Viral diseases and their symptomatic manifestations of oral mucosa. Influenza, FMD, infectious mononucleosis, AIDS. Etiology, clinical picture, diagnosis, tactic of the dentist.

 

 

Infectious mononucleosis

 

Infectious mononucleosis (also known as mono, glandular fever, Pfeiffer’s disease, Filatov’s disease, and sometimes colloquially as the kissing disease from its oral transmission) is an infectious, widespread viral disease caused by the Epstein–Barr virus (EBV), one type of herpes virus, against which over 90% of adults are likely to have acquired immunity by the age of 40. Occasionally, the symptoms can recur at a later period. Most people are exposed to the virus as children, when the disease produces no noticeable or only flu-like symptoms. In developing countries, people are exposed to the virus in early childhood more often than in developed countries. As a result, the disease in its observable form is more common in developed countries. It is most common among adolescents and young adults.

Especially in adolescents and young adults, the disease is characterized by fever, sore throat and fatigue, along with several other possible signs and symptoms. It is primarily diagnosed by observation of symptoms, but suspicion can be confirmed by several diagnostic tests. It is generally a self-limiting disease, and little treatment is normally required.

 

 

Infectious mononucleosis – symptoms.

 

 

Signs and symptoms

 

The signs and symptoms of infectious mononucleosis vary with age.

Adolescents and young adults

In adolescence and young adulthood, the disease presents with a characteristic triad:

Fever – usually lasting 10–14 days; often mild, especially in the last 5–7 days.

Sore throat (acute pharyngitis) – usually severe for 3–5 days, before resolving in the next 7–10 days.

Swollen glands (lymphadenopathy) –  mobile; usually located around the back of the neck (posterior cervical lymph nodes) and sometimes throughout the body.

Another major symptom is tiredness. Headaches are common, and abdominal pains with nausea or vomiting sometimes also occur. Symptoms most often disappear after about 2–3 weeks. However, fatigue and a general feeling of being unwell may sometimes last for months. Fatigue lasts more than one month in an estimated 9–22% of cases. In cases where fatigue lingers, it generally passes spontaneously within 2 years. Mild fever, swolleeck glands and body aches may also persist beyond 4 weeks. Most people are able to resume their usual activities within 2–3 months.

The most prominent sign of the disease is often the pharyngitis, which is frequently accompanied by enlarged tonsils with pus—an exudate similar to that seen in cases of strep throat. In about 50% of cases, small reddish-purple spots called petechiae can be seen on the roof of the mouth. Palatal enanthem can also occur, but is relatively uncommon.

Enlargement of the spleen is common in the second and third weeks, although this may not be apparent on physical examination; some enlargement of the liver may also be present. Jaundice occasionally occurs.

A small minority of people spontaneously present a rash, usually on the arms or trunk, which can be macular (morbilliform) or papular. Almost all people given amoxicillin or ampicillin eventually develop a generalized, itchy maculopapular rash, which however does not imply that the person will have adverse reactions to penicillins again in the future. Occasional cases of erythema nodosum and erythema multiforme have been reported.

 

Older adults

Infectious mononucleosis mainly affects younger adults. When older adults do catch the disease, they less often have characteristic signs and symptoms such as the sore throat and lymphadenopathy. Instead, they may primarily experience prolonged fever, fatigue, malaise and body pains. They are more likely to have liver enlargement and jaundice. People over 40 years of age are more likely to develop serious illness.

 

Children

In infancy and pre-adolescence, the disease produces only flu-like symptoms, if any at all. When found, symptoms tend to be similar to those of common throat infections (mild pharyngitis, with or without tonsillitis).

Incubation period

The exact length of the incubation period is unclear. A review of the literature made a speculative estimate of 33–49 days. In adolescents and young adults, symptoms are thought to appear around 4–6 weeks after initial infection. Onset is often gradual, though it can be abrupt. The main symptoms may be preceded by 1–2 weeks of fatigue, malaise and body aches.

 

 

Cause

 

Epstein-Barr virus

About 90% of cases of infectious mononucleosis are caused by Epstein-Barr virus, a member of the Herpesviridae family of DNA viruses. It is one of the most commonly found viruses throughout the world. Contrary to common belief, EBV is not highly contagious. It can only be contracted through direct contact with an infected person’s saliva, such as through kissing or sharing toothbrushes, cups, etc. About 95% of the population has been exposed to this virus by the age of 40, but only 15-20% of teenagers and about 40% of exposed adults actually become infected.

 

Cytomegalovirus

A minority of cases of infectious mononucleosis are caused by human cytomegalovirus (CMV), another type of herpes virus. This virus is found in body fluids including saliva, urine, blood, and tears. A person becomes infected with this virus by direct contact with infected body fluids. Cytomegalovirus is most commonly transmitted through kissing and sexual intercourse. It can also be transferred from an infected mother to her unborn child. This virus is often “silent” because the signs and symptoms cannot be felt by the person infected. However, it can cause life-threatening illness in infants, HIV patients, transplant recipients, and those with weak immune systems. For those with weak immune systems, cytomegalovirus can cause more serious illnesses such as pneumonia and inflammations of the retina, esophagus, liver, large intestine, and brain. Approximately 90% of the human population has been infected with cytomegalovirus by the time they reach adulthood, but most are unaware of the infection. Once a person becomes infected with cytomegalovirus, the virus stays in his/her body fluids throughout his or her lifetime.

 

Transmission

Epstein–Barr virus infection is spread via saliva, and has an incubation period of four to seven weeks. The length of time that an individual remains contagious is unclear, but the chances of passing the illness to someone else may be the highest during the first six weeks following infection. Some studies indicate that a person can spread the infection for many months after symptoms are completely gone, with one particular study indicating as long as 18 months.

 

 

Pathophysiology

The virus replicates first within epithelial cells in the pharynx (which causes pharyngitis, or sore throat), and later primarily within B cells (which are invaded via their CD21). The host immune response involves cytotoxic (CD8-positive) T cells against infected B lymphocytes, resulting in enlarged, atypical lymphocytes (Downey cells).

When the infection is acute (recent onset, instead of chronic), heterophile antibodies are produced.

When symptoms of infectious mononucleosis have been caused by cytomegalovirus, or by adenovirus or Toxoplasma gondii (toxoplasmosis), a heterophile antibody test will test negative.

Mononucleosis is sometimes accompanied by secondary cold agglutinin disease, an autoimmune disease in which abnormal circulating antibodies directed against red blood cells can lead to a form of autoimmune hemolytic anemia. The cold agglutinin detected is of anti-i specificity.

