
See below for non-alcoholic steatohepatitis (NASH), effectively a consequence of metabolic syndrome.
Obstructive
"Obstructive jaundice" is the term used to describe jaundice due to obstruction of the bile duct (by gallstones or external obstruction by cancer). If longstanding, it leads to destruction and inflammation of liver tissue.
Autoimmune
Anomalous presentation of human leukocyte antigen (HLA) class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection; causes a cell-mediated immune response against the body's own liver, resulting in autoimmune hepatitis.
Alpha 1-antitrypsin deficiency
In severe cases of alpha 1-antitrypsin deficiency (A1AD), the accumulated protein in the endoplasmic reticulum causes liver cell damage and inflammation.
Nonalcoholic steatohepatitis
Non-alcoholic steatohepatitis (NASH) is a type of hepatitis which resembles alcoholic hepatitis on liver biopsy (fat droplets, inflammatory cells, but usually no Mallory's hyaline) but occurs in patients who have no known history of alcohol abuse. NASH is more common in women, and the most common cause is obesity or the metabolic syndrome. A related but less serious condition is called "fatty liver" (steatosis hepatis), which occurs in up to 80% of all clinically obese people. A liver biopsy for fatty liver shows fat droplets throughout the liver, but no signs of inflammation or Mallory's hyaline.
The diagnosis depends on history, physical exam, blood tests, radiological imaging and sometimes a liver biopsy. The initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging including ultrasound, computed tomographic imaging, or magnetic resonance imaging. However, radiologic imaging cannot readily identify inflammation in the liver. Therefore, the differentiation between steatosis and NASH often requires a liver biopsy. It can also be difficult to distinguish NASH from alcoholic hepatitis when the patient has a history of alcohol consumption. Sometimes in such cases a trial of abstinence from alcohol along with follow-up blood tests and a repeated liver biopsy are required.
NASH is becoming recognized as the most important cause of liver disease second only to Hepatitis C in numbers of patients going on to cirrhosis.
Ischemic hepatitis
Ischemic hepatitis is caused by decreased circulation to the liver cells. Usually this is due to decreased blood pressure (or shock), leading to the equivalent term "shock liver". Patients with ischemic hepatitis are usually very ill due to the underlying cause of shock. Rarely, ischemic hepatitis can be caused by local problems with the blood vessels that supply oxygen to the liver (such as thrombosis, or clotting of the hepatic artery which partially supplies blood to liver cells). Blood testing of a person with ischemic hepatitis will show very high levels of transaminase enzymes (AST and ALT), which may exceed 1000 U/L. The elevation in these blood tests is usually transient (lasting 7 to 10 days). It is rare that liver function will be affected by ischemic hepatitis.
Showing posts with label reference. Show all posts
Showing posts with label reference. Show all posts
Saturday, July 12, 2008
Herpes reference
Herpes simplex is a viral disease caused by Herpes simplex viruses; both herpes simplex virus 1 (HSV–1) and herpes simplex virus 2 (HSV–2) cause herpes simplex. Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores, infects the face and mouth. Oral herpes is the most common form of infection. Infection of the genitals, commonly known as herpes, is the second most common form of herpes. Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes (keratitis), cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are all caused by herpes simplex viruses. Most individual disorders may be caused by HSV–1 or HSV–2, though some disorders have significantly different rates of infection by type. Herpes simplex is not typically life-threatening for immunocompetent people.
Herpes viruses cycle between periods of active disease—presenting as blisters containing infectious virus particles—that last 2–21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. After initial infection, the viruses move to sensory nerves, where they reside as life-long, latent viruses. Causes of recurrence are uncertain, though some potential triggers have been identified. Over time episodes of active disease reduce in frequency.
Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual. Transmission may also occur through skin-to-skin contact during periods of asymptomatic shedding. Barrier protection methods are the most reliable, but not failsafe, method of preventing transmission of herpes. Oral herpes is easily diagnosed if the patient presents with visible sores or ulcers. Early stages of orofacial herpes and genital herpes are harder to diagnose; laboratory testing is usually required. Prevalence of HSV infections varies throughout the world. Poor hygiene, overcrowding, lower socioeconomic status, and birth in an undeveloped country have been identified as risk factors associated with increased HSV-1 childhood infection. Additional studies have identified other risk factors for both types of HSV.
There is currently no cure for herpes; no vaccine is currently available to prevent or eliminate herpes. However, treatments are available to reduce viral reproduction and shedding, prevent the virus from entering the skin, and alleviate the severity of symptomatic episodes.
Disorders
HSV infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow). More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). Patients with immature or suppressed immune systems, such as newborn infants, transplant recipients, or AIDS patients are prone to severe complications from HSV infections.
In all cases HSV is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion.[1] As a result of primary infection, the body produces antibodies to the particular type of HSV involved, preventing a subsequent infection of that type at a different site. In HSV-1 infected individuals, seroconversion after an oral infection will prevent additional HSV-1 infections such as whitlow, genital herpes, and keratitis. Prior HSV-1 seroconversion seems to ameliorate the symptoms of a later HSV-2 infection, however HSV-2 can still be contracted. Most indications are that if an HSV-2 infection is contracted prior to HSV-1 seroconversion, that person cannot get an HSV-1 infection later.
Orofacial infection
Herpesviral vesicular dermatitis
Classification and external resources
Herpes lesion on upper lip and face
ICD-10 B00.1
Orofacial herpes affects the face and mouth. Infection occurs when the virus comes into contact with oral mucosa or abraded skin. Infection by the type 1 strain of herpes simplex virus (HSV-1) is the most common cause of orofacial herpes, though cases of oral infection by the type 2 strain are increasing.[2]
Herpes infections are largely asymptomatic; when symptoms appear they will typically resolve within two weeks.[3] The main symptom of oral infection is acute herpetic gingivostomatitis (inflammation of the mucosa of the cheek and gums), which occurs within 5–10 days of infection. Other symptoms may also develop, including painful ulcers—sometimes confused with canker sores—fever, and sore throat.[3] Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy).[3] Primary HSV infections in adults often results in pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely.
Recurrent oral infection is more common with HSV-1 infections than with HSV-2. Prodromal symptoms often precede a recurrence. Symptoms typically begin with tingling (itching) and reddening of the skin around the infected site. Eventually, fluid-filled blisters form on the lip (labial) tissue and the area between the lip and skin (vermilion border). The recurrent infection is thus often called herpes simplex labialis. Rare reinfections occur inside the mouth (intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the tongue, possibly accompanied by herpes labialis.[3][4]
Genital infection
Anogenital herpesviral infection
Classification and external resources
Genital herpes in a female
ICD-10 A60.
MeSH D006558
Genital herpes in a male
Genital herpes in a male
Genital herpes is caused by HSV-2 more often than it is caused by HSV-1, although infections of the genitals by HSV-1 are increasing. The typical symptom a primary HSV-1 or HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores.[5] These usually appear 4–7 days after sexual exposure to HSV for the first time.[1] Genital HSV-1 infection reoccurs at rate of about one sixth of that of genital HSV-2. In males, the lesions occur on the shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions appear on or near the pubis, labia, clitoris, vulva, buttocks or anus.[5] Other common symptoms include pain, itching, and burning. Less frequent, yet still common, symptoms include discharge from the penis or vagina, fever, headache, muscle pain (myalgia), swollen and enlarged lymph nodes and malaise.[1] Women often experience additional symptoms that include painful urination (dysuria) and cervicitis. Herpetic proctitis (inflammation of the anus and rectum) is common for individuals participating in anal intercourse.[1] After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts.[1]
Herpes whitlow
Herpes whitlow (herpetic whitlow) is a painful infection that typically affects the fingers or thumbs. Occasionally infection occurs on the toes or on the nail cuticle. Herpes whitlow can be caused by infection by HSV-1 or HSV-2.[6] HSV-1 whitlow is often contracted by health care workers that come in contact with the virus; it is most commonly contracted by dental workers and medical workers exposed to oral secretions.[7][8] It is also often observed in thumb-sucking children with primary HSV-1 oral infection (autoinoculation) prior to seroconversion,[6] and in adults aged 20 to 30 following contact with HSV-2-infected genitals.[9]
Symptoms of herpetic whitlow include swelling, reddening and tenderness of the skin of infected finger. This may be accompanied by fever and swollen lymph nodes. Small, clear vesicles initially form individually, then merge and become cloudy. Associated pain often seems large relative to the physical symptoms. The herpes whitlow lesion usually heals in two to three weeks.[10]
Herpes gladiatorum
Individuals that participate in contact sports such as wrestling, rugby, and soccer sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler’s herpes, or mat herpes. Abraded skin provides an area of entry for HSV-1. Symptoms present within 2 weeks of direct skin-to-skin contact with an infected person. They include skin ulceration on the face, ears, and neck, fever, headache, sore throat and swollen glands. It occasionally affects the eyes. Physical symptoms sometimes recur in the skin.[11] Previous adolescent HSV-1 serocoversion would preclude most herpes gladiatorum, but being that stress and trauma are recognized triggers, such a person would be likely to infect others.
Ocular herpes
Herpesviral ocular disease
Classification and external resources
Herpes infection of the cornea
ICD-10 B00.5
MeSH D016849
Ocular herpes is a special case of facial herpes infection, known as herpes keratitis. Occular herpes is generally caused by HSV-1. It begins with infection of epithelial cells on the surface of the eye and retrograde infection of nerves serving the cornea.[12] Primary infection typically presents as swelling of the conjunctiva and eye-lids (blepharoconjunctivitis), accompanied by small white itchy lesions on the surface of the cornea. The effect of the lesions varies, from minor damage to the epithelium (superficial punctate keratitis), to formation of dendritic ulcers.[13] Infection is unilateral, affecting one eye at a time. Additional symptoms include dull pain deep inside the eye, mild to acute dryness, and sinusitis. Most primary infections resolve spontaneously in a few weeks. Healing can be aided by the use of oral and topical antivirals.
Subsequent recurrences may be more severe, with infected epithelial cells showing larger dendritic ulceration, and lesions forming white plaques.[13] The epithelial layer is sloughed off as the dendritic ulcer grows, and mild inflammation (iritis) may occur in the underlying stroma of iris. Sensation loss occurs in lesional areas, producing generalised corneal anaesthesia with repeated recurrences.[13] Recurrence can be accompanied by chronic dry eye, low grade intermittent conjunctivitis, or chronic unexplained sinusitis. Following persistent infection the concentration of viral DNA reaches a critical limit. Antibody responses against the viral antigen expression in the stroma can trigger a massive autoimmune response in the eye. The response may result in the destruction of the corneal stroma,[13] resulting in loss of vision due to opacification of the cornea. This is known as immune-mediated stromal keratitis.
Treatment with corneal transplants was once ineffective (with only 14%-61% rate of survival without antiviral therapy), as reinfection of the transplant is common when the virus reactivates. However, with concurrent use of antivirals the chance of graft acceptance has improved.[14]
[edit] Herpes simplex encephalitis
Herpesviral encephalitis
Classification and external resources
ICD-10 B00.4, G05.1
ICD-9 054.3
Herpes simplex encephalitis (HSE) is one of the most severe viral infections of the human central nervous system. It is estimated to affect at least 1 in 500,000 individuals per year.[15] About 1 in 3 cases of HSE result from primary HSV-1 infection, predominantly occurring in individuals under the age of 18; 2 in 3 cases occur in seropositive persons, few of whom have history of recurrent orofacial herpes. Approximately 50% of individuals that develop HSE are over 50 years of age.
HSE is thought to be caused by the retrograde transmission of virus from a peripheral site on the face following HSV-1 reactivation, along a nerve axon, to the brain.[15] The virus lies dormant in the ganglion of the trigeminal cranial nerve, but the reason for reactivation, and its pathway to gain access to the brain, remains unclear. The olfactory nerve may also be involved in HSE.[17] For unknown reasons the virus seems to target the temporal lobes of the brain.
Most individuals with HSE show a decrease in their level of consciousness and an altered mental state presenting as confusion, and changes in personality. Increased numbers of white blood cells can be found in patient's cerebrospinal fluid, without the presence of pathogenic bacteria and fungi. Patients typically have a fever.[15] and may have seizures. The electrical activity of the brain changes as the disease progresses, first showing abnormalities in one temporal lobe of the brain, which spread to the other temporal lobe 7–10 days later.[15]
Without treatment, HSE results in rapid death in approximatley 70% of cases.[15] HSE is fatal in around 20% of cases treated, and causes serious long-term neurological damage in over half of survivors. Only a small population of survivors (2.5%) regain completely normal brain function.[16]
Neonatal herpes simplex
Congenital herpesviral (herpes simplex) infection
Classification and external resources
HSV disease in a newborn child
ICD-10 P35.2
ICD-9 771.2
Neonatal HSV infection is a rare but serious condition, usually caused by vertical transmission of HSV from mother to newborn. Only an estimated 10% of cases are acquired postnatally. Neonatal HSV rates in the U.S. are estimated to be between 1 in 3,000 and 1 in 20,000 live births. Approximately 22% of pregnant women in the U.S. have had previous exposure to HSV-2, and an additional 2% acquire the virus during pregnancy, mirroring the infection rate in the general population.[18] The risk of transmission to the newborn is 30-57% in cases where the mother acquired a primary infection in the third trimester of pregnancy. Risk of transmission by a mother with existing antibodies for both HSV-1 and HSV-2 has a much lower (1-3%) transmission rate. This in part is due to the transfer of significant titer of protective maternal antibodies to the fetus from about the seventh month of pregnancy.[19] However, shedding of HSV-1 from both primary genital infection and reactivations is associated with higher transmission from mother to infant.[19]
Complications of neonatal herpes rates are low birth weight and premature birth. Approximately one quarter of NHSV infected babies will have sepsis before the onset of herpes symptoms, further complicating diagnosis.
HSV-1 neonatal herpes is extremely rare in developing countries because development of HSV-1 specific antibodies usually occurs in childhood or adolescence, precluding a genital HSV-1 infection. HSV-2 infections are much more common in these countries. In industrialized nations, the adolescent HSV-1 seroprevalance has been dropping steadily for the last 5 decades. The resulting increase in the number of young women becoming sexually active while HSV-1 seronegative has contributed to increased HSV-1 genital herpes rates, and as a result, increased HSV-1 neonatal herpes in developed nations. A recent three year study in Canada (2000-2003) revealed a neonatal HSV incidence of 5.9 per 100,000 live births. HSV-1 was the cause of 62.5% of cases of neonatal herpes of known type, and 98.3% of transmission was asymptomatic.[20] Asymptomatic genital HSV-1 has been shown to be more infectious to the neonate, and is more likely to produce neonatal herpes, than HSV-2,[21][22]. However, with prompt application of antiviral therapy, the prognosis of neonatal HSV-1 infection is better than that for HSV-2.
Neonatal herpes manifests itself in three forms: skin, eyes, and mouth herpes (SEM), disseminated herpes (DIS), and central nervous system herpes(CNS).[23] SEM herpes is characterized by external lesions but no internal organ involvement. Lesions are likely to appear on trauma sites such as the attachment site of fetal scalp electrodes, forceps or vacuum extractors that are used during delivery, in the margin of the eyes, the nasopharynx, and in areas associated with trauma or surgery (including circumcision).[19] DIS herpes affects internal organs, particularly the liver. CNS herpes is an infection of the nervous system and the brain that can lead to encephalitis. Infants with CNS herpes present with seizures, tremors, lethargy, and irritability, they feed poorly, have unstable temperatures, and their fontanelle (soft spot of the skull) may bulge.[19] CNS herpes is associated with highest morbidity, and DIS herpes has a higher mortality rate. SEM herpes has the best prognosis of the three, however, if left untreated it may spread to the internal organs and result in DIS or CNS herpes with its attendant increases in mortality and morbidity. Death from neonatal HSV disease in the U.S. is currently decreasing; The current death rate is about 25%, down from as high as 85% a few decades ago.
Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir.[23][24][25][26] However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in the 20-40% of infected neonates that have no visible lesions.[27] Herpes simplex virus infection in the newborn "carries high mortality and morbidity rates from central nervous system involvement", according to Harrison's Principles of Internal Medicine, which recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by cesarean section. Women whose herpes is not active can be managed with acyclovir.[28]
Recurrence
Following active infection herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerve's cell body. HSV latency is static—no virus is produced—and is controlled by a number of viral genes, including Latency Associated Transcript (LAT).[43]
Many HSV infected people experience recurrence within the first year of infection.[1] Prodrome precedes development of lesions. Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence fewer lesions are likely to develop, lesions are less painful, and lesions heal faster (within 5–10 days without antiviral treatment), than those occurring during the primary infection.[1] Subsequent outbreaks tend to be periodic or episodic, occurring on average four to five times a year when not using antiviral therapy.
The causes of reactivation are uncertain, but several potential triggers have been documented. Physical or psychological stress can trigger an outbreak of herpes.[44] Changes in the immune system during menstruation may play a role in HSV-1 reactivation.[45][46] Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to infection is the likely source of the historic terms cold sore and fever blister.
Other identified triggers include: local injury to the face, lips, eyes, or mouth, trauma, surgery, radiotherapy, and exposure to wind, ultraviolet light, or sunlight.
The frequency and severity of recurrent outbreaks may vary greatly between patients. An immunity to the virus is built over time; immunocompromised individuals may experience episodes that are longer, more frequent and more severe. Antiviral medication has been proven to shorten the frequency and duration of outbreaks.[52] Outbreaks may occur at the original site of the infection or in close proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, back of the thighs.
Transmission and prevention
Herpes is contracted through direct contact with an active lesion or body fluid of an infected person.[53] Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person.[1] There are no documented cases of infection via an inanimate object (e.g. a towel, toilet seat, drinking vessels).[citations needed] To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.
HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases.[54] Infected people that show no visible symptoms may still shed and transmit virus through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission.[54] Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding.[55] There are indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with 1 to 12 annual recurrences to those that have no recurrences.[54]
Antibodies that develop following an initial infection with a type of HSV prevents reinfection with the same virus type—a person with a history of orofacial infection caused by HSV-1 cannot contract herpes whitlow or a genital infection caused by HSV-1. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV-1 infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection.
Barrier protection, such as a condom, can reduce the risk of herpes transmission in some cases.
Barrier protection, such as a condom, can reduce the risk of herpes transmission in some cases.