 

 

Diagnosis

Infectious mononucleosis, peripheral smear, high power showing reactive lymphocytes

Exudative pharyngitis in a person with infectious mononucleosis

The most commonly used diagnostic criterion is the presence of 50% lymphocytes with at least 10% atypical lymphocytes (large, irregular nuclei), while the person also has fever, pharyngitis and adenopathy. Furthermore, it should be confirmed by a serological test. The atypical lymphocytes resembled monocytes when they were first discovered, thus the term “mononucleosis” was coined. Diagnostic tests are used to confirm infectious mononucleosis, but the disease should be suspected from symptoms prior to the results from hematology. These criteria are specific; however, they are not particularly sensitive and are more useful for research than for clinical use. Only half the patients presenting with the symptoms held by mononucleosis and a positive heterophile antibody test (monospot test) meet the entire criteria. One key procedure is to differentiate between infectious mononucleosis and mononucleosis-like symptoms.

A few studies on infectious mononucleosis have been conducted in a primary care environment, the best of which studied 700 patients, of which 15 were found to have mononucleosis upon a heterophile antibody test. More useful in a diagnostic sense are the signs and symptoms themselves. The presence of splenomegaly, and posterior cervical, axillary and inguinal adenopathies are the most useful to suspect a diagnosis of infectious mononucleosis. On the other hand, the absence of cervical adenopathy and fatigue are the most useful to dismiss the idea of infectious mononucleosis as the correct diagnosis. The insensitivity of the physical examination in detecting splenomegaly means it should not be used as evidence against infectious mononucleosis.

 In the past, the most common test for diagnosing infectious mononucleosis was the heterophile antibody test, which involves testing heterophile antibodies by agglutination of guinea pig, sheep and horse red blood cells. As with the aforementioned criteria, this test is specific but not particularly sensitive (with a false-negative rate of as high as 25% in the first week, 5–10% in the second and 5% in the third). About 90% of patients have heterophile antibodies by week 3, disappearing in under a year. The antibodies involved in the test do not interact with the Epstein–Barr virus or any of its antigens. More recently, more sensitive tests have been developed, such as the immunoglobulin G (IgG) and immunoglobulin M (IgM) tests. IgG, when positive, reflects a past infection, whereas IgM reflects a current infection. Wheegative, these tests are more accurate in ruling out infectious mononucleosis. However, when positive, they feature similar sensitivities to the heterophile antibody test. Therefore, these tests are useful for diagnosing infectious mononucleosis in people with highly suggestive symptoms and a negative heterophile antibody test. Another test searches for the Epstein–Barr nuclear antigen, while it is not normally recognizable until several weeks into the disease, and is useful for distinguishing between a recent-onset of infectious mononucleosis and symptoms caused by a previous infection. Elevated hepatic transaminase levels is highly suggestive of infectious mononucleosis, occurring in up to 50% of patients.

A fibrin ring granuloma may be present.

 

Differential diagnosis

About 10% of people who present a clinical picture of infectious mononucleosis do not have an acute Epstein-Barr virus infection. A differential diagnosis of acute infectious mononucleosis needs to take into consideration acute cytomegalovirus infection and Toxoplasma gondii infections. Because their management is much the same, it is not always helpful, or possible, to distinguish between Epstein-Barr virus mononucleosis and cytomegalovirus infection. However, in pregnant women, differentiation of mononucleosis from toxoplasmosis is important, since it is associated with significant consequences for the fetus.

Acute HIV infection can mimic signs similar to those of infectious mononucleosis, and tests should be performed for pregnant women for the same reason as toxoplasmosis.

Patients with infectious mononucleosis are sometimes misdiagnosed with a streptococcal pharyngitis (because of the classical clinical triad of fever, pharyngitis and adenopathy) and are given antibiotics such as ampicillin or amoxicillin as treatment.

Other conditions from which to distinguish infectious mononucleosis include leukemia, tonsillitis, diphtheria, common cold and influenza (flu).

 

Treatment

 

Infectious mononucleosis is generally self-limiting, so only symptomatic and/or supportive treatments are used. The need for rest and return to usual activities after the acute phase of the infection may reasonably be based on the person’s general energy levels. In particular, bed rest need not be prescribed, and a return to normal activities is desirable as soon as it is comfortable for them to be resumed (gradually, if necessary). Nevertheless, in an effort to decrease the risk of splenic rupture experts advise avoidance of contact sports and other heavy physical activity, especially when involving increased abdominal pressure or the Valsalva maneuver (as in rowing or weightlifting), for at least the first 3–4 weeks of illness or until splenomegaly has resolved, as determined by a treating physician.

Medications

In terms of medications, paracetamol or NSAIDs, such as ibuprofen, may be used to reduce fever and pain. Prednisone, a corticosteroid, is commonly used as an anti-inflammatory to reduce symptoms of pharyngeal pain, odynophagia, or enlarged tonsils, although its use remains controversial due to the rather limited benefit and the potential of side effects. Intravenous corticosteroids, usually hydrocortisone or dexamethasone, are not recommended for routine use but may be useful if there is a risk of airway obstruction, severe thrombocytopenia, or hemolytic anemia. There is little evidence to support the use of aciclovir, although it may reduce initial viral shedding. However, the antiviral drug valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. Although antivirals are not recommended for patients presenting with simple infectious mononucleosis, they may be useful (in conjunction with steroids) in the management of patients with severe EBV manifestations, such as EBV meningitis, peripheral neuritis, hepatitis, or hematologic complications.

Although antibiotics exert no antiviral action they may be indicated to treat bacterial secondary infections of the throat, such as with streptococcus (strep throat). However, ampicillin and amoxicillin are contraindicated during acute Epstein–Barr virus infection since the vast majority of patients treated with them develop a diffuse non-allergic rash.

Opioid analgesics are also relatively contraindicated due to risk of respiratory depression.

 

 

Prognosis

 

Serious complications are uncommon, occurring in less than 5% of cases:

CNS complications include meningitis, encephalitis, hemiplegia, Guillain-Barré syndrome, and transverse myelitis. EBV infection has also been proposed as a risk factor for the development of multiple sclerosis (MS), but this has not been confirmed.

Hematologic: Hemolytic anemia (direct Coombs test is positive) and various cytopenias, and bleeding (caused by thrombocytopenia) can occur.

Mild jaundice

Hepatitis with EBV is rare.

Upper airway obstruction from tonsillar hypertrophy is rare.

Fulminant disease course of immunocompromised patients is rare.

Splenic rupture is rare.

Myocarditis and pericarditis are rare.

Once the acute symptoms of an initial infection disappear, they often do not return. But once infected, the patient carries the virus for the rest of his or her life. The virus typically lives dormantly in B lymphocytes. Independent infections of mononucleosis may be contracted multiple times, regardless of whether the patient is already carrying the virus dormantly. Periodically, the virus can reactivate, during which time the patient is again infectious, but usually without any symptoms of illness. Usually, a patient has few, if any, further symptoms or problems from the latent B lymphocyte infection. However, in susceptible hosts under the appropriate environmental stressors, the virus can reactivate and cause vague physical symptoms (or may be subclinical), and during this phase the virus can spread to others.

 

History

Surprisingly perhaps, the characteristic symptomatology of infectious mononucleosis does not appear to have been reported until the late nineteenth century. In 1885, the renowned Russian pediatrician Nil Filatov reported an infectious process he called “idiopathic denitis” exhibiting symptoms that correspond to infectious mononucleosis, and in 1889 a German balneologist and pediatrician, Emil Pfeiffer, independently reported similar cases (some of lesser severity) that tended to cluster in families, for which he coined the term Drüsenfieber (“glandular fever”). The term “infectious mononucleosis” was coined in 1920 by Thomas Peck Sprunt and Frank Alexander Evans in a classic clinical description of the disease published in the Bulletin of the Johns Hopkins Hospital, entitled “Mononuclear leukocytosis in reaction to acute infection (infectious mononucleosis)”.

Epstein-Barr virus was first identified in Burkitt’s lymphoma cells by Michael Anthony Epstein and Yvonne Barr at the University of Bristol in 1964. The causative link with infectious mononucleosis was uncovered in 1967 by Werner and Gertrude Henle at the Children’s Hospital of Philadelphia, after a laboratory technician handling the virus contracted the disease: comparison of serum samples collected from the technician before and after the onset revealed development of antibodies to the virus.

Foot-and-mouth disease

 

Foot-and-mouth disease or hoof-and-mouth disease (Aphthae epizooticae) is an infectious and sometimes fatal viral disease that affects cloven-hoofed animals, including domestic and wild bovids. The virus causes a high fever for two or three days, followed by blisters inside the mouth and on the feet that may rupture and cause lameness.

Foot-and-mouth disease (FMD) has severe implications for animal farming, since it is highly infectious and can be spread by infected animals through aerosols, through contact with contaminated farming equipment, vehicles, clothing or feed, and by domestic and wild predators. Its containment demands considerable efforts in vaccination, strict monitoring, trade restrictions and quarantines, and occasionally the elimination of millions of animals.

Susceptible animals include cattle, water buffalo, sheep, goats, pigs, antelope, deer, and bison. It has also been known to infect hedgehogs and elephants; llamas, and alpacas may develop mild symptoms, but are resistant to the disease and do not pass it on to others of the same species. In laboratory experiments, mice, rats, and chickens have been successfully infected by artificial means, but they are not believed to contract the disease under natural conditions. Humans are very rarely infected.

The virus responsible for the disease is a picornavirus, the prototypic member of the genus Aphthovirus. Infection occurs when the virus particle is taken into a cell of the host. The cell is then forced to manufacture thousands of copies of the virus, and eventually bursts, releasing the new particles in the blood. The virus is genetically highly variable, which limits the effectiveness of vaccination.

 

History

The cause of FMD was first shown to be viral in 1897 by Friedrich Loeffler. He passed the blood of an infected animal through a Chamberland filter and found the collected fluid could still cause the disease in healthy animals.

FMD occurs throughout much of the world, and whilst some countries have been free of FMD for some time, its wide host range and rapid spread represent cause for international concern. After World War II, the disease was widely distributed throughout the world. In 1996, endemic areas included Asia, Africa, and parts of South America; as of August 2007, Chile is disease-free, and Uruguay and Argentina have not had an outbreak since 2001. North America and Australia have been free of FMD for many years. New Zealand has never had a case of foot-and-mouth disease. Most European countries have been recognized as disease-free, and countries belonging to the European Union have stopped FMD vaccination.

However, in 2001, a serious outbreak of FMD in Britain resulted in the slaughter of many animals, the postponing of the general election for a month, and the cancellation of many sporting events and leisure activities, such as the Isle of Man TT. Due to strict government policies on sale of livestock, disinfection of all persons leaving and entering farms, and the cancellation of large events likely to be attended by farmers, a potentially economically disastrous epizootic was avoided in the Republic of Ireland,[citatioeeded] with just one case recorded in Proleek, Co. Louth. In August 2007, FMD was found at two farms in Surrey, England. All livestock were culled and a quarantine erected over the area. Two other suspected outbreaks have occurred since, although these seem now not to be related to FMD. The only reported cases in 2010 were a false alarm from GIS Alex Baker, as proven false by the Florida Farm and Agricultural Department, and confirmed quarantine/slaughter of cattle and pigs has been reported from Miyazaki Prefecture in Japan in June after three cows tested positive. A total of some 270,000 cattle have been ordered slaughtered following the disease’s outbreak.

 

Clinical signs

 

Ruptured blisters on the feet of a pig

The incubation period for foot-and-mouth disease virus has a range between two and 12 days. The disease is characterized by high fever that declines rapidly after two or three days, blisters inside the mouth that lead to excessive secretion of stringy or foamy saliva and to drooling, and blisters on the feet that may rupture and cause lameness. Adult animals may suffer weight loss from which they do not recover for several months, as well as swelling in the testicles of mature males, and in cows, milk production can decline significantly. Though most animals eventually recover from FMD, the disease can lead to myocarditis (inflammation of the heart muscle) and death, especially iewborn animals. Some infected animals remain asymptomatic, but they nonetheless carry FMD and can transmit it to others.

 

Evolution

 

Of the seven serotypes of this virus, A, C, O, Asia 1 and SAT3 appear to be distinct lineages; SAT 1 and SAT 2 are unresolved clades. The mutation rate of the protein-encoding sequences of strains isolated between 1932 and 2007 has been estimated to be 1.46 × 10-3 substitutions/site/year, a rate similar to that of other RNA viruses. The most recent common ancestor appears to have evolved about 481 years ago (early 16th century). This ancestor then diverged into two clades which have given rise to the extant circulating Euro-Asiatic and South African. This event occurred around 1800. Skyline plot analysis shows a population expansion in the early 20th century, which was then followed by a rapid decline in population size in the late 20th century.