For genital herpes, condoms are highly effective in limiting transmission of herpes simplex infection.[56][57] however condoms are not completely effective. The virus cannot pass through latex, but a condom's effectiveness is somewhat limited on a public health scale by their limited use in the community,[58] and on an individual scale because the condom may not completely cover blisters on the penis of an infected male, or the base of the penis or testicles not covered by the condom may come into contact with free virus in vaginal fluid of an infected female. In such cases, abstinence from sexual activity or washing of the genitals after sex is recommended. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa) during oral sex. When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir, in conjunction with a condom, further decreases the chances of transmission to the uninfected partner.[1] Topical microbicides which contain chemicals that directly inactivate the virus and block viral entry are currently being investigated.[1] Vaccines for HSV are currently undergoing trials. Once developed, they may be used to help with prevention or minimize initial infections as well as treatment for existing infections.[59]
As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men.[60] On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is approximately 8-10%.[citation needed] This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is approximately 4-5% annually.[citation needed] Suppressive antiviral therapy reduces these risks by 50%.[citation needed] Antivirals also help prevent the development of symptomatic HSV in infection scenarios—meaning the infected partner will be seropositive but symptom free—by about 50%. Condom use also reduces the transmission risk by 50%.[citation needed] Condom use is much more effective at preventing male to female transmission than vice-versa.[56] The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk.[citation needed] These figures reflect experiences with subjects having frequently-recurring genital herpes (>6 recurrences per year). Subjects with low recurrence rates and those with no clinical manifestations were excluded from these studies.[citation needed]
To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1 seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g., fetal scalp electrodes, forceps and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal.[1] The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.[1]
HSV seropositive individuals practising unprotected sex with HIV positive persons pose a high risk of HIV transmission, and are even more susceptible to HIV during an outbreak with active sores.[61]
Diagnosis
Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis.[11] Adults with non-typical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.[11]
Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical symptoms.[11] Further confusing diagnosis, several other conditions resemble genital herpes, including lichen planus, atopic dermatitis, and urethritis.[11] Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include: culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.[11]
Serological tests for antibodies to HSV are rarely useful to diagnosis and not routinely used in clinical practice[11], but are important in epidemiological studies. Serologic assays cannot differentiate between antibodies generated in response to a genital versus an oral HSV infection, and as such cannot confirm the site of infection. Absence of antibody to HSV-2 does not exclude gential infection because of the increasing incidence of genital infections caused by HSV-1.
Epidemiology
Although many people infected with HSV develop labial or genital lesions, many more are either undiagnosed or display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes.[62] Since asymptomatic individuals are often unaware of their infection, they are considered at high risk for spreading HSV. Many studies have been performed around the world to estimate the numbers of individuals infected with HSV-1 and HSV-2 by determining if they have developed antibodies against either viral species.[63] This information provides population prevalence of HSV viral infections in individuals with or without active disease.
Europe
Large differences in HSV-1 seroprevalence are seen in different European countries. HSV-1 seroprevalence is high in Bulgaria (83.9%) and The Czech Republic (80.6%), and lower in Belgium (67.4%), The Netherlands (56.7%), and Finland (52.4%).[66] The typical age at which HSV-1 infection is acquired ranges from 5 to 9 years in Eastern European countries like Bulgaria and the Czech Republic, to over 25 years of age in Northern European countries such as Finland, The Netherlands, Germany, and England and Wales. Young adults in Northern European countries are less likely to be infected with HSV-1. European women are more likely to be HSV-1 seropositive than men.
HSV-2 seropositivity is widely distributed in Europeans older than 12, although there are large differences in the percentage of the population exposed to HSV-2. Bulgaria has a high (23.9%) HSV-2 seroprevalence relative to other European countries: Germany (13.9%), Finland (13.4%), Belgium (11.1%), The Netherlands (8.8%), the Czech Republic (6.0%), and England and Wales (4.2%).[66] Women are more likely to be seropositive than men, and likely acquire the virus at an earlier age. In each country of Europe, HSV-2 seropositivity becomes more common from adolescence onwards and increases in the population with age, with a decline in the older age groups in some countries.[66]
North America
United States
African Americans and immigrants from developing countries typically have an HSV-1 seroprevalance in their adolescent population that is two or three times higher than that of Caucasian Americans, possibly reflecting differences in their socioeconomic backgrounds.[11] Many white Americans become sexually active while seronegative for HSV-1. The absence of antibodies from a prior oral HSV-1 infection leaves these individuals susceptible to primary HSV-1 genital infections. This brings with it a risk of vertical transmission to the neonate if the mother contracts a primary infection during the third trimester of pregnancy. A seronegative mother has up to a 57% chance of conveying an HSV infection to her baby during childbirth whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant.[67]
Women that are seropositive for only one type of HSV are only half as likely to transmit HSV as the seronegative mother. In the U.S. the number of genital infections caused by HSV-1 is now thought to be about 50% of all genetal infections.
In healthy adults, HSV-2 infection occurs more frequently in the USA than in Europe, and infection rates appear to be increasing. In individuals over 12 years old, HSV-2 seroprevalence has increased from 16.4% in 1976 to 21.8% in 1994 and is still rising.[70] The current incidence of genital herpes caused by HSV-2 in the U.S. is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year.[11] African Americans appear more susceptible to HSV-2, although the presence of active genital symptoms is more likely in Caucasian Americans. The largest increase in HSV-2 acquisition during the past few years is in white adolescents. People with many lifetime sexual partners and those who are sexually active from a young age are also at higher-risk for the transmission of HSV-2 in the U.S.[71][72][73][74] Women are at higher risk than men for acquiring HSV-2 infection, and the chance of being infected increases with age.[11]
Canada
According to a study in Ontario, up to 55% of Canadians age of 15 to 16, and 89% of individuals in their early forties have antibodies to HSV-1[citation needed]. Teenagers are less likely to be seropositive for HSV-2—antibodies against this virus are only found in 0–3.8% of 15-16 year olds. However, 21% of individuals in their early forties have antibodies against HSV-2, reflecting the sexually transmitted nature of this virus. When standardising for age, HSV-2 seroprevalence in Ontario for individuals between the ages of 15 to 44 was 9.1%. This is much lower than estimated levels of HSV-2 seroprevalence in people of a similar age range in the United States.[75] HSV-2 seroprevalence in pregnant women between the ages of 15-44 in British Columbia is similar, with 57% having antibodies for HSV-1 and 13% having antibodies for HSV-2.[63]
Africa
Sub-Saharan Africa
HSV-2 is more common in Sub-Saharan Africa than in Europe or the North America. Up to 82% of women and 53% of men in Sub-Saharan Africa are seropositive for HSV-2. These are the highest levels of HSV-2 infection in the world, although exact levels vary from country to country in this continent.[76] In most African countries, HSV-2 prevalence increases with age. However, age-associated decreases in HSV-2 seroprevalence has been observed for women in Uganda and Zambia, an in men in Ethiopia, Benin, and Uganda.[63]
Northern Africa
Genital herpes appears less common in Northern Africa compared to Sub-Saharan Africa. For example, only 26% of middle-aged women have antibodies for HSV-2 in Morocco.[64] Women are more likely to be infected with HSV-2 once they are over the age of 40.[64] Children in Egypt are often infected with HSV from a young age—HSV-1 or HSV-2 antibodies are present in an estimated 54% of children under the age of 5, and 77% in children over 10 years of age.[77] Algerian children are also likely to acquire HSV-1 infection at a young age (under 6) and 81.25% of the population has antibodies to HSV-1 by the age of 15.[78]
Central and South America
Relative to rates in Europe and North America, HSV-2 seroprevalency is high in Central and South America. Infection levels are estimated at 20% to 60%.[63][76] During the mid 1980s, HSV-2 prevalence was 33% in 25–29 year old women and 45% in those aged 40 and over in Costa Rica. In the early 1990s HSV-2 prevalence was approximately 45% among women over 60 in Mexico.[63] The highest HSV-2 prevalence in Central or South America—60%—has been found in Colombian middle-aged women, although similar HSV-2 prevalence has been observed in younger women in Haiti (54%).[63] HSV-2 infects about 30% of women over 30 years old in Colombia, Costa Rica, Mexico, and Panama. HSV-2 antibodies were found in more than 41% of women of childbearing age in Brazil.[63] However, no increase in seroprevalence was associated with age in women over 40 years old in Brazil—HSV-2 prevalence was estimated at 50% among women aged 40–49, 33% among women 50–59, and 42% among women over 60. Women in Brazil are more likely to acquire an HSV-2 infection if their male partners had history of anal sex and had many sexual partners in his lifetime.[64] In Peru, HSV-2 prevalence is also high among women in their 30s but is lower in men.[63]
Eastern and South East Asia
HSV-1 seroprevalence in some Asian countries is low, relative to other countries worldwide, with only 51% women in Thailand, and between 50-60% in Japan possessing antibodies.[64][63] HSV-2 seroprevalence in developing Asian countries is comparable (10-30%) to that observed in North America and Northern Europe.[76] However, estimates of HSV-2 infectivity in Thailand are higher than observed in other Eastern Asian countries; total HSV-2 seroprevalence is approximately 37% in this country.[64] HSV-2 seroprevalence is low in women in the Philippines (9%), although commencing activity while young is associated with an increase risk of acquiring HSV-2 infection; woman starting sexual activity by the time they reach 17 are seven times more likely to be HSV-2 seropositive that those starting sexual activity when over 21.[79] In South Korea, incidence of HSV-2 infection in those under the age of 20 is low, only 2.7% in men and 3.0% in women.[65] Seroprevalence levels increase in older South Koreans however, such that the population over 20 that has antibodies against HSV-2 is 21.7% of men and 28% of women.[65]
[edit] Southern Asia
In India 33.3% of individuals are seropositive for HSV-1 and 16.6% are seropositive for HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. Indian men are more likely to be infected with HSV-2 than women, and increasing seroprevalence of this virus is associated with an increasing age.[80]
Middle East
High levels of HSV-1 (97%) and HSV-2 (42%) were found amongst pregnant women in the city of Erzurum in Eastern Anatolia Region, Turkey.[63] In Istanbul however, lower HSV-2 seroprevalence was observed; HSV-2 antibodies were found in 4.8% of sexually active adults, while HSV-1 antibodies were found in 85.3%.[81] Only 5% of pregnant women were infected with HSV-2, and 98% were infected with HSV-1. Prevalence of these viruses was higher in sex workers of Istanbul, reaching levels of 99% and 60% for HSV-1 and HSV-2 prevalence respectively.[81]
The prevalence of HSV-2 in Jordan is 52.8% for men and 41.5% for women.[82]
HSV-1 seroprevalence is 59.8% in the population of Israel and increases with age in both genders. An estimated 9.2% of Israeli adults are infected with HSV-2. Infection of either HSV-1 or HSV-2 is higher in females; HSV-2 seroprevalence reaches 20.5% in females in their 40s. These values are similar to levels in HSV infection in Europe.[83] Antibodies for HSV-1 or HSV-2 are also more likely to be found individuals born outside of Israel, and individuals residing in Jerusalem and Southern Israel; people of Jewish origin living in Israel are less likely to possess antibodies against herpes.[83] HSV-1 causes 66.3% of genital herpes in individuals living in Tel Aviv.[84]
Genital herpes infection from HSV-2 is predicted to be low in Syria although HSV-1 levels are high. HSV-1 infections is common (95%) among healthy Syrians over the age of 30, while HSV-2 prevalence is low in healthy individuals (0.15%), and persons infected with other sexually transmitted diseases (9.5%). High risk groups for acquiring HSV-2 in Syria, include prostitutes and bar girls; they have 34% and 20% seroprevalence respectively.[85]
Oceania
In Australia the seroprevalence of HSV-1 is 76%, with differences associated with age, gender and Indigenous status.[86] An estimated 12% of Australian adults are seropositive for HSV-2, with higher prevalence in women (16%) than in men (8%).[86] Larger cities have higher HSV-2 seroprevalence (13%) than rural populations (9%). Higher prevalence is found in Indigenous Australians (18%) than non-Indigenous Australians (12%) but is lower than HSV-2 prevalence observed in the United States.[86] As in the U.S., HSV-1 is increasingly identified as the cause of genital herpes in Australians; HSV-1 was identified in the anogenital area of only 3% of the population in 1980, but had risen to 41% in 2001.[87] This was most common in females and persons under 25.[87]
The number of genital herpes infections appears to be rising in New Zealand with three times more cases in 1993 compared to 1977.[88] In this country, HSV-2 affects 60% more women than men of similar age.
Treatment
No treatment that can eradicate herpes virii from the body currently exists. Antiviral medications can reduce the frequency, duration, and severity of outbreaks. Antiviral drugs also reduce asymptomatic shedding; it is believed asymptomatic shedding occurs on 10.8% of days in patients not undergoing antiviral treatment, versus 2.9% of days while on antiviral therapy.[54] Non-prescription analgesics can reduce pain and fever during initial outbreaks. Topical anesthetic treatments such as prilocaine, lidocaine or tetracaine can relieve itching and pain.[89][90]
Antiviral medication
Antiviral medications used against herpes viruses work by interfering with viral replication, effectively slowing the replication rate of the virus and providing a greater opportunity for the immune response to intervene. All drugs in this class depend on the activity of the viral enzyme thymidine kinase to convert the drug sequentially from its prodrug form to monophosphate (with one phosphate group), diphosphate (with two phosphate groups), and finally to the triphosphate (with three phosphate groups) form which interferes with viral DNA replication.[91]
The antiviral medication acyclovir
The antiviral medication acyclovir
There are several prescription antiviral medications for controlling herpes simplex outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and penciclovir. Aciclovir was the original, and prototypical, member of this drug class; it is now available in generic brands at a greatly reduced cost. Valaciclovir and famciclovir—prodrugs of aciclovir and penciclovir, respectively—have improved solubility in water and better bioavailability when taken orally.[91] Aciclovir is the recommended antiviral for suppressive therapy for use during the last months of pregnancy to prevent transmission of herpes simplex to the neonate.[92] The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. Studies with mice provide evidence that treatment with famciclovir, rather than aciclovir, during an initial outbreak can help lower the incidence of future outbreaks, by reducing the amount of latent virus in the neural ganglia. This potential effect on latency drops to zero a few months post-infection.[93]
Antiviral medications are also available as topical creams for treating recurrent outbreaks on the lips, although their effectiveness is disputed.[94] Penciclovir cream has a 7-17 hour longer cellular half-life than aciclovir cream, increasing its effectiveness relative to aciclovir when topically applied.[95]
Topical treatments
Docosanol is available as a cream for direct application to the affected area of skin. It prevents HSV from fusing to cell membranes, thus barring the entry of the virus into the skin. Docosanol was approved for use after clinical trials by the FDA in July 2000.[96] Docosanol is marketed by Avanir Pharmaceuticals under the name Abreva. It was the first over-the-counter antiviral drug approved for sale in the United States and Canada. Avanir Pharmaceuticals and GlaxoSmithKiline Consumer Healthcare were the subject of a U.S. nationwide class-action suit in March, 2007 due to the misleading claim that it cut recovery times in half.[97]
Tromantadine is available as a gel that inhibits the entry and spread of the virus by altering the surface composition of skin cells and inhibiting release of viral genetic material. Zilactin is a topical analgesic barrier treatment, which forms a "shield" at the area of application to prevent a sore from increasing in size, and decrease viral spreading during the healing process.
Other drugs
Cimetidine, a common component of heartburn medication, has been shown to lessen the severity of herpes zoster outbreaks in several different instances.[98][99][100] This is an off-label use of the drug. It and probenecid have been shown to reduce the renal clearance of aciclovir.[101] These compounds also reduce the rate, but not the extent, at which valaciclovir is converted into aciclovir.
Limited evidence suggests that low dose aspirin (125 mg daily) might be beneficial in patients with recurrent HSV infections. Aspirin (acetylsalicylic acid) is an non-steroidal anti-inflammatory drug which reduces the level of prostaglandins—naturally occurring lipid compounds—that are essential in creating inflammation.[102] A recent study in animals showed inhibition of thermal (heat) stress induced viral shedding of HSV-1 in the eye by aspirin, and a possible benefit in reducing the frequency of recurrences.[103]
Another treatment is the use of petroleum jelly. Healing of cold sores is sped by barring water or saliva from reaching the sore.
Vaccines
The National Institutes of Health (NIH) in the United States is currently conducting phase III trials of Herpevac, a vaccine against HSV-2.[104] The vaccine has only been shown to be effective for women who have never been exposed to HSV-1. Overall, the vaccine is approximately 48% effective in preventing HSV-2 seropositivity and about 78% effective in preventing symptomatic HSV-2.[104] Assuming FDA approval, a commercial version of the vaccine is estimated to become available in 2008.[citation needed] During initial trials, the vaccine did not exhibit any evidence of preventing HSV-2 in males.[104] Additionally, the vaccine only reduced the acquisition of HSV-2 and symptoms due to newly acquired HSV-2 among women who did not have HSV-2 infection at the time they got the vaccine.[104] Because about 20% of persons in the United States have HSV-2 infection, this further reduces the population for whom this vaccine might be appropriate.[104]
Researchers at the University of Florida have made a hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead which targets the mRNA of the UL20 gene greatly reduced the level of HSV-1 ocular infection in rabbits and reduced the viral yield in vivo.[105]
Natural compounds
Many people seek benefits in natural products and dietary supplements for treatment of herpes
Certain dietary adjustments, dietary supplements, and alternative remedies are believed to be beneficial in the treatment of herpes, either alone, or in conjunction with prescribed antiviral therapy. There is currently insufficient scientific and clinical evidence to support the effective use of many of these compounds to treat herpes in humans.[106]
Lysine supplementation has been used for the prophylaxis and treatment of herpes simplex Doses smaller than 1 gram per day appear to be ineffective.[107][108][109]
Aloe vera, available as a cream or gel, makes an affected area heal faster and may prevent recurrences.[110]
Lemon balm (Melissa officinalis) has antiviral activity against HSV-2 in cell culture and may reduce HSV symptoms in herpes infected people.[111][112][112]
Carrageenans—linear sulphated polysaccharides extracted from red seaweeds—have been shown to have antiviral effects in HSV-infected cells and in mice.[113] However, there is no evidence that this compound is effective as a treatment in humans.[114]
There is conflicting evidence on a possible benefit from extracts from the plant echinacea in treating oral, but not genital, herpes.
Resveratrol, a compound naturally produced by plants and a component of red wine, prevents HSV replication in cultured cells and reduces cutaneous HSV lesion formation in mice. It is not considered potent enough to be an effective treatment on its own.
Extracts from garlic have shown antiviral activity against HSV in cell culture experiments, although the extremely high concentrations of the extracts required to produce an antiviral effect was also toxic to the cells.[119]
The plant Prunella vulgaris, commonly known as selfheal, also prevents expression of both type 1 and type 2 herpes in cultured cells.[120]
Lactoferrin, a component of whey protein, has been shown to have a synergistic effect with aciclovir against HSV in vitro.[121]
Some dietary supplements have been suggested to positively treat herpes. These include vitamin C, vitamin A, vitamin E, and zinc.[122][123]
Butylated hydroxytoluene (BHT), commonly available as a food preservative, has been shown in cell culture and animal studies to inactivate herpes virus.[124][125] However, BHT has not been clinically tested and approved to treat herpes infections in humans.
Psychological and social effects
Some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Feelings can include depression, fear of rejection, feelings of isolation, fear of being found out, self-destructive feelings, and fear of masturbation.[126] These feelings usually lessen over time. Support groups have been formed in the United States and the UK, providing information about herpes and running message forums and dating websites for sufferers.
People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners that they consider casual.[132] A perceived reaction is sometimes taken into account before making a decision about whether to inform new partners and at what point in the relationship. Many people choose not to disclose their herpes status when they first begin dating someone, but wait until it later becomes clear that they are moving towards a sexual relationship. Other people disclose their herpes status upfront. Still others choose only to date other people who already have herpes.
Herpes viruses cycle between periods of active disease—presenting as blisters containing infectious virus particles—that last 2–21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. After initial infection, the viruses move to sensory nerves, where they reside as life-long, latent viruses. Causes of recurrence are uncertain, though some potential triggers have been identified. Over time episodes of active disease reduce in frequency.
Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual. Transmission may also occur through skin-to-skin contact during periods of asymptomatic shedding. Barrier protection methods are the most reliable, but not failsafe, method of preventing transmission of herpes. Oral herpes is easily diagnosed if the patient presents with visible sores or ulcers. Early stages of orofacial herpes and genital herpes are harder to diagnose; laboratory testing is usually required. Prevalence of HSV infections varies throughout the world. Poor hygiene, overcrowding, lower socioeconomic status, and birth in an undeveloped country have been identified as risk factors associated with increased HSV-1 childhood infection. Additional studies have identified other risk factors for both types of HSV.
There is currently no cure for herpes; no vaccine is currently available to prevent or eliminate herpes. However, treatments are available to reduce viral reproduction and shedding, prevent the virus from entering the skin, and alleviate the severity of symptomatic episodes.
Disorders
HSV infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow). More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis). Patients with immature or suppressed immune systems, such as newborn infants, transplant recipients, or AIDS patients are prone to severe complications from HSV infections.
In all cases HSV is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion.[1] As a result of primary infection, the body produces antibodies to the particular type of HSV involved, preventing a subsequent infection of that type at a different site. In HSV-1 infected individuals, seroconversion after an oral infection will prevent additional HSV-1 infections such as whitlow, genital herpes, and keratitis. Prior HSV-1 seroconversion seems to ameliorate the symptoms of a later HSV-2 infection, however HSV-2 can still be contracted. Most indications are that if an HSV-2 infection is contracted prior to HSV-1 seroconversion, that person cannot get an HSV-1 infection later.
Orofacial infection
Herpesviral vesicular dermatitis
Classification and external resources
Herpes lesion on upper lip and face
ICD-10 B00.1
Orofacial herpes affects the face and mouth. Infection occurs when the virus comes into contact with oral mucosa or abraded skin. Infection by the type 1 strain of herpes simplex virus (HSV-1) is the most common cause of orofacial herpes, though cases of oral infection by the type 2 strain are increasing.[2]
Herpes infections are largely asymptomatic; when symptoms appear they will typically resolve within two weeks.[3] The main symptom of oral infection is acute herpetic gingivostomatitis (inflammation of the mucosa of the cheek and gums), which occurs within 5–10 days of infection. Other symptoms may also develop, including painful ulcers—sometimes confused with canker sores—fever, and sore throat.[3] Primary HSV infection in adolescents frequently manifests as severe pharyngitis with lesions developing on the cheek and gums. Some individuals develop difficulty in swallowing (dysphagia) and swollen lymph nodes (lymphadenopathy).[3] Primary HSV infections in adults often results in pharyngitis similar to that observed in glandular fever (infectious mononucleosis), but gingivostomatitis is less likely.
Recurrent oral infection is more common with HSV-1 infections than with HSV-2. Prodromal symptoms often precede a recurrence. Symptoms typically begin with tingling (itching) and reddening of the skin around the infected site. Eventually, fluid-filled blisters form on the lip (labial) tissue and the area between the lip and skin (vermilion border). The recurrent infection is thus often called herpes simplex labialis. Rare reinfections occur inside the mouth (intraoral HSV stomatitis) affecting the gums, alveolar ridge, hard palate, and the back of the tongue, possibly accompanied by herpes labialis.[3][4]
Genital infection
Anogenital herpesviral infection
Classification and external resources
Genital herpes in a female
ICD-10 A60.
MeSH D006558
Genital herpes in a male
Genital herpes in a male
Genital herpes is caused by HSV-2 more often than it is caused by HSV-1, although infections of the genitals by HSV-1 are increasing. The typical symptom a primary HSV-1 or HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores.[5] These usually appear 4–7 days after sexual exposure to HSV for the first time.[1] Genital HSV-1 infection reoccurs at rate of about one sixth of that of genital HSV-2. In males, the lesions occur on the shaft of the penis or other parts of the genital region, on the inner thigh, buttocks, or anus. In females, lesions appear on or near the pubis, labia, clitoris, vulva, buttocks or anus.[5] Other common symptoms include pain, itching, and burning. Less frequent, yet still common, symptoms include discharge from the penis or vagina, fever, headache, muscle pain (myalgia), swollen and enlarged lymph nodes and malaise.[1] Women often experience additional symptoms that include painful urination (dysuria) and cervicitis. Herpetic proctitis (inflammation of the anus and rectum) is common for individuals participating in anal intercourse.[1] After 2–3 weeks, existing lesions progress into ulcers and then crust and heal, although lesions on mucosal surfaces may never form crusts.[1]
Herpes whitlow
Herpes whitlow (herpetic whitlow) is a painful infection that typically affects the fingers or thumbs. Occasionally infection occurs on the toes or on the nail cuticle. Herpes whitlow can be caused by infection by HSV-1 or HSV-2.[6] HSV-1 whitlow is often contracted by health care workers that come in contact with the virus; it is most commonly contracted by dental workers and medical workers exposed to oral secretions.[7][8] It is also often observed in thumb-sucking children with primary HSV-1 oral infection (autoinoculation) prior to seroconversion,[6] and in adults aged 20 to 30 following contact with HSV-2-infected genitals.[9]
Symptoms of herpetic whitlow include swelling, reddening and tenderness of the skin of infected finger. This may be accompanied by fever and swollen lymph nodes. Small, clear vesicles initially form individually, then merge and become cloudy. Associated pain often seems large relative to the physical symptoms. The herpes whitlow lesion usually heals in two to three weeks.[10]
Herpes gladiatorum
Individuals that participate in contact sports such as wrestling, rugby, and soccer sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler’s herpes, or mat herpes. Abraded skin provides an area of entry for HSV-1. Symptoms present within 2 weeks of direct skin-to-skin contact with an infected person. They include skin ulceration on the face, ears, and neck, fever, headache, sore throat and swollen glands. It occasionally affects the eyes. Physical symptoms sometimes recur in the skin.[11] Previous adolescent HSV-1 serocoversion would preclude most herpes gladiatorum, but being that stress and trauma are recognized triggers, such a person would be likely to infect others.
Ocular herpes
Herpesviral ocular disease
Classification and external resources
Herpes infection of the cornea
ICD-10 B00.5
MeSH D016849
Ocular herpes is a special case of facial herpes infection, known as herpes keratitis. Occular herpes is generally caused by HSV-1. It begins with infection of epithelial cells on the surface of the eye and retrograde infection of nerves serving the cornea.[12] Primary infection typically presents as swelling of the conjunctiva and eye-lids (blepharoconjunctivitis), accompanied by small white itchy lesions on the surface of the cornea. The effect of the lesions varies, from minor damage to the epithelium (superficial punctate keratitis), to formation of dendritic ulcers.[13] Infection is unilateral, affecting one eye at a time. Additional symptoms include dull pain deep inside the eye, mild to acute dryness, and sinusitis. Most primary infections resolve spontaneously in a few weeks. Healing can be aided by the use of oral and topical antivirals.
Subsequent recurrences may be more severe, with infected epithelial cells showing larger dendritic ulceration, and lesions forming white plaques.[13] The epithelial layer is sloughed off as the dendritic ulcer grows, and mild inflammation (iritis) may occur in the underlying stroma of iris. Sensation loss occurs in lesional areas, producing generalised corneal anaesthesia with repeated recurrences.[13] Recurrence can be accompanied by chronic dry eye, low grade intermittent conjunctivitis, or chronic unexplained sinusitis. Following persistent infection the concentration of viral DNA reaches a critical limit. Antibody responses against the viral antigen expression in the stroma can trigger a massive autoimmune response in the eye. The response may result in the destruction of the corneal stroma,[13] resulting in loss of vision due to opacification of the cornea. This is known as immune-mediated stromal keratitis.
Treatment with corneal transplants was once ineffective (with only 14%-61% rate of survival without antiviral therapy), as reinfection of the transplant is common when the virus reactivates. However, with concurrent use of antivirals the chance of graft acceptance has improved.[14]
[edit] Herpes simplex encephalitis
Herpesviral encephalitis
Classification and external resources
ICD-10 B00.4, G05.1
ICD-9 054.3
Herpes simplex encephalitis (HSE) is one of the most severe viral infections of the human central nervous system. It is estimated to affect at least 1 in 500,000 individuals per year.[15] About 1 in 3 cases of HSE result from primary HSV-1 infection, predominantly occurring in individuals under the age of 18; 2 in 3 cases occur in seropositive persons, few of whom have history of recurrent orofacial herpes. Approximately 50% of individuals that develop HSE are over 50 years of age.
HSE is thought to be caused by the retrograde transmission of virus from a peripheral site on the face following HSV-1 reactivation, along a nerve axon, to the brain.[15] The virus lies dormant in the ganglion of the trigeminal cranial nerve, but the reason for reactivation, and its pathway to gain access to the brain, remains unclear. The olfactory nerve may also be involved in HSE.[17] For unknown reasons the virus seems to target the temporal lobes of the brain.
Most individuals with HSE show a decrease in their level of consciousness and an altered mental state presenting as confusion, and changes in personality. Increased numbers of white blood cells can be found in patient's cerebrospinal fluid, without the presence of pathogenic bacteria and fungi. Patients typically have a fever.[15] and may have seizures. The electrical activity of the brain changes as the disease progresses, first showing abnormalities in one temporal lobe of the brain, which spread to the other temporal lobe 7–10 days later.[15]
Without treatment, HSE results in rapid death in approximatley 70% of cases.[15] HSE is fatal in around 20% of cases treated, and causes serious long-term neurological damage in over half of survivors. Only a small population of survivors (2.5%) regain completely normal brain function.[16]
Neonatal herpes simplex
Congenital herpesviral (herpes simplex) infection
Classification and external resources
HSV disease in a newborn child
ICD-10 P35.2
ICD-9 771.2
Neonatal HSV infection is a rare but serious condition, usually caused by vertical transmission of HSV from mother to newborn. Only an estimated 10% of cases are acquired postnatally. Neonatal HSV rates in the U.S. are estimated to be between 1 in 3,000 and 1 in 20,000 live births. Approximately 22% of pregnant women in the U.S. have had previous exposure to HSV-2, and an additional 2% acquire the virus during pregnancy, mirroring the infection rate in the general population.[18] The risk of transmission to the newborn is 30-57% in cases where the mother acquired a primary infection in the third trimester of pregnancy. Risk of transmission by a mother with existing antibodies for both HSV-1 and HSV-2 has a much lower (1-3%) transmission rate. This in part is due to the transfer of significant titer of protective maternal antibodies to the fetus from about the seventh month of pregnancy.[19] However, shedding of HSV-1 from both primary genital infection and reactivations is associated with higher transmission from mother to infant.[19]
Complications of neonatal herpes rates are low birth weight and premature birth. Approximately one quarter of NHSV infected babies will have sepsis before the onset of herpes symptoms, further complicating diagnosis.
HSV-1 neonatal herpes is extremely rare in developing countries because development of HSV-1 specific antibodies usually occurs in childhood or adolescence, precluding a genital HSV-1 infection. HSV-2 infections are much more common in these countries. In industrialized nations, the adolescent HSV-1 seroprevalance has been dropping steadily for the last 5 decades. The resulting increase in the number of young women becoming sexually active while HSV-1 seronegative has contributed to increased HSV-1 genital herpes rates, and as a result, increased HSV-1 neonatal herpes in developed nations. A recent three year study in Canada (2000-2003) revealed a neonatal HSV incidence of 5.9 per 100,000 live births. HSV-1 was the cause of 62.5% of cases of neonatal herpes of known type, and 98.3% of transmission was asymptomatic.[20] Asymptomatic genital HSV-1 has been shown to be more infectious to the neonate, and is more likely to produce neonatal herpes, than HSV-2,[21][22]. However, with prompt application of antiviral therapy, the prognosis of neonatal HSV-1 infection is better than that for HSV-2.
Neonatal herpes manifests itself in three forms: skin, eyes, and mouth herpes (SEM), disseminated herpes (DIS), and central nervous system herpes(CNS).[23] SEM herpes is characterized by external lesions but no internal organ involvement. Lesions are likely to appear on trauma sites such as the attachment site of fetal scalp electrodes, forceps or vacuum extractors that are used during delivery, in the margin of the eyes, the nasopharynx, and in areas associated with trauma or surgery (including circumcision).[19] DIS herpes affects internal organs, particularly the liver. CNS herpes is an infection of the nervous system and the brain that can lead to encephalitis. Infants with CNS herpes present with seizures, tremors, lethargy, and irritability, they feed poorly, have unstable temperatures, and their fontanelle (soft spot of the skull) may bulge.[19] CNS herpes is associated with highest morbidity, and DIS herpes has a higher mortality rate. SEM herpes has the best prognosis of the three, however, if left untreated it may spread to the internal organs and result in DIS or CNS herpes with its attendant increases in mortality and morbidity. Death from neonatal HSV disease in the U.S. is currently decreasing; The current death rate is about 25%, down from as high as 85% a few decades ago.
Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir.[23][24][25][26] However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in the 20-40% of infected neonates that have no visible lesions.[27] Herpes simplex virus infection in the newborn "carries high mortality and morbidity rates from central nervous system involvement", according to Harrison's Principles of Internal Medicine, which recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by cesarean section. Women whose herpes is not active can be managed with acyclovir.[28]
Recurrence
Following active infection herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system. The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerve's cell body. HSV latency is static—no virus is produced—and is controlled by a number of viral genes, including Latency Associated Transcript (LAT).[43]
Many HSV infected people experience recurrence within the first year of infection.[1] Prodrome precedes development of lesions. Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop. Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence fewer lesions are likely to develop, lesions are less painful, and lesions heal faster (within 5–10 days without antiviral treatment), than those occurring during the primary infection.[1] Subsequent outbreaks tend to be periodic or episodic, occurring on average four to five times a year when not using antiviral therapy.
The causes of reactivation are uncertain, but several potential triggers have been documented. Physical or psychological stress can trigger an outbreak of herpes.[44] Changes in the immune system during menstruation may play a role in HSV-1 reactivation.[45][46] Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks. Reactivation due to infection is the likely source of the historic terms cold sore and fever blister.
Other identified triggers include: local injury to the face, lips, eyes, or mouth, trauma, surgery, radiotherapy, and exposure to wind, ultraviolet light, or sunlight.
The frequency and severity of recurrent outbreaks may vary greatly between patients. An immunity to the virus is built over time; immunocompromised individuals may experience episodes that are longer, more frequent and more severe. Antiviral medication has been proven to shorten the frequency and duration of outbreaks.[52] Outbreaks may occur at the original site of the infection or in close proximity to nerve endings that reach out from the infected ganglia. In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, back of the thighs.
Transmission and prevention
Herpes is contracted through direct contact with an active lesion or body fluid of an infected person.[53] Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person.[1] There are no documented cases of infection via an inanimate object (e.g. a towel, toilet seat, drinking vessels).[citations needed] To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.
HSV asymptomatic shedding occurs at some time in most individuals infected with herpes. It can occur more than a week before or after a symptomatic recurrence in 50% of cases.[54] Infected people that show no visible symptoms may still shed and transmit virus through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission.[54] Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding.[55] There are indications that some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with 1 to 12 annual recurrences to those that have no recurrences.[54]
Antibodies that develop following an initial infection with a type of HSV prevents reinfection with the same virus type—a person with a history of orofacial infection caused by HSV-1 cannot contract herpes whitlow or a genital infection caused by HSV-1. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV-1 infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection.
Barrier protection, such as a condom, can reduce the risk of herpes transmission in some cases.
Barrier protection, such as a condom, can reduce the risk of herpes transmission in some cases.
For genital herpes, condoms are highly effective in limiting transmission of herpes simplex infection.[56][57] however condoms are not completely effective. The virus cannot pass through latex, but a condom's effectiveness is somewhat limited on a public health scale by their limited use in the community,[58] and on an individual scale because the condom may not completely cover blisters on the penis of an infected male, or the base of the penis or testicles not covered by the condom may come into contact with free virus in vaginal fluid of an infected female. In such cases, abstinence from sexual activity or washing of the genitals after sex is recommended. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa) during oral sex. When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir, in conjunction with a condom, further decreases the chances of transmission to the uninfected partner.[1] Topical microbicides which contain chemicals that directly inactivate the virus and block viral entry are currently being investigated.[1] Vaccines for HSV are currently undergoing trials. Once developed, they may be used to help with prevention or minimize initial infections as well as treatment for existing infections.[59]
As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men.[60] On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is approximately 8-10%.[citation needed] This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is approximately 4-5% annually.[citation needed] Suppressive antiviral therapy reduces these risks by 50%.[citation needed] Antivirals also help prevent the development of symptomatic HSV in infection scenarios—meaning the infected partner will be seropositive but symptom free—by about 50%. Condom use also reduces the transmission risk by 50%.[citation needed] Condom use is much more effective at preventing male to female transmission than vice-versa.[56] The effects of combining antiviral and condom use is roughly additive, thus resulting in approximately a 75% combined reduction in annual transmission risk.[citation needed] These figures reflect experiences with subjects having frequently-recurring genital herpes (>6 recurrences per year). Subjects with low recurrence rates and those with no clinical manifestations were excluded from these studies.[citation needed]
To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1 seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g., fetal scalp electrodes, forceps and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal.[1] The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.[1]
HSV seropositive individuals practising unprotected sex with HIV positive persons pose a high risk of HIV transmission, and are even more susceptible to HIV during an outbreak with active sores.[61]
Diagnosis
Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis.[11] Adults with non-typical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.[11]
Genital herpes can be more difficult to diagnose than oral herpes since most HSV-2-infected persons have no classical symptoms.[11] Further confusing diagnosis, several other conditions resemble genital herpes, including lichen planus, atopic dermatitis, and urethritis.[11] Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include: culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction (PCR) to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.[11]
Serological tests for antibodies to HSV are rarely useful to diagnosis and not routinely used in clinical practice[11], but are important in epidemiological studies. Serologic assays cannot differentiate between antibodies generated in response to a genital versus an oral HSV infection, and as such cannot confirm the site of infection. Absence of antibody to HSV-2 does not exclude gential infection because of the increasing incidence of genital infections caused by HSV-1.
Epidemiology
Although many people infected with HSV develop labial or genital lesions, many more are either undiagnosed or display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes.[62] Since asymptomatic individuals are often unaware of their infection, they are considered at high risk for spreading HSV. Many studies have been performed around the world to estimate the numbers of individuals infected with HSV-1 and HSV-2 by determining if they have developed antibodies against either viral species.[63] This information provides population prevalence of HSV viral infections in individuals with or without active disease.
Europe
Large differences in HSV-1 seroprevalence are seen in different European countries. HSV-1 seroprevalence is high in Bulgaria (83.9%) and The Czech Republic (80.6%), and lower in Belgium (67.4%), The Netherlands (56.7%), and Finland (52.4%).[66] The typical age at which HSV-1 infection is acquired ranges from 5 to 9 years in Eastern European countries like Bulgaria and the Czech Republic, to over 25 years of age in Northern European countries such as Finland, The Netherlands, Germany, and England and Wales. Young adults in Northern European countries are less likely to be infected with HSV-1. European women are more likely to be HSV-1 seropositive than men.