At least seven genotypes of serotype Asia 1 are known

 

Transmission

 

The FMD virus can be transmitted in a number of ways, including close-contact animal-to-animal spread, long-distance aerosol spread and fomites, or inanimate objects, typically fodder and motor vehicles. The clothes and skin of animal handlers, such as farmers, standing water, and uncooked food scraps and feed supplements containing infected animal products can harbor the virus, as well. Cows can also catch FMD from the semen of infected bulls. Control measures include quarantine and destruction of infected livestock, and export bans for meat and other animal products to countries not infected with the disease.

Just as humans may spread the disease by carrying the virus on their clothes and bodies, animals that are not susceptible to the disease may still aid in spreading it. This was the case in Canada in 1952, when an outbreak flared up again after dogs had carried off bones from dead animals. Wolves are thought to play a similar role in the former Soviet Union.

 

Foot-and-mouth disease infecting humans

 

Humans can be infected with foot-and-mouth disease through contact with infected animals, but this is extremely rare. Some cases were caused by laboratory accidents. Because the virus that causes FMD is sensitive to stomach acid, it cannot spread to humans via consumption of infected meat, except in the mouth before the meat is swallowed. In the UK, the last confirmed human case occurred in 1966, and only a few other cases have been recorded in countries of continental Europe, Africa, and South America. Symptoms of FMD in humans include malaise, fever, vomiting, red ulcerative lesions (surface-eroding damaged spots) of the oral tissues, and sometimes vesicular lesions (small blisters) of the skin. According to a newspaper report, FMD killed two children in England in 1884, supposedly due to infected milk.

Another viral disease with similar symptoms, hand, foot and mouth disease, occurs more frequently in humans, especially in young children; the cause, Coxsackie A virus, is different from FMDV. Coxsackie viruses belong to the Enteroviruses within the Picornaviridae.

Because FMD rarely infects humans, but spreads rapidly among animals, it is a much greater threat to the agriculture industry than to human health. Farmers around the world can lose huge amounts of money during a foot-and-mouth epizootic, when large numbers of animals are destroyed, and revenues from milk and meat production go down.

 

 

Vaccination

 

Like other viruses, the FMD virus continually evolves and mutates, thus one of the difficulties in vaccinating against it is the huge variation between, and even within, serotypes. There is no cross-protection between serotypes (meaning that a vaccine for one serotype will not protect against any others) and in addition, two strains within a given serotype may have nucleotide sequences that differ by as much as 30% for a given gene. This means FMD vaccines must be highly specific to the strain involved. Vaccination only provides temporary immunity that lasts from months to years.

Currently, the World Organisation for Animal Health recognizes countries to be in one of three disease states with regards to FMD: FMD present with or without vaccination, FMD-free with vaccination, and FMD-free without vaccination. Countries designated FMD-free without vaccination have the greatest access to export markets, so many developed nations, including Canada, the United States, and the UK, work hard to maintain their current status.

Reasons cited for restricting export from countries using FMD vaccines include, probably most importantly, routine blood tests relying on antibodies cannot distinguish between an infected and a vaccinated animal, which severely hampers screening of animals used in export products, risking a spread of FMD to importing countries. A widespread preventive vaccination would also conceal the existence of the virus in a country. From there, it could potentially spread to countries without vaccine programs. Lastly, an animal infected shortly after being vaccinated can harbor and spread FMD without showing symptoms itself, hindering containment and culling of sick animals as a remedy.

Many early vaccines used dead samples of FMDV to inoculate animals, but those early vaccines sometimes caused real outbreaks. In the 1970s, scientists discovered that a vaccine could be made using only a single key protein from the virus. The task was to produce enough quantities of the protein to be used in the vaccination. On June 18, 1981, the US government announced the creation of a vaccine targeted against FMD, the world’s first genetically engineered vaccine.

 

Hand, foot and mouth disease

 

Hand, foot and mouth disease (HFMD) is a human syndrome caused by intestinal viruses of the picornaviridae family. The most common strains causing HFMD are coxsackie A virus and enterovirus 71 (EV-71).

HFMD usually affects infants and children, and is quite common. It is moderately contagious and is spread through direct contact with the mucus, saliva, or feces of an infected person. It typically occurs in small epidemics iursery schools or kindergartens, usually during the summer and autumn months. The usual incubation period is 3–7 days.

It is less common in adults; however, it is still possible to catch it especially if never exposed to the virus previously. HFMD is not to be confused with foot-and-mouth disease (also called hoof-and-mouth disease), which is a separate disease affecting sheep, cattle, and swine (both are caused by members of the picornaviridae family, but are not trans-communicable between humans and livestock).

 

 

Signs and symptoms

 

Symptoms of HFMD include:

Fever

Fatigue

Malaise

Sore throat

Painful oral, nasal, or facial lesions, ulcers or blisters

Body rash, followed by sores with blisters on palms of hand, soles of feet, and sometimes on the lips. The rash is rarely itchy for children, but can be extremely itchy for adults.

Sores or blisters may be present on the buttocks of small children and infants

Irritability in infants and toddlers

Loss of appetite.

Diarrhea

 

The common incubation period (the time between infection and onset of symptoms) is from three to seven days.

Early symptoms are likely to be fever often followed by a sore throat. Loss of appetite and general malaise may also occur. Between one and two days after the onset of fever, painful sores (lesions) may appear in the mouth or throat, or both. A rash (vesicle) may become evident on the hands, feet, mouth, tongue, inside of the cheeks, and occasionally the buttocks (but generally, the rash on the buttocks will be caused by the diarrhea).

 

Diagnosis

A diagnosis can usually be made based on the clinical symptoms alone. In case of doubt, a throat swab or stool specimen may be taken to identify the virus.

 

Treatment

There is no specific treatment for hand, foot and mouth disease. Individual symptoms, such as fever and pain from the sores, may be eased with the use of analgesics. HFMD is a viral disease that has to run its course; many doctors do not prescribe medicine for this illness. Infection in older children, adolescents, and adults is typically mild and lasts approximately 1 week, occasionally longer. Fever reducers and luke-warm baths can help bring temperature down.

Only a very small minority of sufferers require hospital admission, mainly as a result of uncommoeurological complications (encephalitis, meningitis, or acute flaccid paralysis) or pulmonary edema/pulmonary hemorrhage.