HSV-2 seropositivity is widely distributed in Europeans older than 12, although there are large differences in the percentage of the population exposed to HSV-2. Bulgaria has a high (23.9%) HSV-2 seroprevalence relative to other European countries: Germany (13.9%), Finland (13.4%), Belgium (11.1%), The Netherlands (8.8%), the Czech Republic (6.0%), and England and Wales (4.2%).[66] Women are more likely to be seropositive than men, and likely acquire the virus at an earlier age. In each country of Europe, HSV-2 seropositivity becomes more common from adolescence onwards and increases in the population with age, with a decline in the older age groups in some countries.[66]
North America
United States
African Americans and immigrants from developing countries typically have an HSV-1 seroprevalance in their adolescent population that is two or three times higher than that of Caucasian Americans, possibly reflecting differences in their socioeconomic backgrounds.[11] Many white Americans become sexually active while seronegative for HSV-1. The absence of antibodies from a prior oral HSV-1 infection leaves these individuals susceptible to primary HSV-1 genital infections. This brings with it a risk of vertical transmission to the neonate if the mother contracts a primary infection during the third trimester of pregnancy. A seronegative mother has up to a 57% chance of conveying an HSV infection to her baby during childbirth whereas a woman seropositive for both HSV-1 and HSV-2 has around a 1-3% chance of transmitting infection to her infant.[67]
Women that are seropositive for only one type of HSV are only half as likely to transmit HSV as the seronegative mother. In the U.S. the number of genital infections caused by HSV-1 is now thought to be about 50% of all genetal infections.
In healthy adults, HSV-2 infection occurs more frequently in the USA than in Europe, and infection rates appear to be increasing. In individuals over 12 years old, HSV-2 seroprevalence has increased from 16.4% in 1976 to 21.8% in 1994 and is still rising.[70] The current incidence of genital herpes caused by HSV-2 in the U.S. is roughly one in four or five adults, with approximately 50 million people infected with genital herpes and an estimated 0.5 million new genital herpes infections occurring each year.[11] African Americans appear more susceptible to HSV-2, although the presence of active genital symptoms is more likely in Caucasian Americans. The largest increase in HSV-2 acquisition during the past few years is in white adolescents. People with many lifetime sexual partners and those who are sexually active from a young age are also at higher-risk for the transmission of HSV-2 in the U.S.[71][72][73][74] Women are at higher risk than men for acquiring HSV-2 infection, and the chance of being infected increases with age.[11]
Canada
According to a study in Ontario, up to 55% of Canadians age of 15 to 16, and 89% of individuals in their early forties have antibodies to HSV-1[citation needed]. Teenagers are less likely to be seropositive for HSV-2—antibodies against this virus are only found in 0–3.8% of 15-16 year olds. However, 21% of individuals in their early forties have antibodies against HSV-2, reflecting the sexually transmitted nature of this virus. When standardising for age, HSV-2 seroprevalence in Ontario for individuals between the ages of 15 to 44 was 9.1%. This is much lower than estimated levels of HSV-2 seroprevalence in people of a similar age range in the United States.[75] HSV-2 seroprevalence in pregnant women between the ages of 15-44 in British Columbia is similar, with 57% having antibodies for HSV-1 and 13% having antibodies for HSV-2.[63]
Africa
Sub-Saharan Africa
HSV-2 is more common in Sub-Saharan Africa than in Europe or the North America. Up to 82% of women and 53% of men in Sub-Saharan Africa are seropositive for HSV-2. These are the highest levels of HSV-2 infection in the world, although exact levels vary from country to country in this continent.[76] In most African countries, HSV-2 prevalence increases with age. However, age-associated decreases in HSV-2 seroprevalence has been observed for women in Uganda and Zambia, an in men in Ethiopia, Benin, and Uganda.[63]
Northern Africa
Genital herpes appears less common in Northern Africa compared to Sub-Saharan Africa. For example, only 26% of middle-aged women have antibodies for HSV-2 in Morocco.[64] Women are more likely to be infected with HSV-2 once they are over the age of 40.[64] Children in Egypt are often infected with HSV from a young age—HSV-1 or HSV-2 antibodies are present in an estimated 54% of children under the age of 5, and 77% in children over 10 years of age.[77] Algerian children are also likely to acquire HSV-1 infection at a young age (under 6) and 81.25% of the population has antibodies to HSV-1 by the age of 15.[78]
Central and South America
Relative to rates in Europe and North America, HSV-2 seroprevalency is high in Central and South America. Infection levels are estimated at 20% to 60%.[63][76] During the mid 1980s, HSV-2 prevalence was 33% in 25–29 year old women and 45% in those aged 40 and over in Costa Rica. In the early 1990s HSV-2 prevalence was approximately 45% among women over 60 in Mexico.[63] The highest HSV-2 prevalence in Central or South America—60%—has been found in Colombian middle-aged women, although similar HSV-2 prevalence has been observed in younger women in Haiti (54%).[63] HSV-2 infects about 30% of women over 30 years old in Colombia, Costa Rica, Mexico, and Panama. HSV-2 antibodies were found in more than 41% of women of childbearing age in Brazil.[63] However, no increase in seroprevalence was associated with age in women over 40 years old in Brazil—HSV-2 prevalence was estimated at 50% among women aged 40–49, 33% among women 50–59, and 42% among women over 60. Women in Brazil are more likely to acquire an HSV-2 infection if their male partners had history of anal sex and had many sexual partners in his lifetime.[64] In Peru, HSV-2 prevalence is also high among women in their 30s but is lower in men.[63]
Eastern and South East Asia
HSV-1 seroprevalence in some Asian countries is low, relative to other countries worldwide, with only 51% women in Thailand, and between 50-60% in Japan possessing antibodies.[64][63] HSV-2 seroprevalence in developing Asian countries is comparable (10-30%) to that observed in North America and Northern Europe.[76] However, estimates of HSV-2 infectivity in Thailand are higher than observed in other Eastern Asian countries; total HSV-2 seroprevalence is approximately 37% in this country.[64] HSV-2 seroprevalence is low in women in the Philippines (9%), although commencing activity while young is associated with an increase risk of acquiring HSV-2 infection; woman starting sexual activity by the time they reach 17 are seven times more likely to be HSV-2 seropositive that those starting sexual activity when over 21.[79] In South Korea, incidence of HSV-2 infection in those under the age of 20 is low, only 2.7% in men and 3.0% in women.[65] Seroprevalence levels increase in older South Koreans however, such that the population over 20 that has antibodies against HSV-2 is 21.7% of men and 28% of women.[65]
[edit] Southern Asia
In India 33.3% of individuals are seropositive for HSV-1 and 16.6% are seropositive for HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. Indian men are more likely to be infected with HSV-2 than women, and increasing seroprevalence of this virus is associated with an increasing age.[80]
Middle East
High levels of HSV-1 (97%) and HSV-2 (42%) were found amongst pregnant women in the city of Erzurum in Eastern Anatolia Region, Turkey.[63] In Istanbul however, lower HSV-2 seroprevalence was observed; HSV-2 antibodies were found in 4.8% of sexually active adults, while HSV-1 antibodies were found in 85.3%.[81] Only 5% of pregnant women were infected with HSV-2, and 98% were infected with HSV-1. Prevalence of these viruses was higher in sex workers of Istanbul, reaching levels of 99% and 60% for HSV-1 and HSV-2 prevalence respectively.[81]
The prevalence of HSV-2 in Jordan is 52.8% for men and 41.5% for women.[82]
HSV-1 seroprevalence is 59.8% in the population of Israel and increases with age in both genders. An estimated 9.2% of Israeli adults are infected with HSV-2. Infection of either HSV-1 or HSV-2 is higher in females; HSV-2 seroprevalence reaches 20.5% in females in their 40s. These values are similar to levels in HSV infection in Europe.[83] Antibodies for HSV-1 or HSV-2 are also more likely to be found individuals born outside of Israel, and individuals residing in Jerusalem and Southern Israel; people of Jewish origin living in Israel are less likely to possess antibodies against herpes.[83] HSV-1 causes 66.3% of genital herpes in individuals living in Tel Aviv.[84]
Genital herpes infection from HSV-2 is predicted to be low in Syria although HSV-1 levels are high. HSV-1 infections is common (95%) among healthy Syrians over the age of 30, while HSV-2 prevalence is low in healthy individuals (0.15%), and persons infected with other sexually transmitted diseases (9.5%). High risk groups for acquiring HSV-2 in Syria, include prostitutes and bar girls; they have 34% and 20% seroprevalence respectively.[85]
Oceania
In Australia the seroprevalence of HSV-1 is 76%, with differences associated with age, gender and Indigenous status.[86] An estimated 12% of Australian adults are seropositive for HSV-2, with higher prevalence in women (16%) than in men (8%).[86] Larger cities have higher HSV-2 seroprevalence (13%) than rural populations (9%). Higher prevalence is found in Indigenous Australians (18%) than non-Indigenous Australians (12%) but is lower than HSV-2 prevalence observed in the United States.[86] As in the U.S., HSV-1 is increasingly identified as the cause of genital herpes in Australians; HSV-1 was identified in the anogenital area of only 3% of the population in 1980, but had risen to 41% in 2001.[87] This was most common in females and persons under 25.[87]
The number of genital herpes infections appears to be rising in New Zealand with three times more cases in 1993 compared to 1977.[88] In this country, HSV-2 affects 60% more women than men of similar age.
Treatment
No treatment that can eradicate herpes virii from the body currently exists. Antiviral medications can reduce the frequency, duration, and severity of outbreaks. Antiviral drugs also reduce asymptomatic shedding; it is believed asymptomatic shedding occurs on 10.8% of days in patients not undergoing antiviral treatment, versus 2.9% of days while on antiviral therapy.[54] Non-prescription analgesics can reduce pain and fever during initial outbreaks. Topical anesthetic treatments such as prilocaine, lidocaine or tetracaine can relieve itching and pain.[89][90]
Antiviral medication
Antiviral medications used against herpes viruses work by interfering with viral replication, effectively slowing the replication rate of the virus and providing a greater opportunity for the immune response to intervene. All drugs in this class depend on the activity of the viral enzyme thymidine kinase to convert the drug sequentially from its prodrug form to monophosphate (with one phosphate group), diphosphate (with two phosphate groups), and finally to the triphosphate (with three phosphate groups) form which interferes with viral DNA replication.[91]
The antiviral medication acyclovir
The antiviral medication acyclovir
There are several prescription antiviral medications for controlling herpes simplex outbreaks, including aciclovir (Zovirax), valaciclovir (Valtrex), famciclovir (Famvir), and penciclovir. Aciclovir was the original, and prototypical, member of this drug class; it is now available in generic brands at a greatly reduced cost. Valaciclovir and famciclovir—prodrugs of aciclovir and penciclovir, respectively—have improved solubility in water and better bioavailability when taken orally.[91] Aciclovir is the recommended antiviral for suppressive therapy for use during the last months of pregnancy to prevent transmission of herpes simplex to the neonate.[92] The use of valaciclovir and famciclovir, while potentially improving treatment compliance and efficacy, are still undergoing safety evaluation in this context. Studies with mice provide evidence that treatment with famciclovir, rather than aciclovir, during an initial outbreak can help lower the incidence of future outbreaks, by reducing the amount of latent virus in the neural ganglia. This potential effect on latency drops to zero a few months post-infection.[93]
Antiviral medications are also available as topical creams for treating recurrent outbreaks on the lips, although their effectiveness is disputed.[94] Penciclovir cream has a 7-17 hour longer cellular half-life than aciclovir cream, increasing its effectiveness relative to aciclovir when topically applied.[95]
Topical treatments
Docosanol is available as a cream for direct application to the affected area of skin. It prevents HSV from fusing to cell membranes, thus barring the entry of the virus into the skin. Docosanol was approved for use after clinical trials by the FDA in July 2000.[96] Docosanol is marketed by Avanir Pharmaceuticals under the name Abreva. It was the first over-the-counter antiviral drug approved for sale in the United States and Canada. Avanir Pharmaceuticals and GlaxoSmithKiline Consumer Healthcare were the subject of a U.S. nationwide class-action suit in March, 2007 due to the misleading claim that it cut recovery times in half.[97]
Tromantadine is available as a gel that inhibits the entry and spread of the virus by altering the surface composition of skin cells and inhibiting release of viral genetic material. Zilactin is a topical analgesic barrier treatment, which forms a "shield" at the area of application to prevent a sore from increasing in size, and decrease viral spreading during the healing process.
Other drugs
Cimetidine, a common component of heartburn medication, has been shown to lessen the severity of herpes zoster outbreaks in several different instances.[98][99][100] This is an off-label use of the drug. It and probenecid have been shown to reduce the renal clearance of aciclovir.[101] These compounds also reduce the rate, but not the extent, at which valaciclovir is converted into aciclovir.
Limited evidence suggests that low dose aspirin (125 mg daily) might be beneficial in patients with recurrent HSV infections. Aspirin (acetylsalicylic acid) is an non-steroidal anti-inflammatory drug which reduces the level of prostaglandins—naturally occurring lipid compounds—that are essential in creating inflammation.[102] A recent study in animals showed inhibition of thermal (heat) stress induced viral shedding of HSV-1 in the eye by aspirin, and a possible benefit in reducing the frequency of recurrences.[103]
Another treatment is the use of petroleum jelly. Healing of cold sores is sped by barring water or saliva from reaching the sore.
Vaccines
The National Institutes of Health (NIH) in the United States is currently conducting phase III trials of Herpevac, a vaccine against HSV-2.[104] The vaccine has only been shown to be effective for women who have never been exposed to HSV-1. Overall, the vaccine is approximately 48% effective in preventing HSV-2 seropositivity and about 78% effective in preventing symptomatic HSV-2.[104] Assuming FDA approval, a commercial version of the vaccine is estimated to become available in 2008.[citation needed] During initial trials, the vaccine did not exhibit any evidence of preventing HSV-2 in males.[104] Additionally, the vaccine only reduced the acquisition of HSV-2 and symptoms due to newly acquired HSV-2 among women who did not have HSV-2 infection at the time they got the vaccine.[104] Because about 20% of persons in the United States have HSV-2 infection, this further reduces the population for whom this vaccine might be appropriate.[104]
Researchers at the University of Florida have made a hammerhead ribozyme that targets and cleaves the mRNA of essential genes in HSV-1. The hammerhead which targets the mRNA of the UL20 gene greatly reduced the level of HSV-1 ocular infection in rabbits and reduced the viral yield in vivo.[105]
Natural compounds
Many people seek benefits in natural products and dietary supplements for treatment of herpes
Certain dietary adjustments, dietary supplements, and alternative remedies are believed to be beneficial in the treatment of herpes, either alone, or in conjunction with prescribed antiviral therapy. There is currently insufficient scientific and clinical evidence to support the effective use of many of these compounds to treat herpes in humans.[106]
Lysine supplementation has been used for the prophylaxis and treatment of herpes simplex Doses smaller than 1 gram per day appear to be ineffective.[107][108][109]
Aloe vera, available as a cream or gel, makes an affected area heal faster and may prevent recurrences.[110]
Lemon balm (Melissa officinalis) has antiviral activity against HSV-2 in cell culture and may reduce HSV symptoms in herpes infected people.[111][112][112]
Carrageenans—linear sulphated polysaccharides extracted from red seaweeds—have been shown to have antiviral effects in HSV-infected cells and in mice.[113] However, there is no evidence that this compound is effective as a treatment in humans.[114]
There is conflicting evidence on a possible benefit from extracts from the plant echinacea in treating oral, but not genital, herpes.
Resveratrol, a compound naturally produced by plants and a component of red wine, prevents HSV replication in cultured cells and reduces cutaneous HSV lesion formation in mice. It is not considered potent enough to be an effective treatment on its own.
Extracts from garlic have shown antiviral activity against HSV in cell culture experiments, although the extremely high concentrations of the extracts required to produce an antiviral effect was also toxic to the cells.[119]
The plant Prunella vulgaris, commonly known as selfheal, also prevents expression of both type 1 and type 2 herpes in cultured cells.[120]
Lactoferrin, a component of whey protein, has been shown to have a synergistic effect with aciclovir against HSV in vitro.[121]
Some dietary supplements have been suggested to positively treat herpes. These include vitamin C, vitamin A, vitamin E, and zinc.[122][123]
Butylated hydroxytoluene (BHT), commonly available as a food preservative, has been shown in cell culture and animal studies to inactivate herpes virus.[124][125] However, BHT has not been clinically tested and approved to treat herpes infections in humans.
Psychological and social effects
Some people experience negative feelings related to the condition following diagnosis, particularly if they have acquired the genital form of the disease. Feelings can include depression, fear of rejection, feelings of isolation, fear of being found out, self-destructive feelings, and fear of masturbation.[126] These feelings usually lessen over time. Support groups have been formed in the United States and the UK, providing information about herpes and running message forums and dating websites for sufferers.
People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners that they consider casual.[132] A perceived reaction is sometimes taken into account before making a decision about whether to inform new partners and at what point in the relationship. Many people choose not to disclose their herpes status when they first begin dating someone, but wait until it later becomes clear that they are moving towards a sexual relationship. Other people disclose their herpes status upfront. Still others choose only to date other people who already have herpes.
Human papillomavirus
Papillomaviruses are a diverse group of DNA-based viruses that infect the skin and mucous membranes of humans and a variety of animals. Approximately 130 human papillomavirus (HPV) types have been identified.
Some HPV types can cause warts while others may cause a subclinical infection resulting in precancerous lesions. All HPVs are transmitted by skin-to-skin contact and/or by fomites.
About 30-40 HPV types are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPVs may cause genital warts. However, other HPV types which may infect the genitals do not cause any noticeable signs of infection.
Persistent infection with a "high-risk" subset of sexually transmitted HPVs — different from the ones that cause warts — may lead to potentially precancerous lesions and can progress to invasive cancer. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.
A cervical Pap smear is used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccines Gardasil and Cervarix, which block initial infection with some of the most common sexually transmitted HPV types may lead to further decreases in the incidence of HPV-induced cancer.