 

 

Complications

 

Complications from the virus infections that cause HFMD are not common, but if they do occur, medical care should be sought. Viral or aseptic meningitis can rarely occur with HFMD. Viral meningitis causes fever, headache, stiff neck, or back pain. The condition is usually mild and clears without treatment; however, some patients may need to be hospitalized for a short time. Other more serious diseases, such as encephalitis (swelling of the brain), a polio-like paralysis, result even more rarely. Encephalitis can be fatal.

There have been reports of fingernail and toenail loss occurring mostly in children within 4 weeks of their having hand, foot, and mouth disease (HFMD). At this time, it is not known whether the reported nail loss is or is not a result of the infection. However, in the reports reviewed, the nail loss has been temporary and nail growth resumed without medical treatment.

 

Influenza

 

Influenza, commonly known as “the flu”, is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses. The most common symptoms are chills, fever, runny nose, sore throat, muscle pains, headache (often severe), coughing, weakness/fatigue and general discomfort. Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more severe disease caused by a different type of virus. Influenza may produce nausea and vomiting, particularly in children, but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as “stomach flu” or “24-hour flu”.

Flu can occasionally lead to pneumonia, either direct viral pneumonia or secondary bacterial pneumonia, even for persons who are usually very healthy. In particular it is a warning sign if a child (or presumably an adult) seems to be getting better and then relapses with a high fever as this relapse may be bacterial pneumonia. Another warning sign is if the person starts to have trouble breathing.

Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus. Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which means of transmission is most important is not absolutely clear. Influenza viruses can be inactivated by sunlight, disinfectants and detergents. As the virus can be inactivated by soap, frequent hand washing reduces the risk of infection.

Vaccinations against influenza are usually made available to people in developed countries. Farmed poultry is often vaccinated to avoid decimation of the flocks. The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated antigens from three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain. The TIV carries no risk of transmitting the disease, and it has very low reactivity[clarificatioeeded]. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs such as the neuraminidase inhibitor oseltamivir (Tamiflu) have been used to treat influenza; however, their effectiveness is difficult to determine due to much of the data remaining unpublished.

 

Signs and symptoms

 

Approximately 33% of people with influenza are asymptomatic.

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38–39 °C (approximately 100–103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of influenza may include:

Fever and extreme coldness (chills shivering, shaking (rigor))

Cough

Nasal congestion

runny nose

Body aches, especially joints and throat

Fatigue

Headache

Irritated, watering eyes

Reddened eyes, skin (especially face), mouth, throat and nose

Petechial Rash

In children, gastrointestinal symptoms such as diarrhea and abdominal pain, (may be severe in children with influenza B)

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections, but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Influenza is a mixture of symptoms of common cold and pneumonia, body ache, headache, and fatigue. Diarrhea is not normally a symptom of influenza in adults, although it has been seen in some human cases of the H5N1 “bird flu” and can be a symptom in children. The symptoms most reliably seen in influenza are shown in the table to the right.

Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal congestion can improve diagnostic accuracy. Two decision analysis studies suggest that during local outbreaks of influenza, the prevalence will be over 70%, and thus patients with any of these combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.

On the more serious side, influenza can occasionally cause either direct viral or secondary bacterial pneumonia. The obvious symptom is trouble breathing. In addition, if a child (or presumably an adult) seems to be getting better and then relapses with a high fever, that is a danger sign since this relapse can be bacterial pneumonia.

 

 

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:

Influenzavirus A

Influenzavirus B

Influenzavirus C

These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging to the paramyxovirus family that are a common cause of respiratory infections in children such as croup, but can also cause a disease similar to influenza in adults.

 

Transmission

 

Influenza virus shedding (the time during which a person might be infectious to another person) begins the day before symptoms appear and virus is then released for five to seven days, although some people may shed virus for longer periods[citatioeeded]. People who contract influenza are most infective between the second and third days after infection. The amount of virus shed appears to correlate with fever, with higher amounts of virus shed when temperatures are highest. Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.

Influenza can be spread in three main ways: by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a hand-shake. The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus. In the airborne route, the droplets that are small enough for people to inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an infection. Although a single sneeze releases up to 40,000 droplets, most of these droplets are quite large and will quickly settle out of the air. How long influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter aiding its survival.

As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes, doorknobs, light switches and other household items. The length of time the virus will persist on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin. However, if the virus is present in mucus, this can protect it for longer periods (up to 17 days on banknotes). Avian influenza viruses can survive indefinitely when frozen. They are inactivated by heating to 56 °C (133 °F) for a minimum of 60 minutes, as well as by acids (at pH <2).

 

Pathophysiology

 

The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1. This influences their lethality and ability to spread.

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone (ACTH) resulting in lowered cortisol levels. Knowing which genes are carried by a particular strain can help predict how well it will infect humans and how severe this infection will be (that is, predict the strain’s pathophysiology).

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several human proteases. In mild and avirulent viruses, the structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.

The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind. Strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs. This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing.

Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells. In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response. This massive immune response might produce a life-threatening cytokine storm. This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza, and the 1918 pandemic strain. However, another possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication produced by these strains, and the immune response does not itself contribute to the disease.

 

Treatment

 

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve the fever and muscle aches associated with the flu. Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye’s syndrome, a rare but potentially fatal disease of the liver. Since influenza is caused by a virus, antibiotics have no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia. Antiviral medication may be effective, but some strains of influenza can show resistance to the standard antiviral drugs and there is concern about the quality of the research.

 

Antivirals

The two classes of antiviral drugs used against influenza are neuraminidase inhibitors (oseltamivir and zanamivir) and M2 protein inhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are less toxic and possibly more effective. However, their effectiveness is disputed. In 2009, the World Health Organization recommended that persons in high-risk groups, including pregnant women, children under two, and persons with respiratory problems, begin taking antivirals as soon as they start experiencing flu symptoms.

 

Neuraminidase inhibitors

Neuraminidase inhibitors include the antiviral medications oseltamivir (Tamiflu) and zanamivir (Relenza). These medications may be effective against both influenza A and B, however the confidence of the research community in this conclusion is low as much of the trial data remains unpublished. In those believed to have the flu they decreased the length of time symptoms are present by about a day and do not appear to affect the risk of complications such as needing hospitalization or pneumonia. Different strains of influenza viruses have differing degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future pandemic strain might have. The FDA deems their effect to be modest.

 

M2 inhibitors

The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus from infecting cells. These drugs are sometimes effective against influenza A if given early in the infection but are ineffective against influenza B viruses, which lack the M2 drug target. Measured resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005. This high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia, and their use to prevent outbreaks of influenza in farmed poultry. The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of drug resistance.

 

Prognosis

 

Influenza’s effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop life-threatening complications (such as pneumonia). Influenza, thus, can be deadly, especially for the weak, young and old, or chronically ill. People with a weak immune system, such as people with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease. Other high-risk groups include pregnant women and young children.

The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure. Smoking is another risk factor associated with more serious disease and increased mortality from influenza.

According to the World Health Organization: “Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don’t usually verify who actually died of influenza and who died of a flu-like illness.” Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.

In some cases, an autoimmune response to an influenza infection may contribute to the development of Guillain-Barré syndrome. However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics. This syndrome has been believed to also be a rare side effect of influenza vaccines. One review gives an incidence of about one case per million vaccinations. Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing GBS to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by recent estimates).

Oral Manifestations of HIV

1.    FUNGAL LESIONS

Candidiasis

Oral candidiasis is most commonly associated with Candida albicans, although other species, such as C. glabrata and C. tropicalis, are frequently part of the normal oral flora. A number of factors predispose patients to develop candidiasis: infancy, old age, antibiotic therapy, steroid and other immunosuppressive drugs, xerostomia, anemia, endocrine disorders, and primary and acquired immunodeficiency. Candidiasis is a common finding in people with HIV infection. Reports describe oral candidiasis during the acute stage of HIV infection,(10) but it occurs most commonly with falling CD4+ T-cell count in middle and late stages of HIV disease. Several reports indicate that most persons with HIV infection carry a single strain of Candida during clinically apparent candidiasis and when candidiasis is quiescent.

Clinical Features

The clinical appearances of oral candidiasis vary. The most common presentations include pseudomembranous and erythematous candidiasis, which are equally predictive of the development of AIDS,  and angular cheilitis. These lesions may be associated with a variety of symptoms, including a burning mouth, problems eating spicy food, and changes in taste (Figure 6 -8). All three of these common forms may appear in one individual.

Fig. 6.  Pseudomembranous Candidiasis

Fig. 7. Pseudomembranous Candidiasis

 

Pseudomembranous Candidiasis (Thrush)

Characteristic creamy white, removable plaques on the oral mucosa are caused by overgrowth of fungal hyphae mixed with desquamated epithelium and inflammatory cells. The mucosa may appear red when the plaque is removed. This type of candidiasis may involve any part of the mouth or pharynx.

Fig. 8. Erythematous Candidiasis

 

Erythematous Candidiasis

Erythematous candidiasis appears as flat, red patches of varying size. It commonly occurs on the palate and the dorsal surface of the tongue. Erythematous candidiasis is frequently subtle in appearance and clinicians may easily overlook lesions, which may persist for several weeks if untreated.

Angular Cheilitis

Angular cheilitis appears clinically as redness, ulceration, and fissuring, either unilaterally or bilaterally at the corners of the mouth. It can appear alone or in conjunction with another form of candidiasis.

Fig. 9. Angular cheilitis and pseudomembranous candidiasis.

 

Hyperplastic Candidiasis

This type of candidiasis is unusual in persons with HIV infection. The lesions appear white and hyperplastic. The white areas are due to hyperkeratosis and, unlike the plaques of pseudomembranous candidiasis, cannot be removed by scraping. These lesions may be confused with hairy leukoplakia. Diagnosis of hyperplastic candidiasis is made from the histologic appearance of hyperkeratosis and the presence of hyphae. Periodic acid-Schiff (PAS) stain is often used to demonstrate hyphae.

Fig. 10. Chronic hyperplastic candidiasis.

 

Differential Diagnosis

Erythematous candidiasis should be differentiated from other red lesions, such as Kaposi’s sarcoma or erythroplakia. Histologically, oral candidiasis contains Candida hyphae in the superficial epithelium when viewed under a PAS stain. The inflammatory responses often associated with Candida infection may be absent in immunocompromised patients. The creamy white plaques of pseudomembranous candidiasis are removable; the white lesions of hairy leukoplakia are nonremovable.

Diagnosis

Candida is a commensal organism in the oral cavity. Candidiasis is diagnosed by its clinical appearance and by detection of organisms on smears. Smears taken from clinical lesions are examined using potassium hydroxide (KOH), PAS, or Gram’s stain. Smears are taken by gently drawing a wooden tongue depressor across the lesion. The specimen is then transferred into a drop of KOH on a glass slide and protected by a cover slip. The smear is examined under the microscope and Candida is detected by finding hyphae and blastospores. Hyphae and spores are only seen in smears from lesions and are rarely seen in the healthy individual in the carrier state. Cultures are grown on specific media, such as Sabouraud’s agar; they may be positive and yet reveal very low colony counts. This probably represents a carrier state rather than active infection.  Culture is useful for establishing the Candida species but may not be useful for diagnosis.

Treatment

Oral candidiasis may be treated either topically or systemically. Treatment should be maintained for 7 days. Response to treatment is often good; oral lesions and symptoms may disappear in a fairly short period (ranging from 2 to 5 days), but relapses are common because of the underlying immunodeficiency. As with other causes of oral candidiasis, recurrences are common if the underlying problem persists.

Topical Treatment

Topical treatments are preferred because they limit systemic absorption, but the effectiveness depends entirely on patient compliance. Topical medications require that the patient hold medications in the mouth for 20 to 30 minutes. If the patient uses formulations containing sweetening agents for long periods, consider as concurrent treatment daily fluoride rinses (e.g., ACT or Fluorigard, available as over-the-counter preparations) for 1 minute once a day and then expectorated.

Clotrimazole is an effective topical treatment (one oral troche [10-mg tablet]) when dissolved in the mouth five times daily. Used less frequently, one vaginal troche can be dissolved in the mouth daily. Nystatin preparations include a suspension, a vaginal tablet, and an oral pastille. Regimens are nystatin vaginal tablets (one tablet, 100,000 units, dissolved in the mouth three times a day), or nystatin oral pastille (available as a 200,000-unit oral pastille, one or two pastilles dissolved slowly in the mouth five times a day). Nystatin suspension has a high sugar content and cannot be held in the mouth long enough to be effective. Topical creams and ointments containing nystatin, ketoconazole, or clotrimazole may be useful in treating angular cheilitis. Another therapeutic choice is amphotericin B (0.1 mg/ml). Five to 10 ml of oral solution is used as a rinse and then expectorated three to four times daily.