Prevalence in the United States
Estimates of prevalence vary from 14% to 90%.[4] One reason for the difference is that some studies report women who are currently infected, while other studies report women who have ever been infected.[5][6]
HPV is estimated to be the most common sexually transmitted infection in the United States.[7] According to the National Cervical Cancer Coalition (NCCC), 11% of American women do not have regular cervical cancer screenings; women who do not have cervical cancer screenings on a regular basis dramatically increase their chances of developing cervical cancer.[2] The American Cancer Society estimates that in 2008, about 11,070 women in the United States will be diagnosed with invasive cervical cancer, and that about 3,870 US women will die from this disease.[8]
At a given time
One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates. 15.2% were infected with one or more of the high-risk types that can cause cancer. However only 3.4% were infected with one or more of the four types prevented by the Gardasil vaccine, which was lower than previous estimates
Lifetime
Genital HPV infection is very common, with estimates suggesting that most (>50%) sexually active women will become infected with one or more of the sexually transmitted HPV types.[11] The American Social Health Association reported estimates that about 75-80% of sexually active Americans will be infected with HPV at some point in their lifetime.[12][13] According to the Centers for Disease Control (CDC), by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV.[14]
HPV lifecycle
The HPV lifecycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby, the virion associates with putative receptors such as alpha integrins and laminins, leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium. The viral oncogenes, E6 and E7, are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is amiable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6 AP (associated protein), which has ubiquitin ligase activity act to ubiquitinate p53 leading to its proteosomal degradation. E7 (inoncogenic HPV's) acts as the primary transforming protein. E7 competes for pRb binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forwards. All HPV can induce transient proliferation, but only 16 and 18 can immortalise cell intes (in vitro). It has also been shown that HPV 16 and 18 cannot immortalise primary rat cells alone, there needs to be activation of the ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins which encapsidate (Encapsidation is the process of incorporating a nucleic acid sequence (e.g., a vector, or a viral genome) into a viral particle) the amplified viral genomes. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.[citation needed]
The concern about life-long recurrences may be based on a misconception rather than a myth. It is true that at present there is no cure for genital human papillomavirus. As a virus, it will remain in the infected person's cells for an indefinite time--most often in a latent state, but occasionally producing symptoms or disease.[citation needed]
Recent studies from the Albert Einstein College of Medicine and from the University of Washington suggest that HPV may eventually be cleared, or rooted out altogether, in most people with well functioning immune systems. It appears that in some cases the virus does remain in the body indefinitely, producing symptoms if the immune system weakens.[citation needed]
Latency period
Once cells are invaded by HPV, a latency (quiet) period of months to years may occur. The latency period means the HPV virus is in an incubation period. Having sex with a partner whose HPV infection is in the incubation period still leaves one vulnerable to becoming infected. HPV virus can last from 3 months to 2 years without visible changes, making it difficult for an infectee to establish the source of infection
Warts
Skin warts
Some HPV infections can cause warts, which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin.[23] Types of warts include:
* Common warts: Some "cutaneous" HPV types, such as HPV-1 and HPV-2,[citation needed] cause common skin warts. Common warts are often found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types do not usually cause genital warts and are not associated with the development of cancer.
* Plantar warts are found on the soles of the feet. Plantar warts grow inward, generally causing pain when walking.
* Subungual or periungual warts form under the fingernail (subungual), around the fingernail or on the cuticle (periungual). They may be more difficult to treat than warts in other locations.[citation needed]
* Flat warts: Flat warts are most commonly found on the arms, face or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer.[24]
Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person. All warts can spread from one part of your own body to another.[25]
Genital warts
Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases.[26][27]
Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they don't display overt symptoms of infection. However, in the vast majority of cases, this is not a cause for concern if proper tests are routinely administered.
HPV types that tend to cause genital warts are not the same ones that cause cervical cancer. However, since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high risk types of the virus also being present.
Respiratory papillomatosis
HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.[28][18]
These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.[29][18]
HPV in immunocompromised patients
In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.[30]
Cervical cancer prevention
Most people become infected with various cutaneous HPV types during childhood. Papillomaviruses have a sturdy outer protein shell or "capsid" that renders them capable of lingering in the environment for long periods of time. Avoiding contact with contaminated surfaces, such as the floors of communal showers or airport security lines, might reduce the risk of cutaneous HPV infection. Treating common warts soon after they first appear may also reduce the spread of the infection to additional sites.
Genital HPV infections may be distributed widely over genital skin and mucosal surfaces, and transmission can occur even when there are no overt symptoms. Several strategies should be employed to minimize the risk of developing diseases caused by genital HPVs:
Pap smear screening
ThinPrep Pap smear with group of normal cervical cells on left and HPV-infected cells on right. The HPV-infected cells show features typical of koilocytes: enlarged (x2 or x3) nuclei and hyperchromasia.
ThinPrep Pap smear with group of normal cervical cells on left and HPV-infected cells on right. The HPV-infected cells show features typical of koilocytes: enlarged (x2 or x3) nuclei and hyperchromasia.
Certain types of sexually transmitted HPVs can cause cervical cancer. Persistent infection with one or more of about a dozen of these "high-risk" HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by regular cervical cytology Papanicolaou screening, colloquially known as "Pap" smear testing. The Pap test is an effective strategy for reducing the risk of invasive cervical cancer. The Pap test involves taking cells from the cervix and putting them on a small glass slide and examining them under a microscope to look for abnormal cells. This method is 70% to 80% effective in detecting HPV-caused cellular abnormalities.[citation needed] A more sensitive method is a “Thin Prep,” in which the cells from the cervix are placed in a liquid solution. This test is 85% to 95% effective in detecting HPV-caused cellular abnormalities.[citation needed] The last Pap test method is mainly used on women over 30. It is a combination Pap-HPV DNA test. If this test comes back negative women can usually wait 3 years before having the test done again. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear. A frequently occurring example of an abnormal cell found in association with HPV is the koilocyte. (See figure.) The American College of Obstetricians and Gynecologists states that the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer.
The Center for Disease Control (CDC) recommends that women get a Pap test no later than 3 years after their first sexual encounter and no later than 21 years of age. Women should have a Pap test every year until age 30. After age 30, women should discuss risk factors with their health care provider to determine whether a Pap test should be done yearly. If risk factors are low and previous Pap tests have been negative, most women only need to have tests every 2-3 years until 65 years of age (Centers for Disease Control 2005). All women are encouraged to get a yearly pap smear solely to detect cellular abnormalities caused by HPV.[14]
Since the Pap test was developed there has been a 70% decrease in cervical cancer deaths over the last 50 years.[citation needed] Pap smear testing has proven to be one of the most successful screening tests in the history of medicine.[citation needed]
A study published in April 2007 suggests that the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."[31]
It has been suggested that Pap smear screening for anal cancer might be of benefit for some sub-populations of gay men.[32]
HPV testing
An HPV test detects certain types of human papillomavirus (HPVs), depending on the test. A method for detecting the DNA of high-risk HPVs has recently been added to the range of clinical options for cervical cancer screening. In March 2003, the US FDA approved a "hybrid-capture" test, marketed by Digene, as a primary screening tool for detecting high-risk HPV infections that may lead to cervical cancer. This test was also approved for use as an adjunct to Pap testing, and may be ordered in response to abnormal Pap smear results.
When patients are screened with both HPV testing and Pap testing the sensitivity reaches 100%. HPV testing can diagnose CIN 2-3 among women older than 30 years.[33] The sensitivity of HPV testing alone was 94.6% and specificity was 94.1%. For patients at similar risk to those in this study (0.4% had CIN 2-3), this leads to a positive predictive value of 6.0% and negative predictive value of 100.0% (click here to adjust these results for patients at higher or lower risk of CIN 2-3).
The CDC states on its "STD Facts-HPV Vaccine" page that "An HPV test or a Pap test can tell that a woman may have HPV, but these tests cannot tell the specific HPV type(s) that a woman has."
In Australia, a self-sampling HPV DNA test - that women can do at home using an ordinary tampon - is being marketed by Tam Pap. It has been approved by the Therapeutic Goods Administration for distribution in Australia.[citation needed]
HPV testing in males
Although it is possible to test for HPV DNA in men,[34] there are no FDA-approved tests for general screening, since the testing is inconclusive and considered medically unnecessary.[21][35]
Genital warts are the only visible sign of HPV in men, and can be identified with a visual check of the genital area. These visible growths, however, are usually the result of non-carcinogenic HPV types. Vinegar solutions have been used to identify flat warts (with limited success[21]) by making them more distinct, but most providers have found this technique helpful only in moist areas, such as the female genital tract.[21]
HPV vaccine
Main article: HPV vaccine
On June 8, 2006, the US Food and Drug Administration approved Gardasil, a prophylactic HPV vaccine which is marketed by Merck. The vaccine trial,[36] conducted in adult women with a mean age of 23, showed protection against initial infection with HPV types 16 and 18, which together cause 70% of cervical cancers, and can cause other cancers, such as anal cancer. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts.
GlaxoSmithKline is seeking approval for a prophylactic vaccine known as Cervarix targeting HPV types 16 and 18. It is delivered in three shots over six months. It is intended for females from 10 years of age onwards.[37]
Gardasil vaccine is delivered in a series of three shots over six months at a cost of approximately $360 (US dollars). The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated,[14] though girls as young as 9 may benefit.[38] Females not yet sexually active can be expected to receive the full benefit of vaccination.
HPV vaccine is made up of proteins from the outer coat of the virus (HPV). There is no infectious material in this vaccine. There is also no thimerosal, a mercury based preservative, in the HPV vaccine.[14] This vaccine has been tested in over 11,000 females (ages 9-26 years) around the world. These studies have shown no serious side effects. The most common side effect is soreness at the injection site. CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use.[39]
The vaccine does not appear to protect against HPV types that females are infected with at the time of vaccination. However, females already infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types covered by the vaccine. Therefore, although overall vaccine effectiveness would be lower when administered to females who have been sexually active, and would decrease with age and likelihood of HPV exposure with increasing number of sex partners, the majority of females in this age group will derive at least partial benefit from vaccination. The vaccine will not have any therapeutic effect on existing HPV infection or cervical lesions.[40]
Since the current vaccine will not protect women against all the HPV types that cause cervical cancer, women should continue to seek Pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine.[40]
Both men and women are carriers of HPV. [41] Possible benefits or efficacy of vaccinating men are being studied.
Smoking avoidance
Main article: Smoking cessation
Carcinogens from tobacco and second-hand smoke are concentrated in the cervix, increasing rate of dysplasia by four to five times, and doubling the risk of cervical cancer.[42]
Condoms
The Centers for Disease Control and Prevention says that "While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with a lower rate of cervical cancer, an HPV-associated disease."[43]
According to Marcus Steiner and Willard Cates in the New England Journal of Medicine, "the protection that condoms offer cannot be precisely quantified."[44] However, in a study reported in the same issue,[45] of 82 female university students followed for eight months, the incidence of genital HPV infection was 37.8 per 100 patient-years among women whose partners used condoms for all instances of intercourse, compared with 89.3 per 100 patient-years in women whose partners used condoms less than 5% of the time. The researchers concluded that "Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection."
Other studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected.[46][47]
Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts. Planned Parenthood recommends condom use to reduce the risk of contracting HPV.[48]
Microbicides
Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact.[49] These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing. A recent study indicates that some sexual lubricant brands that use a gelling agent called carrageenan can inhibit papillomavirus infection in vitro.[50] See Carrageenan#Sexual lubricant and microbicide for details.
Clinical trials are needed to determine whether carrageenan-based sexual lubricant gels are effective for blocking the sexual transmission of HPVs in vivo.
Nutrition
Fruits and vegetables
Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.[51] Consumption of papaya at least once a week was inversely associated with persistent HPV infection.[52]
Vitamin A
There is weak evidence to suggest a significant deficiency of retinol can increase chances of cervical dysplasia, independently of HPV infection. A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile.[53]
However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population.[54]
Vitamin C
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C in the upper quartile compared with those reporting intake in the lowest quartile.[55]
Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherols, but significant trends in these associations were limited to infections lasting 120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.[56]
A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.[57]
Folic acid
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.[58][59]
However, another study showed no relationship between folate status and cervical dysplasia.[53]
Carotenoids
Higher circulating levels of carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids.[56]
The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopenes.[60] A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.[51][52][61]
CoQ10
Women who had either CIN or cervical cancer had markedly lower levels of CoQ10 in their blood and in their cervical cells than the women who were healthy.[citation needed]
Fish oil
In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.[62]
[edit] Treatment
"There is currently no cure or treatment for HPV infection."[42][14]
Therapies for conditions caused by HPV are addressed in main articles covering the various HPV-related diseases.
Epidemiology
Cutaneous HPVs
Infection with cutaneous HPVs is ubiquitous.[63] Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Like remora suckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts. All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.
Genital HPVs
A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31 and 45, can lead to the development of cervical cancer or other types of cancer.[64] In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzo[a]pyrene (BaP) enhance development of certain HPV-induced cancers.[65]
High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases.[66][11] Type 16 causes 41 to 54% of cervical cancers,[67][11] and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers,[68] penile cancers, anal cancers and head and neck cancers.[69]
Public health and genital HPVs
According to the Centers for Disease Control, "At least 50% of sexually active people will get HPV at some time in their lives."[14] All women who have had sex are encouraged to get a regular pap smear to detect cellular abnormalities caused by HPV and help prevent cervical cancer.[70]
The HPV vaccine Gardasil protects against the two strains of HPV that cause 70% of cervical cancer cases, and two strains of HPV that cause 90% of genital warts. The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated.[14]
Perinatal transmission
Although genital HPV types are sometimes transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States.[18] Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.
Some HPV types can cause warts while others may cause a subclinical infection resulting in precancerous lesions. All HPVs are transmitted by skin-to-skin contact and/or by fomites.
About 30-40 HPV types are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPVs may cause genital warts. However, other HPV types which may infect the genitals do not cause any noticeable signs of infection.
Persistent infection with a "high-risk" subset of sexually transmitted HPVs — different from the ones that cause warts — may lead to potentially precancerous lesions and can progress to invasive cancer. HPV infection is a necessary factor in the development of nearly all cases of cervical cancer.
A cervical Pap smear is used to detect cellular abnormalities. This allows targeted surgical removal of condylomatous and/or potentially precancerous lesions prior to the development of invasive cervical cancer. Although the widespread use of Pap testing has reduced the incidence and lethality of cervical cancer in developed countries, the disease still kills several hundred thousand women per year worldwide. HPV vaccines Gardasil and Cervarix, which block initial infection with some of the most common sexually transmitted HPV types may lead to further decreases in the incidence of HPV-induced cancer.
Prevalence in the United States
Estimates of prevalence vary from 14% to 90%.[4] One reason for the difference is that some studies report women who are currently infected, while other studies report women who have ever been infected.[5][6]
HPV is estimated to be the most common sexually transmitted infection in the United States.[7] According to the National Cervical Cancer Coalition (NCCC), 11% of American women do not have regular cervical cancer screenings; women who do not have cervical cancer screenings on a regular basis dramatically increase their chances of developing cervical cancer.[2] The American Cancer Society estimates that in 2008, about 11,070 women in the United States will be diagnosed with invasive cervical cancer, and that about 3,870 US women will die from this disease.[8]
At a given time
One study found that, during 2003–2004, at any given time, 26.8% of women aged 14 to 59 were infected with at least one type of HPV. This was higher than previous estimates. 15.2% were infected with one or more of the high-risk types that can cause cancer. However only 3.4% were infected with one or more of the four types prevented by the Gardasil vaccine, which was lower than previous estimates
Lifetime
Genital HPV infection is very common, with estimates suggesting that most (>50%) sexually active women will become infected with one or more of the sexually transmitted HPV types.[11] The American Social Health Association reported estimates that about 75-80% of sexually active Americans will be infected with HPV at some point in their lifetime.[12][13] According to the Centers for Disease Control (CDC), by the age of 50 more than 80% of American women will have contracted at least one strain of genital HPV.[14]
HPV lifecycle
The HPV lifecycle strictly follows the differentiation program of the host keratinocyte. It is thought that the HPV virion infects epithelial tissues through micro-abrasions, whereby, the virion associates with putative receptors such as alpha integrins and laminins, leading to entry of the virions into basal epithelial cells through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV. At this point, the viral genome is transported to the nucleus by unknown mechanisms and establishes itself at a copy number between 10-200 viral genomes per cell. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium. The viral oncogenes, E6 and E7, are thought to modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is amiable to the amplification of viral genome replication and consequent late gene expression. E6 in association with host E6 AP (associated protein), which has ubiquitin ligase activity act to ubiquitinate p53 leading to its proteosomal degradation. E7 (inoncogenic HPV's) acts as the primary transforming protein. E7 competes for pRb binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forwards. All HPV can induce transient proliferation, but only 16 and 18 can immortalise cell intes (in vitro). It has also been shown that HPV 16 and 18 cannot immortalise primary rat cells alone, there needs to be activation of the ras oncogene. In the upper layers of the host epithelium, the late genes L1 and L2 are transcribed/translated and serve as structural proteins which encapsidate (Encapsidation is the process of incorporating a nucleic acid sequence (e.g., a vector, or a viral genome) into a viral particle) the amplified viral genomes. Virions can then be sloughed off in the dead squames of the host epithelium and the viral lifecycle continues.[citation needed]
The concern about life-long recurrences may be based on a misconception rather than a myth. It is true that at present there is no cure for genital human papillomavirus. As a virus, it will remain in the infected person's cells for an indefinite time--most often in a latent state, but occasionally producing symptoms or disease.[citation needed]
Recent studies from the Albert Einstein College of Medicine and from the University of Washington suggest that HPV may eventually be cleared, or rooted out altogether, in most people with well functioning immune systems. It appears that in some cases the virus does remain in the body indefinitely, producing symptoms if the immune system weakens.[citation needed]
Latency period
Once cells are invaded by HPV, a latency (quiet) period of months to years may occur. The latency period means the HPV virus is in an incubation period. Having sex with a partner whose HPV infection is in the incubation period still leaves one vulnerable to becoming infected. HPV virus can last from 3 months to 2 years without visible changes, making it difficult for an infectee to establish the source of infection
Warts
Skin warts
Some HPV infections can cause warts, which are noncancerous skin growths. Infection with these types of HPV causes a rapid growth of cells on the outer layer of the skin.[23] Types of warts include:
* Common warts: Some "cutaneous" HPV types, such as HPV-1 and HPV-2,[citation needed] cause common skin warts. Common warts are often found on the hands and feet, but can also occur in other areas, such as the elbows or knees. Common warts have a characteristic cauliflower-like surface and are typically slightly raised above the surrounding skin. Cutaneous HPV types do not usually cause genital warts and are not associated with the development of cancer.
* Plantar warts are found on the soles of the feet. Plantar warts grow inward, generally causing pain when walking.
* Subungual or periungual warts form under the fingernail (subungual), around the fingernail or on the cuticle (periungual). They may be more difficult to treat than warts in other locations.[citation needed]
* Flat warts: Flat warts are most commonly found on the arms, face or forehead. Like common warts, flat warts occur most frequently in children and teens. In people with normal immune function, flat warts are not associated with the development of cancer.[24]
Genital warts are quite contagious, while common, flat, and plantar warts are much less likely to spread from person to person. All warts can spread from one part of your own body to another.[25]
Genital warts
Genital or anal warts (condylomata acuminata or venereal warts) are the most easily recognized sign of genital HPV infection. Although a wide variety of HPV types can cause genital warts, types 6 and 11 account for about 90% of all cases.[26][27]
Most people who acquire genital wart-associated HPV types clear the infection rapidly without ever developing warts or any other symptoms. People may transmit the virus to others even if they don't display overt symptoms of infection. However, in the vast majority of cases, this is not a cause for concern if proper tests are routinely administered.
HPV types that tend to cause genital warts are not the same ones that cause cervical cancer. However, since an individual can be infected with multiple types of HPV, the presence of warts does not rule out the possibility of high risk types of the virus also being present.
Respiratory papillomatosis
HPV types 6 and 11 can cause a rare condition known as recurrent respiratory papillomatosis, in which warts form on the larynx or other areas of the respiratory tract.[28][18]
These warts can recur frequently, may require repetitive surgery, may interfere with breathing, and in extremely rare cases can progress to cancer.[29][18]
HPV in immunocompromised patients
In very rare cases, HPV may cause epidermodysplasia verruciformis in immunocompromised individuals. The virus, unchecked by the immune system, causes the overproduction of keratin by skin cells, resulting in lesions resembling warts or cutaneous horns.[30]
Cervical cancer prevention
Most people become infected with various cutaneous HPV types during childhood. Papillomaviruses have a sturdy outer protein shell or "capsid" that renders them capable of lingering in the environment for long periods of time. Avoiding contact with contaminated surfaces, such as the floors of communal showers or airport security lines, might reduce the risk of cutaneous HPV infection. Treating common warts soon after they first appear may also reduce the spread of the infection to additional sites.
Genital HPV infections may be distributed widely over genital skin and mucosal surfaces, and transmission can occur even when there are no overt symptoms. Several strategies should be employed to minimize the risk of developing diseases caused by genital HPVs:
Pap smear screening
ThinPrep Pap smear with group of normal cervical cells on left and HPV-infected cells on right. The HPV-infected cells show features typical of koilocytes: enlarged (x2 or x3) nuclei and hyperchromasia.
ThinPrep Pap smear with group of normal cervical cells on left and HPV-infected cells on right. The HPV-infected cells show features typical of koilocytes: enlarged (x2 or x3) nuclei and hyperchromasia.
Certain types of sexually transmitted HPVs can cause cervical cancer. Persistent infection with one or more of about a dozen of these "high-risk" HPV types is an important factor in nearly all cases of cervical cancer. The development of HPV-induced cervical cancer is a slow process that generally takes many years. During this development phase, pre-cancerous cells can be detected by regular cervical cytology Papanicolaou screening, colloquially known as "Pap" smear testing. The Pap test is an effective strategy for reducing the risk of invasive cervical cancer. The Pap test involves taking cells from the cervix and putting them on a small glass slide and examining them under a microscope to look for abnormal cells. This method is 70% to 80% effective in detecting HPV-caused cellular abnormalities.[citation needed] A more sensitive method is a “Thin Prep,” in which the cells from the cervix are placed in a liquid solution. This test is 85% to 95% effective in detecting HPV-caused cellular abnormalities.[citation needed] The last Pap test method is mainly used on women over 30. It is a combination Pap-HPV DNA test. If this test comes back negative women can usually wait 3 years before having the test done again. Detailed inspection of the cervix by colposcopy may be indicated if abnormal cells are detected by routine Pap smear. A frequently occurring example of an abnormal cell found in association with HPV is the koilocyte. (See figure.) The American College of Obstetricians and Gynecologists states that the newer liquid based cytology methods (Thinprep and Surepath) may miss 15-35% of CIN3's and cancer.
The Center for Disease Control (CDC) recommends that women get a Pap test no later than 3 years after their first sexual encounter and no later than 21 years of age. Women should have a Pap test every year until age 30. After age 30, women should discuss risk factors with their health care provider to determine whether a Pap test should be done yearly. If risk factors are low and previous Pap tests have been negative, most women only need to have tests every 2-3 years until 65 years of age (Centers for Disease Control 2005). All women are encouraged to get a yearly pap smear solely to detect cellular abnormalities caused by HPV.[14]
Since the Pap test was developed there has been a 70% decrease in cervical cancer deaths over the last 50 years.[citation needed] Pap smear testing has proven to be one of the most successful screening tests in the history of medicine.[citation needed]
A study published in April 2007 suggests that the act of performing a Pap smear produces an inflammatory cytokine response, which may initiate immunologic clearance of HPV, therefore reducing the risk of cervical cancer. Women who had even a single Pap smear in their history had a lower incidence of cancer. "A statistically significant decline in the HPV positivity rate correlated with the lifetime number of Pap smears received."[31]
It has been suggested that Pap smear screening for anal cancer might be of benefit for some sub-populations of gay men.[32]
HPV testing
An HPV test detects certain types of human papillomavirus (HPVs), depending on the test. A method for detecting the DNA of high-risk HPVs has recently been added to the range of clinical options for cervical cancer screening. In March 2003, the US FDA approved a "hybrid-capture" test, marketed by Digene, as a primary screening tool for detecting high-risk HPV infections that may lead to cervical cancer. This test was also approved for use as an adjunct to Pap testing, and may be ordered in response to abnormal Pap smear results.
When patients are screened with both HPV testing and Pap testing the sensitivity reaches 100%. HPV testing can diagnose CIN 2-3 among women older than 30 years.[33] The sensitivity of HPV testing alone was 94.6% and specificity was 94.1%. For patients at similar risk to those in this study (0.4% had CIN 2-3), this leads to a positive predictive value of 6.0% and negative predictive value of 100.0% (click here to adjust these results for patients at higher or lower risk of CIN 2-3).
The CDC states on its "STD Facts-HPV Vaccine" page that "An HPV test or a Pap test can tell that a woman may have HPV, but these tests cannot tell the specific HPV type(s) that a woman has."
In Australia, a self-sampling HPV DNA test - that women can do at home using an ordinary tampon - is being marketed by Tam Pap. It has been approved by the Therapeutic Goods Administration for distribution in Australia.[citation needed]
HPV testing in males
Although it is possible to test for HPV DNA in men,[34] there are no FDA-approved tests for general screening, since the testing is inconclusive and considered medically unnecessary.[21][35]
Genital warts are the only visible sign of HPV in men, and can be identified with a visual check of the genital area. These visible growths, however, are usually the result of non-carcinogenic HPV types. Vinegar solutions have been used to identify flat warts (with limited success[21]) by making them more distinct, but most providers have found this technique helpful only in moist areas, such as the female genital tract.[21]
HPV vaccine
Main article: HPV vaccine
On June 8, 2006, the US Food and Drug Administration approved Gardasil, a prophylactic HPV vaccine which is marketed by Merck. The vaccine trial,[36] conducted in adult women with a mean age of 23, showed protection against initial infection with HPV types 16 and 18, which together cause 70% of cervical cancers, and can cause other cancers, such as anal cancer. The vaccine also protects against HPV types 6 and 11, which cause 90 percent of genital warts.
GlaxoSmithKline is seeking approval for a prophylactic vaccine known as Cervarix targeting HPV types 16 and 18. It is delivered in three shots over six months. It is intended for females from 10 years of age onwards.[37]
Gardasil vaccine is delivered in a series of three shots over six months at a cost of approximately $360 (US dollars). The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated,[14] though girls as young as 9 may benefit.[38] Females not yet sexually active can be expected to receive the full benefit of vaccination.
HPV vaccine is made up of proteins from the outer coat of the virus (HPV). There is no infectious material in this vaccine. There is also no thimerosal, a mercury based preservative, in the HPV vaccine.[14] This vaccine has been tested in over 11,000 females (ages 9-26 years) around the world. These studies have shown no serious side effects. The most common side effect is soreness at the injection site. CDC, working with the FDA, will continue to monitor the safety of the vaccine after it is in general use.[39]
The vaccine does not appear to protect against HPV types that females are infected with at the time of vaccination. However, females already infected with one or more vaccine HPV types before vaccination would be protected against disease caused by the other vaccine HPV types covered by the vaccine. Therefore, although overall vaccine effectiveness would be lower when administered to females who have been sexually active, and would decrease with age and likelihood of HPV exposure with increasing number of sex partners, the majority of females in this age group will derive at least partial benefit from vaccination. The vaccine will not have any therapeutic effect on existing HPV infection or cervical lesions.[40]
Since the current vaccine will not protect women against all the HPV types that cause cervical cancer, women should continue to seek Pap smear testing, even after receiving the vaccine. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine.[40]
Both men and women are carriers of HPV. [41] Possible benefits or efficacy of vaccinating men are being studied.
Smoking avoidance
Main article: Smoking cessation
Carcinogens from tobacco and second-hand smoke are concentrated in the cervix, increasing rate of dysplasia by four to five times, and doubling the risk of cervical cancer.[42]
Condoms
The Centers for Disease Control and Prevention says that "While the effect of condoms in preventing HPV infection is unknown, condom use has been associated with a lower rate of cervical cancer, an HPV-associated disease."[43]
According to Marcus Steiner and Willard Cates in the New England Journal of Medicine, "the protection that condoms offer cannot be precisely quantified."[44] However, in a study reported in the same issue,[45] of 82 female university students followed for eight months, the incidence of genital HPV infection was 37.8 per 100 patient-years among women whose partners used condoms for all instances of intercourse, compared with 89.3 per 100 patient-years in women whose partners used condoms less than 5% of the time. The researchers concluded that "Among newly sexually active women, consistent condom use by their partners appears to reduce the risk of cervical and vulvovaginal HPV infection."
Other studies have suggested that regular condom use can effectively limit the ongoing persistence and spread of HPV to additional genital sites in individuals who are already infected.[46][47]
Thus, condom use may reduce the risk that infected individuals will progress to cervical cancer or develop additional genital warts. Planned Parenthood recommends condom use to reduce the risk of contracting HPV.[48]
Microbicides
Ongoing research has suggested that several inexpensive chemicals might serve to block HPV transmission if applied to the genitals prior to sexual contact.[49] These candidate agents, known as topical microbicides, are currently undergoing clinical efficacy testing. A recent study indicates that some sexual lubricant brands that use a gelling agent called carrageenan can inhibit papillomavirus infection in vitro.[50] See Carrageenan#Sexual lubricant and microbicide for details.
Clinical trials are needed to determine whether carrageenan-based sexual lubricant gels are effective for blocking the sexual transmission of HPVs in vivo.
Nutrition
Fruits and vegetables
Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence.[51] Consumption of papaya at least once a week was inversely associated with persistent HPV infection.[52]
Vitamin A
There is weak evidence to suggest a significant deficiency of retinol can increase chances of cervical dysplasia, independently of HPV infection. A small (n~=500) case-control study of a narrow ethnic group (native Americans in New Mexico) assessed serum micro-nutrients as risk factors for cervical dysplasia. Subjects in the lowest serum retinol quartile were at increased risk of CIN I compared with women in the highest quartile.[53]
However, the study population had low overall serum retinol, suggesting deficiency. A study of serum retinol in a well-nourished population reveals that the bottom 20% had serum retinol close to that of the highest levels in this New Mexico sub-population.[54]
Vitamin C
Risk of type-specific, persistent HPV infection was lower among women reporting intake values of vitamin C in the upper quartile compared with those reporting intake in the lowest quartile.[55]
Vitamin E
HPV clearance time was significantly shorter among women with the highest compared with the lowest serum levels of tocopherols, but significant trends in these associations were limited to infections lasting 120 days) was not significantly associated with circulating levels of tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.[56]
A statistically significantly lower level of alpha-tocopherol was observed in the blood serum of HPV-positive patients with cervical intraepithelial neoplasia. The risk of dysplasia was four times higher for an alpha-tocopherol level < 7.95 mumol/l.[57]
Folic acid
Higher folate status was inversely associated with becoming HPV test-positive. Women with higher folate status were significantly less likely to be repeatedly HPV test-positive and more likely to become test-negative. Studies have shown that lower levels of antioxidants coexisting with low levels of folic acid increases the risk of CIN development. Improving folate status in subjects at risk of getting infected or already infected with high-risk HPV may have a beneficial impact in the prevention of cervical cancer.[58][59]
However, another study showed no relationship between folate status and cervical dysplasia.[53]
Carotenoids
Higher circulating levels of carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (120 days) was not significantly associated with circulating levels of carotenoids.[56]
The likelihood of clearing an oncogenic HPV infection is significantly higher with increasing levels of lycopenes.[60] A 56% reduction in HPV persistence risk was observed in women with the highest plasma [lycopene] concentrations compared with women with the lowest plasma lycopene concentrations. These data suggests that vegetable consumption and circulating lycopene may be protective against HPV persistence.[51][52][61]
CoQ10
Women who had either CIN or cervical cancer had markedly lower levels of CoQ10 in their blood and in their cervical cells than the women who were healthy.[citation needed]
Fish oil
In a 1999 study, Docosahexaenoic acid inhibited growth of HPV16 immortalized cells.[62]
[edit] Treatment
"There is currently no cure or treatment for HPV infection."[42][14]
Therapies for conditions caused by HPV are addressed in main articles covering the various HPV-related diseases.
Epidemiology
Cutaneous HPVs
Infection with cutaneous HPVs is ubiquitous.[63] Some HPV types, such as HPV-5, may establish infections that persist for the lifetime of the individual without ever manifesting any clinical symptoms. Like remora suckerfish that hitchhike harmlessly on sharks, these HPV types can be thought of as human commensals. Other cutaneous HPVs, such as HPV types 1 or 2, may cause common warts in some infected individuals. Skin warts are most common in childhood and typically appear and regress spontaneously over the course of weeks to months. About 10% of adults also suffer from recurring skin warts. All HPVs are believed to be capable of establishing long-term "latent" infections in small numbers of stem cells present in the skin. Although these latent infections may never be fully eradicated, immunological control is thought to block the appearance of symptoms such as warts. Immunological control is likely HPV type-specific, meaning that an individual may become immunologically resistant to one HPV type while remaining susceptible to other types.
Genital HPVs
A large increase in the incidence of genital HPV infection occurs at the age when individuals begin to engage in sexual activity. The great majority of genital HPV infections never cause any overt symptoms and are cleared by the immune system in a matter of months. As with cutaneous HPVs, immunity is believed to be HPV type-specific. Some infected individuals may fail to bring genital HPV infection under immunological control. Lingering infection with high-risk HPV types, such as HPVs 16, 18, 31 and 45, can lead to the development of cervical cancer or other types of cancer.[64] In addition to persistent infection with high-risk HPV types, epidemiological and molecular data suggest that co-factors such as the cigarette smoke carcinogen benzo[a]pyrene (BaP) enhance development of certain HPV-induced cancers.[65]
High-risk HPV types 16 and 18 are together responsible for over 65% of cervical cancer cases.[66][11] Type 16 causes 41 to 54% of cervical cancers,[67][11] and accounts for an even greater majority of HPV-induced vaginal/vulvar cancers,[68] penile cancers, anal cancers and head and neck cancers.[69]
Public health and genital HPVs
According to the Centers for Disease Control, "At least 50% of sexually active people will get HPV at some time in their lives."[14] All women who have had sex are encouraged to get a regular pap smear to detect cellular abnormalities caused by HPV and help prevent cervical cancer.[70]
The HPV vaccine Gardasil protects against the two strains of HPV that cause 70% of cervical cancer cases, and two strains of HPV that cause 90% of genital warts. The CDC recommends that girls and women between the ages of 11 and 26 be vaccinated.[14]
Perinatal transmission
Although genital HPV types are sometimes transmitted from mother to child during birth, the appearance of genital HPV-related diseases in newborns is rare. Perinatal transmission of HPV types 6 and 11 can result in the development of juvenile-onset recurrent respiratory papillomatosis (JORRP). JORRP is very rare, with rates of about 2 cases per 100,000 children in the United States.[18] Although JORRP rates are substantially higher if a woman presents with genital warts at the time of giving birth, the risk of JORRP in such cases is still less than 1%.
hypertension reference
Hypertension, referred to as high blood pressure, HTN or HPN, is a medical condition in which the blood pressure is chronically elevated. It was previously referred to as nonarterial hypertension[citation needed], but in current usage, the word "hypertension"[citation needed] without a qualifier normally refers to arterial hypertension. [1]
Hypertension can be classified either essential (primary) or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. Secondary hypertension indicates that the high blood pressure is a result of (i.e., secondary to) another condition, such as kidney disease or tumours (pheochromocytoma and paraganglioma). Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Even moderate elevation of arterial blood pressure leads to shortened life expectancy. At severely high pressures, defined as mean arterial pressures 50% or more above average, a person can expect to live no more than a few years unless appropriately treated.[2]
Hypertension is considered to be present when a person's systolic blood pressure is consistently 140 mmHg or greater, and/or their diastolic blood pressure is consistently 90 mmHg or greater. Recently, as of 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure[4] has defined blood pressure 120/80 mmHg to 139/89 mmHg as "prehypertension." Prehypertension is not a disease category; rather, it is a designation chosen to identify individuals at high risk of developing hypertension. The Mayo Clinic website specifies blood pressure is "normal if it's below 120/80" but that "some data indicate that 115/75 mm Hg should be the gold standard." In patients with diabetes mellitus or kidney disease studies have shown that blood pressure over 130/80 mmHg should be considered high and warrants further treatment.
Hypertension is labeled resistant if a person’s blood pressure remains above their target blood pressure despite taking three or more medications to lower it. The American Heart Association released a scientific statement in May 2008 with guidelines for treating resistant hypertension.
Factors of essential hypertension
Although no specific medical cause can be determined in essential hypertension, the most common form has several contributing factors. These include salt sensitivity, renin homeostasis, insulin resistance, genetics, and age.
Liquorice
Consumption of liquorice (which can be of potent strength in liquorice candy) can lead to a surge in blood pressure. People with hypertension or history of cardio-vascular disease should avoid liquorice raising their blood pressure to risky levels. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present.
Liquorice extracts are present in many medicines (for example cough syrups, throat lozenges and peptic ulcer treatments).
Sodium sensitivity
Sodium is an environmental factor that has received the greatest attention. Approximately one third of the essential hypertensive population is responsive to sodium intake[7]. This is due to the fact that increasing amounts of salt in a person's bloodstream causes cells to release water (due to osmotic pressure) to equilibrate concentration gradient of salt between the cells and the bloodstream; increasing the pressure on the blood vessel walls.
Role of renin
Renin is an enzyme secreted by the juxtaglomerular apparatus of the kidney and linked with aldosterone in a negative feedback loop. The range of renin activity observed in hypertensive subjects tends to be broader than in normotensive individuals. In consequence, some hypertensive patients have been defined as having low-renin and others as having essential hypertension. Low-renin hypertension is more common in African Americans than white Americans, and may explain why African Americans tend to respond better to diuretic therapy than drugs that interfere with the renin-angiotensin system.
High Renin levels predispose to Hypertension: Increased Renin → Increased Angiotensin II → Increased Vasoconstriction, Thirst/ADH and Aldosterone → Increased Sodium Resorption in the Kidneys (DCT and CD) → Increased Blood Pressure. According to the Fifth Edition Annotated Instructor's Edition Nutrition Concepts & Controversies by authors, Eva May Nunnelley Hamilton, M.S., Eleanor Noss Whitney, Ph.d, R.D., Frances Sienkiewicz Sizer, M.S., R.D.published by West Publishing Company 1991 ISBN 0-314-81092-7 "Some authorities believe that potassium might both prevent and treat hypertension. It goes on to advise that salt avoidance may assist in lowering blood pressure in two ways, one of which is by replacing highly processed (salted foods) with natural foods which contain higher levels of potassium, and the other is by reducing salt intake.
Insulin resistance
Insulin is a polypeptide hormone secreted by cells in the islets of langerhans, which are contained throughout the pancreas. Its main purpose is to regulate the levels of glucose in the body antagonistically with glucagon through negative feedback loops. Insulin also exhibits vasodilatory properties. In normotensive individuals, insulin may stimulate sympathetic activity without elevating mean arterial pressure. However, in more extreme conditions such as that of the metabolic syndrome, the increased sympathetic neural activity may over-ride the vasodilatory effects of insulin. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. This feature is now widely recognized as part of syndrome X, or the metabolic syndrome.
Sleep apnea
Sleep apnea is a common, under-recognized cause of hypertension.[8] It is often best treated with nocturnal nasal continuous positive airway pressure, but other approaches include the Mandibular advancement splint (MAS), UPPP, tonsilectomy, adenoidectomy, sinus surgery, or weight loss.