Systemic Treatment

Several agents are effective for systemic treatment. Ketoconazole (Nizoral) is a 200-mg tablet taken with food once daily. Patient compliance is usually good. Careful monitoring of liver function is necessary for long-term use because of reported side effects, including hepatotoxicity. Lack of efficacy of ketoconazole may occur because of poor absorption in those with an abnormally high gastric pH.

Fluconazole (Diflucan) is a triazole antifungal agent effective in treating candidiasis (100-mg tablet taken once daily for 2 weeks).  Several studies suggest fluconazole is effective as a prophylactic agent, although the most effective prophylaxis dosing regimen is still unclear. Numerous reports, however, describe oral and esophageal candidiasis failing to respond to treatment with fluconazole, and in some of these cases investigators isolated resistant strains. Itraconazole (100-mg capsules) may be used for the treatment of oral candidiasis (200 mg daily orally for 14 days).  Itraconazole oral suspension is now available (200 mg daily for 2 weeks. Salivary levels of itraconazole are maintained for several hours after administration.

Ketoconazole, fluconazole, and itraconazole may interact with other medications including rifampicin, phenytoin, cyclosporin A, terfenadine, digoxin, coumarin-like medications, and oral hypoglycemic medications.

Prognostic Significance

Both erythematous and pseudomembranous oral candidiasis are associated with increased risk for the subsequent development of opportunistic infections classifying the patient as having AIDS as defined by the Centers for Disease Control (CDC).Several studies have shown a statistical correlation between frequency of oral candidiasis in HIV infection and falling CD4+ T-cell counts.

 

2.    VIRAL LESIONS

Herpes Simplex

Herpes simplex causes both primary and secondary or recurrent disease in the oral cavity. Primary herpetic gingivostomatitis commonly occurs in children and young adults and may be followed by frequent recurrences. Following the primary episode, the virus becomes latent in the trigeminal ganglion. Recurrent oral herpes occurs at any age extraorally or intraorally.

Clinical Features

Recurrent herpes labialis occurs on the vermilion border of the lips. The patient may report a history of itching or pain, followed by the appearance of small vesicles. These rupture and form crusts. Recurrent intraoral herpes appears as clusters of painful small vesicles that rupture and ulcerate and usually heal within 1 week to 10 days. The lesions usually occur on the keratinized mucosa, such as the hard palate and gingiva, although lesions may arise on the dorsal surface of the tongue.

Fig. 11. Herpes simplex lesion

Fig. 12. Herpes simplex on the patients lips.

Differential Diagnosis

Rising antibody titers from initial and convalescent sera confirm primary herpetic gingivostomatitis. Examining smears of lesions (treated with Papanicolaou stain) for multinucleated giant cells confirms recurrent herpes. It is possible to demonstrate herpes simplex type 1 or type 2 by applying monoclonal antibodies to smears from the lesions (the Syva Kit, Syva Corporation, Palo Alto, CA). Swabs taken from fluid-filled vesicles may grow herpes simplex in culture if vesicles are a few days or less old. Clinicians can distinguish between recurrent intraoral herpes simplex lesions, which always occur on keratinized mucosa (such as the hard palate and gingiva), and recurrent aphthous ulcers, which always appear oonkeratinized mucosa. Recurrent intraoral herpes may appear more frequently in HIV-infected patients. The lesions may be painful and slow to heal.

Treatment

No treatment will permanently eradicate oral herpes simplex infections, but acyclovir may shorten the healing time for individual episodes. The optimum oral dosage of acyclovir is 1,000 to 1600 mg daily for 7 to 10 days. Topical acyclovir is not useful for treating intraoral lesions and may not be effective for lesions on the lips. Recurrent outbreaks of acyclovir-resistant herpes have been reported, including a case involving the facial skin, lips, nose, and mouth. In this case, the lesions resolved after treatment with foscarnet Phosphonoformate may also prove effective.

Prognostic Significance

There is no known association between recurrent intraoral herpes and more rapid progression of HIV disease. However, there is a clinical impression that recurrent herpes simplex infections may be more common in patients with symptomatic HIV disease.

Herpes Zoster

The reactivation of varicella zoster virus (VZV) causes herpes zoster (shingles). The disease occurs in the elderly and the immunosuppressed.

Clinical Features

Oral herpes zoster generally causes skin lesions. Following a prodrome of pain, multiple vesicles appear on the facial skin, lips, and oral mucosa. Skin and oral lesions are frequently unilateral and follow the distribution of the maxillary and/or mandibular branches of the trigeminal nerve. The skin lesions form crusts and the oral lesions coalesce to form large ulcers. The ulcers frequently affect the gingiva, so tooth pain may be an early complaint.

Fig. 13. Herpes zoster

Fig. 14. Herpes zoster in mouth.

Differential Diagnosis

The appearance of the lesions and their distribution are pathognomonic.

Treatment

Acyclovir limits the duration of the lesions. For herpes zoster, the standard oral dosage is 800 mg five daily for 7 to 10 days, which is considerably higher than that recommended for treatment of herpes simplex.

Human Papillomavirus Lesions

Oral warts, papillomas, skin warts, and genital warts are associated with the human papillomavirus (HPV). Lesions caused by HPV are common on the skin and mucous membranes of persons with HIV disease. Anal warts have frequently been reported among homosexual men. Because the HPV types found in oral lesions in HIV-infected persons are different from the HPV types associated with anogenital warts, clinicians should probably not use the term condyloma acuminata to describe oral HPV lesions.

Clinical Features

HPV lesions in the oral cavity may appear as solitary or multiple nodules. They may be sessile or pedunculated and appear as multiple, smooth-surfaced raised masses resembling focal epithelial hyperplasia or as multiple, small papilliferous or cauliflower-like projections (Figure 3). I have identified HPV types 7, 13, and 32 in some of these oral warts.(26) Malignant transformation of HPV oral lesions has not been reported, but the identification of four new HPV types in these lesions warrants further study.

Fig. 15. HPV in mouth.

Differential Diagnosis

A biopsy is necessary for histologic diagnosis.

Prognosis

There is no known association between oral HPV lesions and more rapid progression of HIV disease, but oral warts are seen more commonly in HIV-infected persons than in the general population.

Treatment

Oral HPV lesions can be removed surgically using local anesthetic. Carbon dioxide laser surgery can remove multiple flat warts, but relapses occur and several repeat procedures may be necessary.