Genetics
Hypertension is one of the most common complex disorders, with genetic heritability averaging 30%.[citation needed] Data supporting this view emerge from animal studies as well as in population studies in humans. Most of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.
More than 50 genes have been examined in association studies with hypertension, and the number is constantly growing.
Age
Over time, the number of collagen fibers in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross-sectional area in systole, and so a raised mean arterial blood pressure.
Other etiologies
There are some anecdotal or transient causes of high blood pressure. These are not to be confused with the disease called hypertension in which there is an intrinsic physiopathological mechanism as described below.
Etiology of secondary hypertension
Only in a small minority of patients with elevated arterial pressure can a specific cause be identified. In 90 percent to 95 percent of high blood pressure cases, the American Heart Association says there's no identifiable cause. These individuals will probably have an endocrine or renal defect that, if corrected, could bring blood pressure back to normal values.
Renal hypertension
Hypertension produced by diseases of the kidney. This includes diseases such as polycystic kidney disease or chronic glomerulonephritis. Hypertension can also be produced by diseases of the renal arteries supplying the kidney. This is known as renovascular hypertension; it is thought that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin-angiotensin system.
Adrenal hypertension
Hypertension is a feature of a variety of adrenal cortical abnormalities. In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.
Cushing's syndrome (hypersecretion of cortisol)
Both adrenal glands can overproduce the hormone cortisol or it can arise in a benign or malignant tumor. Hypertension results from the interplay of several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which may be increased. More than 80% of patients with Cushing's syndrome have hypertension.
In patients with pheochromocytoma increased secretion of catecholamines such as epinephrine and norepinephrine by a tumor (most often located in the adrenal medulla) causes excessive stimulation of [adrenergic receptors], which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).
Genetic causes
Hypertension can be caused by mutations in single genes, inherited on a mendelian basis.[9]
Coarctation of the aorta
Drugs
Certain medications, especially NSAIDS (Motrin/Ibuprofen) and steroids can cause hypertension. Licorice (Glycyrrhiza glabra) inhibits the 11-hydroxysteroid hydrogenase enzyme (catalyzes the reaction of cortisol to cortison) which allows cortisol to stimulate the Mineralocorticoid Receptor (MR) which will lead to effects similar to hyperaldosteronism, which itself is a cause of hypertension.[10]
Rebound hypertension
High blood pressure that is associated with the sudden withdrawal of various antihypertensive medications. The increases in blood pressure may result in blood pressures greater than when the medication was initiated. Depending on the severity of the increase in blood pressure, rebound hypertension may result in a hypertensive emergency. Rebound hypertension is avoided by gradually reducing the dose (also known as "dose tapering"), thereby giving the body enough time to adjust to reduction in dose.
Medications commonly associated with rebound hypertension include centrally-acting antihypertensive agents, such as clonidine and beta-blockers.
Pathophysiology
Most of the secondary mechanisms associated with hypertension are generally fully understood, and are outlined at secondary hypertension. However, those associated with essential (primary) hypertension are far less understood. What is known is that cardiac output is raised early in the disease course, with total peripheral resistance (TPR) normal; over time cardiac output drops to normal levels but TPR is increased. Three theories have been proposed to explain this:
* Inability of the kidneys to excrete sodium, resulting in natriuretic factors such as Atrial Natriuretic Factor being secreted to promote salt excretion with the side-effect of raising total peripheral resistance.
* An overactive renin / angiotensin system leads to vasoconstriction and retention of sodium and water. The increase in blood volume leads to hypertension.
* An overactive sympathetic nervous system, leading to increased stress responses.
It is also known that hypertension is highly heritable and polygenic (caused by more than one gene) and a few candidate genes have been postulated in the etiology of this condition.
Signs and symptoms
Hypertension is usually found incidentally - "case finding" - by healthcare professionals during a routine checkup. The only test for hypertension is a blood pressure measurement. Hypertension in isolation usually produces no symptoms although some people report headaches, fatigue, dizziness, blurred vision, facial flushing, transient insomnia or difficulty sleeping due to feeling hot or flushed, and tinnitus [14] during beginning onset or prior to hypertention diagnosis.
Malignant hypertension (or accelerated hypertension) is distinct as a late phase in the condition, and may present with headaches, blurred vision and end-organ damage.
Hypertension is often confused with mental tension, stress and anxiety. While chronic anxiety and/or irritability is associated with poor outcomes in people with hypertension, it alone does not cause it. Accelerated hypertension is associated with somnolence, confusion, visual disturbances, and nausea and vomiting (hypertensive encephalopathy). [15]
Hypertensive urgencies and emergencies
Hypertension is rarely severe enough to cause symptoms. These typically only surface with a systolic blood pressure over 240 mmHg and/or a diastolic blood pressure over 120 mmHg. These pressures without signs of end-organ damage (such as renal failure) are termed "accelerated" hypertension. When end-organ damage is possible or already ongoing, but in absence of raised intracranial pressure, it is called hypertensive emergency. Hypertension under this circumstance needs to be controlled, but prolonged hospitalization is not necessarily required. When hypertension causes increased intracranial pressure, it is called malignant hypertension. Increased intracranial pressure causes papilledema, which is visible on ophthalmoscopic examination of the retina.
Complications
While elevated blood pressure alone is not an illness, it often requires treatment due to its short- and long-term effects on many organs. The risk is increased for:
* Cerebrovascular accident (CVAs or strokes)
* Myocardial infarction (heart attack)
* Hypertensive cardiomyopathy (heart failure due to chronically high blood pressure)
* Hypertensive retinopathy - damage to the retina
* Hypertensive nephropathy - chronic renal failure due to chronically high blood pressure
* Hypertensive encephalopathy - confusion, headache , convulsion due to vasogenic edema in brain due to high blood pressure.
Pregnancy
Main article: Hypertension of pregnancy
Although few women of childbearing age have high blood pressure, up to 10% develop hypertension of pregnancy. While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary.
[edit] Children and adolescents
As with adults, blood pressure is a variable parameter in children. It varies between individuals and within individuals from day to day and at various times of the day. The epidemic of childhood obesity, the risk of developing left ventricular hypertrophy, and evidence of the early development of atherosclerosis in children would make the detection of and intervention in childhood hypertension important to reduce long-term health risks; however, supporting data are lacking.
Most childhood hypertension, particularly in preadolescents, is secondary to an underlying disorder. Renal parenchymal disease is the most common (60 to 70%) cause of hypertension. Adolescents usually have primary or essential hypertension, making up 85 to 95% of cases. [16]
Diagnosis
Measuring blood pressure
Main article: Blood pressure
Diagnosis of hypertension is generally on the basis of a persistently high blood pressure. Usually this requires three separate measurements at least one week apart. Exceptionally, if the elevation is extreme, or end-organ damage is present then the diagnosis may be applied and treatment commenced immediately.
Obtaining reliable blood pressure measurements relies on following several rules and understanding the many factors that influence blood pressure reading[17].
For instance, measurements in control of hypertension should be at least 1 hour after caffeine, 30 minutes after smoking or strenuous exercise and without any stress. Cuff size is also important. The bladder should encircle and cover two-thirds of the length of the (upper) arm. The patient should be sitting upright in a chair with both feet flat on the floor for a minimum of five minutes prior to taking a reading. The patient should not be on any adrenergic stimulants, such as those found in many cold medications.
When taking manual measurements, the person taking the measurement should be careful to inflate the cuff suitably above anticipated systolic pressure. The person should inflate the cuff to 200 mmHg and then slowly release the air while palpating the radial pulse. After one minute, the cuff should be reinflated to 30 mmHg higher than the pressure at which the radial pulse was no longer palpable. A stethoscope should be placed lightly over the brachial artery. The cuff should be at the level of the heart and the cuff should be deflated at a rate of 2 to 3 mmHg/s. Systolic pressure is the pressure reading at the onset of the sounds described by Korotkoff (Phase one). Diastolic pressure is then recorded as the pressure at which the sounds disappear (K5) or sometimes the K4 point, where the sound is abruptly muffled. Two measurements should be made at least 5 minutes apart, and, if there is a discrepancy of more than 5 mmHg, a third reading should be done. The readings should then be averaged. An initial measurement should include both arms. In elderly patients who particularly when treated may show orthostatic hypotension, measuring lying sitting and standing BP may be useful. The BP should at some time have been measured in each arm, and the higher pressure arm preferred for subsequent measurements.
BP varies with time of day, as may the effectiveness of treatment, and archetypes used to record the data should include the time taken. Analysis of this is rare at present.
Automated machines are commonly used and reduce the variability in manually collected readings [18]. Routine measurements done in medical offices of patients with known hypertension may incorrectly diagnose 20% of patients with uncontrolled hypertension [19]
Home blood pressure monitoring can provide a measurement of a person's blood pressure at different times throughout the day and in different environments, such as at home and at work. Home monitoring may assist in the diagnosis of high or low blood pressure. It may also be used to monitor the effects of medication or lifestyle changes taken to lower or regulate blood pressure levels.
Home monitoring of blood pressure can also assist in the diagnosis of white coat hypertension. The American Heart Association[20] states, "You may have what's called 'white coat hypertension'; that means your blood pressure goes up when you're at the doctor's office. Monitoring at home will help you measure your true blood pressure and can provide your doctor with a log of blood pressure measurements over time. This is helpful in diagnosing and preventing potential health problems."
Some home blood pressure monitoring devices also make use of blood pressure charting software.[21] These charting methods provide printouts for the patient's physician and reminders to take a blood pressure reading. However, a simple and cheap way is simply to manually record values with pen and paper, which can then be inspected by a doctor.
Distinguishing primary vs. secondary hypertension
Once the diagnosis of hypertension has been made it is important to attempt to exclude or identify reversible (secondary) causes.
* Over 91% of adult hypertension has no clear cause and is therefore called essential/primary hypertension. Often, it is part of the metabolic "syndrome X" in patients with insulin resistance: it occurs in combination with diabetes mellitus (type 2), combined hyperlipidemia and central obesity.
* Secondary hypertension is more common in preadolescent children, with most cases caused by renal disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension. [22]
Investigations commonly performed in newly diagnosed hypertension
Tests are undertaken to identify possible causes of secondary hypertension, and seek evidence for end-organ damage to the heart itself or the eyes (retina) and kidneys. Diabetes and raised cholesterol levels being additional risk factors for the development of cardiovascular disease are also tested for as they will also require management.
Blood tests commonly performed include:
* Creatinine (renal function) - to identify both underlying renal disease as a cause of hypertension and conversely hypertension causing onset of kidney damage. Also a baseline for later monitoring the possible side-effects of certain antihypertensive drugs.
* Electrolytes (sodium, potassium)
* Glucose - to identify diabetes mellitus
* Cholesterol
Additional tests often include:
* Testing of urine samples for proteinuria - again to pick up underlying kidney disease or evidence of hypertensive renal damage.
* Electrocardiogram (EKG/ECG) - for evidence of the heart being under strain from working against a high blood pressure. Also may show resulting thickening of the heart muscle (left ventricular hypertrophy) or of the occurrence of previous silent cardiac disease (either subtle electrical conduction disruption or even a myocardial infarction).
* Chest X-ray - again for signs of cardiac enlargement or evidence of cardiac failure.
Epidemiology
The level of blood pressure regarded as deleterious has been revised down during years of epidemiological studies. A widely quoted and important series of such studies is the Framingham Heart Study carried out in an American town: Framingham, Massachusetts. The results from Framingham and of similar work in Busselton, Western Australia have been widely applied. To the extent that people are similar this seems reasonable, but there are known to be genetic variations in the most effective drugs for particular sub-populations. Recently (2004), the Framingham figures have been found to overestimate risks for the UK population considerably. The reasons are unclear. Nevertheless the Framingham work has been an important element of UK health policy.
Treatment
Lifestyle modification (nonpharmacologic treatment)
* Weight reduction and regular aerobic exercise (e.g., jogging) are recommended as the first steps in treating mild to moderate hypertension. Regular mild exercise improves blood flow and helps to reduce resting heart rate and blood pressure. These steps are highly effective in reducing blood pressure, although drug therapy is still necessary for many patients with moderate or severe hypertension to bring their blood pressure down to a safe level.
* Reducing sodium (salt) diet is proven very effective: it decreases blood pressure in about 60% of people (see above). Many people choose to use a salt substitute to reduce their salt intake.
* Additional dietary changes beneficial to reducing blood pressure includes the DASH diet (Dietary Approaches to Stop Hypertension), which is rich in fruits and vegetables and low fat or fat-free dairy foods. This diet is shown effective based on National Institutes of Health sponsored research. In addition, an increase in daily calcium intake has the benefit of increasing dietary potassium, which theoretically can offset the effect of sodium and act on the kidney to decrease blood pressure. This has also been shown to be highly effective in reducing blood pressure.
* Discontinuing tobacco use and alcohol consumption has been shown to lower blood pressure. The exact mechanisms are not fully understood, but blood pressure (especially systolic) always transiently increases following alcohol and/or nicotine consumption. Besides, abstention from cigarette smoking is important for people with hypertension because it reduces the risk of many dangerous outcomes of hypertension, such as stroke and heart attack. Note that coffee drinking (caffeine ingestion) also increases blood pressure transiently, but does not produce chronic hypertension.
* Relaxation therapy, such as meditation, that reduces environmental stress, reducing high sound levels and over-illumination can be an additional method of ameliorating hypertension. Jacobson's Progressive Muscle Relaxation and biofeedback are also used [1] particularly device guided paced breathing [2] [3].
Medications
Main article: Antihypertensive
Unless hypertension is severe, lifestyle changes such as those discussed in the preceding section are strongly recommended before initiation of drug therapy. Adoption of the DASH diet is one example of lifestyle change repeatedly shown to effectively lower mildly-elevated blood pressure. If hypertension is high enough to justify immediate use of medications, lifestyle changes are initiated concomitantly.
There are many classes of medications for treating hypertension, together called antihypertensives, which — by varying means — act by lowering blood pressure. Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood of dementia, heart failure, and mortality from vascular disease.
The aim of treatment should be blood pressure control to <140/90 mmHg for most patients, and lower in certain contexts such as diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg).[4] Each added drug may reduce the systolic blood pressure by 5-10 mmHg, so often multiple drugs are necessary to achieve blood pressure control.
Commonly used drugs include:
* ACE inhibitors such as creatine captopril, enalapril, fosinopril (Monopril), lisinopril (Zestril), quinapril, ramipril (Altace)
* Angiotensin II receptor antagonists: eg, telmisartan (Micardis, Pritor), irbesartan (Avapro), losartan (Cozaar), valsartan (Diovan), candesartan (Amias)
* Alpha blockers such as doxazosin, prazosin, or terazosin
* Beta blockers such as atenolol, labetalol, metoprolol (Lopressor, Toprol-XL), propranolol.
* Calcium channel blockers such as nifedipine (Adalat)[23] amlodipine (Norvasc), diltiazem, verapamil
* Direct renin inhibitors such as aliskiren (Tekturna)
* Diuretics: eg, bendroflumethiazide, chlortalidone, hydrochlorothiazide (also called HCTZ)
* Combination products (which usually contain HCTZ and one other drug)
Choice of initial medication
Unless the blood pressure is severely elevated, consensus guidelines call for medically-supervised lifestyle changes and observation before recommending initiation of drug therapy. All drug treatments have side effects, and while the evidence of benefit at higher blood pressures is overwhelming, drug trials to lower moderately-elevated blood pressure have failed to reduce overall death rates.
If lifestyle changes are ineffective or the presenting blood pressure is critical, then drug therapy is initiated, often requiring more than one agent to effective lower hypertension. Which type of many medications should be used initially for hypertension has been the subject of several large studies and various national guidelines.
The ALLHAT study showed better cost-effectiveness and slightly better outcomes for the thiazide diuretic chlortalidone compared with a calcium channel blocker and an ACE inhibitor in a 33,357-member ethnically mixed study group.[24] The 1993 consensus recommendation for use of thiazide diuretics as initial treatment stems in part from the ALLHAT study results, which concluded in 2002 that "Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy."[24]
A subsequent smaller study (ANBP2) did not show the slight advantages in thiazide diuretic outcomes observed in the ALLHAT study, and actually showed slightly better outcomes for ACE-inhibitors in older white male patients.[25]
Thiazide diuretics are effective, recommended as the best first-line drug for hypertension by many experts, and much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Arguably, this is partly because they are off-patent, less profitable, and thus rarely promoted by the drug industry.[26]
The consensus recommendations of thiazide diuretics as first-line therapy for hypertension stand against a the backdrop that all blood pressure treatments have side-effects. Potentially serious side effects of the thiazide diuretics include hypercholesterinemia, and impaired glucose tolerance with consequent increased risk of developing Diabetes mellitus type 2. The thiazide diuretics also deplete circulating potassium unless combined with a potassium-sparing diuretic or supplemental potassium. On this basis, the consensus recommendations to prefer use of thiazides as first line treatment for essential hypertension have been repeatedly and strongly questioned.[27][28][29] However as the Merck Manual of Geriatrics notes, "thiazide-type diuretics are especially safe and effective in the elderly
Hypertension can be classified either essential (primary) or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. Secondary hypertension indicates that the high blood pressure is a result of (i.e., secondary to) another condition, such as kidney disease or tumours (pheochromocytoma and paraganglioma). Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure. Even moderate elevation of arterial blood pressure leads to shortened life expectancy. At severely high pressures, defined as mean arterial pressures 50% or more above average, a person can expect to live no more than a few years unless appropriately treated.[2]
Hypertension is considered to be present when a person's systolic blood pressure is consistently 140 mmHg or greater, and/or their diastolic blood pressure is consistently 90 mmHg or greater. Recently, as of 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure[4] has defined blood pressure 120/80 mmHg to 139/89 mmHg as "prehypertension." Prehypertension is not a disease category; rather, it is a designation chosen to identify individuals at high risk of developing hypertension. The Mayo Clinic website specifies blood pressure is "normal if it's below 120/80" but that "some data indicate that 115/75 mm Hg should be the gold standard." In patients with diabetes mellitus or kidney disease studies have shown that blood pressure over 130/80 mmHg should be considered high and warrants further treatment.
Hypertension is labeled resistant if a person’s blood pressure remains above their target blood pressure despite taking three or more medications to lower it. The American Heart Association released a scientific statement in May 2008 with guidelines for treating resistant hypertension.
Factors of essential hypertension
Although no specific medical cause can be determined in essential hypertension, the most common form has several contributing factors. These include salt sensitivity, renin homeostasis, insulin resistance, genetics, and age.
Liquorice
Consumption of liquorice (which can be of potent strength in liquorice candy) can lead to a surge in blood pressure. People with hypertension or history of cardio-vascular disease should avoid liquorice raising their blood pressure to risky levels. Frequently, if liquorice is the cause of the high blood pressure, a low blood level of potassium will also be present.
Liquorice extracts are present in many medicines (for example cough syrups, throat lozenges and peptic ulcer treatments).
Sodium sensitivity
Sodium is an environmental factor that has received the greatest attention. Approximately one third of the essential hypertensive population is responsive to sodium intake[7]. This is due to the fact that increasing amounts of salt in a person's bloodstream causes cells to release water (due to osmotic pressure) to equilibrate concentration gradient of salt between the cells and the bloodstream; increasing the pressure on the blood vessel walls.
Role of renin
Renin is an enzyme secreted by the juxtaglomerular apparatus of the kidney and linked with aldosterone in a negative feedback loop. The range of renin activity observed in hypertensive subjects tends to be broader than in normotensive individuals. In consequence, some hypertensive patients have been defined as having low-renin and others as having essential hypertension. Low-renin hypertension is more common in African Americans than white Americans, and may explain why African Americans tend to respond better to diuretic therapy than drugs that interfere with the renin-angiotensin system.
High Renin levels predispose to Hypertension: Increased Renin → Increased Angiotensin II → Increased Vasoconstriction, Thirst/ADH and Aldosterone → Increased Sodium Resorption in the Kidneys (DCT and CD) → Increased Blood Pressure. According to the Fifth Edition Annotated Instructor's Edition Nutrition Concepts & Controversies by authors, Eva May Nunnelley Hamilton, M.S., Eleanor Noss Whitney, Ph.d, R.D., Frances Sienkiewicz Sizer, M.S., R.D.published by West Publishing Company 1991 ISBN 0-314-81092-7 "Some authorities believe that potassium might both prevent and treat hypertension. It goes on to advise that salt avoidance may assist in lowering blood pressure in two ways, one of which is by replacing highly processed (salted foods) with natural foods which contain higher levels of potassium, and the other is by reducing salt intake.
Insulin resistance
Insulin is a polypeptide hormone secreted by cells in the islets of langerhans, which are contained throughout the pancreas. Its main purpose is to regulate the levels of glucose in the body antagonistically with glucagon through negative feedback loops. Insulin also exhibits vasodilatory properties. In normotensive individuals, insulin may stimulate sympathetic activity without elevating mean arterial pressure. However, in more extreme conditions such as that of the metabolic syndrome, the increased sympathetic neural activity may over-ride the vasodilatory effects of insulin. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. This feature is now widely recognized as part of syndrome X, or the metabolic syndrome.
Sleep apnea
Sleep apnea is a common, under-recognized cause of hypertension.[8] It is often best treated with nocturnal nasal continuous positive airway pressure, but other approaches include the Mandibular advancement splint (MAS), UPPP, tonsilectomy, adenoidectomy, sinus surgery, or weight loss.
Genetics
Hypertension is one of the most common complex disorders, with genetic heritability averaging 30%.[citation needed] Data supporting this view emerge from animal studies as well as in population studies in humans. Most of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.
More than 50 genes have been examined in association studies with hypertension, and the number is constantly growing.
Age
Over time, the number of collagen fibers in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross-sectional area in systole, and so a raised mean arterial blood pressure.
Other etiologies
There are some anecdotal or transient causes of high blood pressure. These are not to be confused with the disease called hypertension in which there is an intrinsic physiopathological mechanism as described below.
Etiology of secondary hypertension
Only in a small minority of patients with elevated arterial pressure can a specific cause be identified. In 90 percent to 95 percent of high blood pressure cases, the American Heart Association says there's no identifiable cause. These individuals will probably have an endocrine or renal defect that, if corrected, could bring blood pressure back to normal values.
Renal hypertension
Hypertension produced by diseases of the kidney. This includes diseases such as polycystic kidney disease or chronic glomerulonephritis. Hypertension can also be produced by diseases of the renal arteries supplying the kidney. This is known as renovascular hypertension; it is thought that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin-angiotensin system.
Adrenal hypertension
Hypertension is a feature of a variety of adrenal cortical abnormalities. In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.
Cushing's syndrome (hypersecretion of cortisol)
Both adrenal glands can overproduce the hormone cortisol or it can arise in a benign or malignant tumor. Hypertension results from the interplay of several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which may be increased. More than 80% of patients with Cushing's syndrome have hypertension.
In patients with pheochromocytoma increased secretion of catecholamines such as epinephrine and norepinephrine by a tumor (most often located in the adrenal medulla) causes excessive stimulation of [adrenergic receptors], which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).
Genetic causes
Hypertension can be caused by mutations in single genes, inherited on a mendelian basis.[9]
Coarctation of the aorta
Drugs
Certain medications, especially NSAIDS (Motrin/Ibuprofen) and steroids can cause hypertension. Licorice (Glycyrrhiza glabra) inhibits the 11-hydroxysteroid hydrogenase enzyme (catalyzes the reaction of cortisol to cortison) which allows cortisol to stimulate the Mineralocorticoid Receptor (MR) which will lead to effects similar to hyperaldosteronism, which itself is a cause of hypertension.[10]
Rebound hypertension
High blood pressure that is associated with the sudden withdrawal of various antihypertensive medications. The increases in blood pressure may result in blood pressures greater than when the medication was initiated. Depending on the severity of the increase in blood pressure, rebound hypertension may result in a hypertensive emergency. Rebound hypertension is avoided by gradually reducing the dose (also known as "dose tapering"), thereby giving the body enough time to adjust to reduction in dose.
Medications commonly associated with rebound hypertension include centrally-acting antihypertensive agents, such as clonidine and beta-blockers.
Pathophysiology
Most of the secondary mechanisms associated with hypertension are generally fully understood, and are outlined at secondary hypertension. However, those associated with essential (primary) hypertension are far less understood. What is known is that cardiac output is raised early in the disease course, with total peripheral resistance (TPR) normal; over time cardiac output drops to normal levels but TPR is increased. Three theories have been proposed to explain this:
* Inability of the kidneys to excrete sodium, resulting in natriuretic factors such as Atrial Natriuretic Factor being secreted to promote salt excretion with the side-effect of raising total peripheral resistance.
* An overactive renin / angiotensin system leads to vasoconstriction and retention of sodium and water. The increase in blood volume leads to hypertension.
* An overactive sympathetic nervous system, leading to increased stress responses.
It is also known that hypertension is highly heritable and polygenic (caused by more than one gene) and a few candidate genes have been postulated in the etiology of this condition.
Signs and symptoms
Hypertension is usually found incidentally - "case finding" - by healthcare professionals during a routine checkup. The only test for hypertension is a blood pressure measurement. Hypertension in isolation usually produces no symptoms although some people report headaches, fatigue, dizziness, blurred vision, facial flushing, transient insomnia or difficulty sleeping due to feeling hot or flushed, and tinnitus [14] during beginning onset or prior to hypertention diagnosis.
Malignant hypertension (or accelerated hypertension) is distinct as a late phase in the condition, and may present with headaches, blurred vision and end-organ damage.
Hypertension is often confused with mental tension, stress and anxiety. While chronic anxiety and/or irritability is associated with poor outcomes in people with hypertension, it alone does not cause it. Accelerated hypertension is associated with somnolence, confusion, visual disturbances, and nausea and vomiting (hypertensive encephalopathy). [15]
Hypertensive urgencies and emergencies
Hypertension is rarely severe enough to cause symptoms. These typically only surface with a systolic blood pressure over 240 mmHg and/or a diastolic blood pressure over 120 mmHg. These pressures without signs of end-organ damage (such as renal failure) are termed "accelerated" hypertension. When end-organ damage is possible or already ongoing, but in absence of raised intracranial pressure, it is called hypertensive emergency. Hypertension under this circumstance needs to be controlled, but prolonged hospitalization is not necessarily required. When hypertension causes increased intracranial pressure, it is called malignant hypertension. Increased intracranial pressure causes papilledema, which is visible on ophthalmoscopic examination of the retina.
Complications
While elevated blood pressure alone is not an illness, it often requires treatment due to its short- and long-term effects on many organs. The risk is increased for:
* Cerebrovascular accident (CVAs or strokes)
* Myocardial infarction (heart attack)
* Hypertensive cardiomyopathy (heart failure due to chronically high blood pressure)
* Hypertensive retinopathy - damage to the retina
* Hypertensive nephropathy - chronic renal failure due to chronically high blood pressure
* Hypertensive encephalopathy - confusion, headache , convulsion due to vasogenic edema in brain due to high blood pressure.
Pregnancy
Main article: Hypertension of pregnancy
Although few women of childbearing age have high blood pressure, up to 10% develop hypertension of pregnancy. While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary.
[edit] Children and adolescents
As with adults, blood pressure is a variable parameter in children. It varies between individuals and within individuals from day to day and at various times of the day. The epidemic of childhood obesity, the risk of developing left ventricular hypertrophy, and evidence of the early development of atherosclerosis in children would make the detection of and intervention in childhood hypertension important to reduce long-term health risks; however, supporting data are lacking.
Most childhood hypertension, particularly in preadolescents, is secondary to an underlying disorder. Renal parenchymal disease is the most common (60 to 70%) cause of hypertension. Adolescents usually have primary or essential hypertension, making up 85 to 95% of cases. [16]
Diagnosis
Measuring blood pressure
Main article: Blood pressure
Diagnosis of hypertension is generally on the basis of a persistently high blood pressure. Usually this requires three separate measurements at least one week apart. Exceptionally, if the elevation is extreme, or end-organ damage is present then the diagnosis may be applied and treatment commenced immediately.
Obtaining reliable blood pressure measurements relies on following several rules and understanding the many factors that influence blood pressure reading[17].
For instance, measurements in control of hypertension should be at least 1 hour after caffeine, 30 minutes after smoking or strenuous exercise and without any stress. Cuff size is also important. The bladder should encircle and cover two-thirds of the length of the (upper) arm. The patient should be sitting upright in a chair with both feet flat on the floor for a minimum of five minutes prior to taking a reading. The patient should not be on any adrenergic stimulants, such as those found in many cold medications.
When taking manual measurements, the person taking the measurement should be careful to inflate the cuff suitably above anticipated systolic pressure. The person should inflate the cuff to 200 mmHg and then slowly release the air while palpating the radial pulse. After one minute, the cuff should be reinflated to 30 mmHg higher than the pressure at which the radial pulse was no longer palpable. A stethoscope should be placed lightly over the brachial artery. The cuff should be at the level of the heart and the cuff should be deflated at a rate of 2 to 3 mmHg/s. Systolic pressure is the pressure reading at the onset of the sounds described by Korotkoff (Phase one). Diastolic pressure is then recorded as the pressure at which the sounds disappear (K5) or sometimes the K4 point, where the sound is abruptly muffled. Two measurements should be made at least 5 minutes apart, and, if there is a discrepancy of more than 5 mmHg, a third reading should be done. The readings should then be averaged. An initial measurement should include both arms. In elderly patients who particularly when treated may show orthostatic hypotension, measuring lying sitting and standing BP may be useful. The BP should at some time have been measured in each arm, and the higher pressure arm preferred for subsequent measurements.
BP varies with time of day, as may the effectiveness of treatment, and archetypes used to record the data should include the time taken. Analysis of this is rare at present.
Automated machines are commonly used and reduce the variability in manually collected readings [18]. Routine measurements done in medical offices of patients with known hypertension may incorrectly diagnose 20% of patients with uncontrolled hypertension [19]
Home blood pressure monitoring can provide a measurement of a person's blood pressure at different times throughout the day and in different environments, such as at home and at work. Home monitoring may assist in the diagnosis of high or low blood pressure. It may also be used to monitor the effects of medication or lifestyle changes taken to lower or regulate blood pressure levels.
Home monitoring of blood pressure can also assist in the diagnosis of white coat hypertension. The American Heart Association[20] states, "You may have what's called 'white coat hypertension'; that means your blood pressure goes up when you're at the doctor's office. Monitoring at home will help you measure your true blood pressure and can provide your doctor with a log of blood pressure measurements over time. This is helpful in diagnosing and preventing potential health problems."
Some home blood pressure monitoring devices also make use of blood pressure charting software.[21] These charting methods provide printouts for the patient's physician and reminders to take a blood pressure reading. However, a simple and cheap way is simply to manually record values with pen and paper, which can then be inspected by a doctor.
Distinguishing primary vs. secondary hypertension
Once the diagnosis of hypertension has been made it is important to attempt to exclude or identify reversible (secondary) causes.
* Over 91% of adult hypertension has no clear cause and is therefore called essential/primary hypertension. Often, it is part of the metabolic "syndrome X" in patients with insulin resistance: it occurs in combination with diabetes mellitus (type 2), combined hyperlipidemia and central obesity.
* Secondary hypertension is more common in preadolescent children, with most cases caused by renal disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension. [22]
Investigations commonly performed in newly diagnosed hypertension
Tests are undertaken to identify possible causes of secondary hypertension, and seek evidence for end-organ damage to the heart itself or the eyes (retina) and kidneys. Diabetes and raised cholesterol levels being additional risk factors for the development of cardiovascular disease are also tested for as they will also require management.
Blood tests commonly performed include:
* Creatinine (renal function) - to identify both underlying renal disease as a cause of hypertension and conversely hypertension causing onset of kidney damage. Also a baseline for later monitoring the possible side-effects of certain antihypertensive drugs.
* Electrolytes (sodium, potassium)
* Glucose - to identify diabetes mellitus
* Cholesterol
Additional tests often include:
* Testing of urine samples for proteinuria - again to pick up underlying kidney disease or evidence of hypertensive renal damage.
* Electrocardiogram (EKG/ECG) - for evidence of the heart being under strain from working against a high blood pressure. Also may show resulting thickening of the heart muscle (left ventricular hypertrophy) or of the occurrence of previous silent cardiac disease (either subtle electrical conduction disruption or even a myocardial infarction).
* Chest X-ray - again for signs of cardiac enlargement or evidence of cardiac failure.
Epidemiology
The level of blood pressure regarded as deleterious has been revised down during years of epidemiological studies. A widely quoted and important series of such studies is the Framingham Heart Study carried out in an American town: Framingham, Massachusetts. The results from Framingham and of similar work in Busselton, Western Australia have been widely applied. To the extent that people are similar this seems reasonable, but there are known to be genetic variations in the most effective drugs for particular sub-populations. Recently (2004), the Framingham figures have been found to overestimate risks for the UK population considerably. The reasons are unclear. Nevertheless the Framingham work has been an important element of UK health policy.
Treatment
Lifestyle modification (nonpharmacologic treatment)
* Weight reduction and regular aerobic exercise (e.g., jogging) are recommended as the first steps in treating mild to moderate hypertension. Regular mild exercise improves blood flow and helps to reduce resting heart rate and blood pressure. These steps are highly effective in reducing blood pressure, although drug therapy is still necessary for many patients with moderate or severe hypertension to bring their blood pressure down to a safe level.
* Reducing sodium (salt) diet is proven very effective: it decreases blood pressure in about 60% of people (see above). Many people choose to use a salt substitute to reduce their salt intake.
* Additional dietary changes beneficial to reducing blood pressure includes the DASH diet (Dietary Approaches to Stop Hypertension), which is rich in fruits and vegetables and low fat or fat-free dairy foods. This diet is shown effective based on National Institutes of Health sponsored research. In addition, an increase in daily calcium intake has the benefit of increasing dietary potassium, which theoretically can offset the effect of sodium and act on the kidney to decrease blood pressure. This has also been shown to be highly effective in reducing blood pressure.
* Discontinuing tobacco use and alcohol consumption has been shown to lower blood pressure. The exact mechanisms are not fully understood, but blood pressure (especially systolic) always transiently increases following alcohol and/or nicotine consumption. Besides, abstention from cigarette smoking is important for people with hypertension because it reduces the risk of many dangerous outcomes of hypertension, such as stroke and heart attack. Note that coffee drinking (caffeine ingestion) also increases blood pressure transiently, but does not produce chronic hypertension.
* Relaxation therapy, such as meditation, that reduces environmental stress, reducing high sound levels and over-illumination can be an additional method of ameliorating hypertension. Jacobson's Progressive Muscle Relaxation and biofeedback are also used [1] particularly device guided paced breathing [2] [3].
Medications
Main article: Antihypertensive
Unless hypertension is severe, lifestyle changes such as those discussed in the preceding section are strongly recommended before initiation of drug therapy. Adoption of the DASH diet is one example of lifestyle change repeatedly shown to effectively lower mildly-elevated blood pressure. If hypertension is high enough to justify immediate use of medications, lifestyle changes are initiated concomitantly.
There are many classes of medications for treating hypertension, together called antihypertensives, which — by varying means — act by lowering blood pressure. Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood of dementia, heart failure, and mortality from vascular disease.
The aim of treatment should be blood pressure control to <140/90 mmHg for most patients, and lower in certain contexts such as diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg).[4] Each added drug may reduce the systolic blood pressure by 5-10 mmHg, so often multiple drugs are necessary to achieve blood pressure control.
Commonly used drugs include:
* ACE inhibitors such as creatine captopril, enalapril, fosinopril (Monopril), lisinopril (Zestril), quinapril, ramipril (Altace)
* Angiotensin II receptor antagonists: eg, telmisartan (Micardis, Pritor), irbesartan (Avapro), losartan (Cozaar), valsartan (Diovan), candesartan (Amias)
* Alpha blockers such as doxazosin, prazosin, or terazosin
* Beta blockers such as atenolol, labetalol, metoprolol (Lopressor, Toprol-XL), propranolol.
* Calcium channel blockers such as nifedipine (Adalat)[23] amlodipine (Norvasc), diltiazem, verapamil
* Direct renin inhibitors such as aliskiren (Tekturna)
* Diuretics: eg, bendroflumethiazide, chlortalidone, hydrochlorothiazide (also called HCTZ)
* Combination products (which usually contain HCTZ and one other drug)
Choice of initial medication
Unless the blood pressure is severely elevated, consensus guidelines call for medically-supervised lifestyle changes and observation before recommending initiation of drug therapy. All drug treatments have side effects, and while the evidence of benefit at higher blood pressures is overwhelming, drug trials to lower moderately-elevated blood pressure have failed to reduce overall death rates.
If lifestyle changes are ineffective or the presenting blood pressure is critical, then drug therapy is initiated, often requiring more than one agent to effective lower hypertension. Which type of many medications should be used initially for hypertension has been the subject of several large studies and various national guidelines.
The ALLHAT study showed better cost-effectiveness and slightly better outcomes for the thiazide diuretic chlortalidone compared with a calcium channel blocker and an ACE inhibitor in a 33,357-member ethnically mixed study group.[24] The 1993 consensus recommendation for use of thiazide diuretics as initial treatment stems in part from the ALLHAT study results, which concluded in 2002 that "Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy."[24]
A subsequent smaller study (ANBP2) did not show the slight advantages in thiazide diuretic outcomes observed in the ALLHAT study, and actually showed slightly better outcomes for ACE-inhibitors in older white male patients.[25]
Thiazide diuretics are effective, recommended as the best first-line drug for hypertension by many experts, and much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Arguably, this is partly because they are off-patent, less profitable, and thus rarely promoted by the drug industry.[26]
The consensus recommendations of thiazide diuretics as first-line therapy for hypertension stand against a the backdrop that all blood pressure treatments have side-effects. Potentially serious side effects of the thiazide diuretics include hypercholesterinemia, and impaired glucose tolerance with consequent increased risk of developing Diabetes mellitus type 2. The thiazide diuretics also deplete circulating potassium unless combined with a potassium-sparing diuretic or supplemental potassium. On this basis, the consensus recommendations to prefer use of thiazides as first line treatment for essential hypertension have been repeatedly and strongly questioned.[27][28][29] However as the Merck Manual of Geriatrics notes, "thiazide-type diuretics are especially safe and effective in the elderly
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