Cytomegalovirus

Oral ulcers caused by cytomegalovirus (CMV) have been reported. These ulcers can appear on any mucosal surface and may be confused with aphthous ulcers, necrotizing ulcerative periodontitis (NUP), and lymphoma. Unlike aphthous ulcers, however, which usually have an erythematous margin, CMV ulcers appear necrotic with a white halo. Diagnosis of CMV ulcers is made from a biopsy. Immunohistochemistry may be helpful.

CMV ulcers in the oral cavity usually occur in individuals with disseminated CMV disease. Therefore, diagnosis of CMV-infected oral ulcers should be followed by examination for the systemic disease. CMV ulcers resolve when ganciclovir is used to treat CMV disease.

Hairy Leukoplakia and Epstein-Barr Virus

Oral hairy leukoplakia (HL), which presents as a nonmovable, corrugated or “hairy” white lesion on the lateral margins of the tongue, occurs in all risk groups for HIV infections, although less commonly in children than in adults. HL occurs in about 20% of persons with asymptomatic HIV infection and becomes more common as the CD4+ T-cell count falls. HL is in group 4, category C2 of the original Centers for Disease Control (CDC) definition of AIDS and in B3 of the 1993 criteria.No report describes HL in mucosal sites other than the mouth. HL has occurred in non-HIV-infected people including recipients of bone marrow, cardiac, and renal transplants.

Fig. 16. Oral hairy leukoplakia

Hairy Leukoplakia and Progression of HIV Disease

Diagnosis of HL is an indication of both HIV infection and immunodeficiency; it is an indication for a work-up to evaluate and treat HIV disease. HL correlates with a statistical risk for more rapid progression of HIV disease. In an early study, 30% of persons with HL progressed to late-stage HIV disease characterized by CDC-defined AIDS within 36 months. In a later study, 47% of a group developed CDC-defined AIDS within 2 years and 67% within four years. Those persons with HL who progressed to CDC-defined AIDS most rapidly, however, were more often anergic to Candida antigen at diagnosis of HL, indicating significant immunosuppression at that time. Progression to CDC-defined AIDS was more rapid in those HIV-infected persons with HL than in those without HL, even after adjustment for CD4+ T-cell count.

Pathogenesis

The Epstein-Barr virus (EBV) in HL is both unusual in that deletions in the EBNA 2 gene have been described  and in that to date no viral DNA is found in the basal layers of HIV. Intraepithelial Langerhans’ cells (LCs) are reduced or absent in the HL lesion, which correlates with the presence of viral antigens. It is not known whether the lack of LCs is a cause of HL or a consequence of EBV infection.

In electron microscopic specimens, investigators have found structures consistent with a herpes group virus. One structure consisted of 100-nm intranuclear virions and 240-nm encapsulated virus particles. Other structures are 48- to 52-nm particles visible in the suprabasal layer.  Closer to specimen surfaces, where the nuclei are more condensed, arrays of these particles and herpes group particles occurred in the same cell. Several studies described the appearance of these particles in HL biopsies.

Clinical Appearance and Manifestations

HL lesions vary in size and appearance and may be unilateral or bilateral. The surface is irregular and may have prominent folds or projections, sometimes markedly resembling hairs. Occasionally, however, some areas may be smooth and flat. Lesions occur most commonly on the lateral margins of the tongue and may spread to cover the entire dorsal surface. They may also spread downward onto the ventral surface of the tongue, where they usually appear flat. HL lesions can also occur on the buccal mucosa, generally as flat lesions. Rarely, lesions occur on the soft palate. HL usually does not cause symptoms.

Differential Diagnosis

Candida albicans may be found in association with many HL lesions, and hyphae can be seen in specimens taken from lesions and examined using potassium hydroxide. Hyphae can be seen in sections stained with periodic acid-Schiff. Administration of antifungal drugs may change the appearance of the lesions but does not cause them to disappear. Clinicians must distinguish them from other white lesions, such as lichen planus, idiopathic leukoplakia, white sponge nevus, dysplasia, and squamous cell carcinoma.

Diagnosis

HL should be diagnosed by biopsy for definitive diagnosis. Experienced clinicians can make a presumptive diagnosis of HL in association with HIV disease from the clinical appearance, although HL can be confused with oral candidiasis. The typical microscopic appearance of HL includes acanthosis, marked parakeratosis with the formation of ridges and keratin projections, areas of ballooning cells, and little or no inflammation in the connective tissue. The ballooning changes resemble koilocytosis. Cells are enlarged; some contain enlarged ballooning cells with pyknotic nuclei. Some contain perinuclear haloes.

Definitive diagnosis of HL requires demonstration of EBV. EBV may be readily demonstrated in biopsy specimens by a variety of techniques. Cells taken from the HL lesion by scraping can be used for a noninvasive diagnosis using in situ hybridization.

Treatment

Hairy leukoplakia usually is asymptomatic and does not require treatment. HL is almost always a manifestation of HIV infection, and clinicians should arrange evaluation of HIV disease and appropriate treatment for patients with HL. HL has disappeared in patients receiving high-dose acyclovir for herpes zoster, presumably because of the anti-EBV activity of acyclovir. Doses of acyclovir (2.5 to 3 mg per day for 2 to 3 weeks) usually eliminate HL, but the lesion usually recurs with cessation of treatment.

Elimination or almost complete clinical resolution of the lesion has occurred in patients treated with agents such as desciclovir, an analog of acyclovir, phosphonoformate, Retin A, and podophyllin resin, although lesions tend to recur within a few months. Case reports describe HL disappearing during treatment with ganciclovir, zidovudine, and aerosolized pentamidine.  Katz and colleagues have shown that HL both appears and disappears in patients receiving zidovudine, although no case-controlled studies are available.

Occasionally, Candida albicans may be found in HL lesions. Treatment consists of antifungal medications.

3.    BACTERIAL LESIONS

Periodontal Disease

Periodontal disease is a fairly common problem in both asymptomatic and symptomatic HIV-infected patients. It can take two forms: the rapid and severe condition called necrotizing ulcerative periodontitis (NUP) and its associated and possibly precursor condition called linear gingival erythema (LGE). The presenting clinical features of these diseases often differ from those ion-HIV-infected persons.

Clinical Features

LGE and NUP often occur in clean mouths where there is very little plaque or calculus to account for the gingivitis. The onset is often sudden, with rapid loss of bone and soft tissue. In LGE, the gingiva may be reddened and edematous. Patients sometimes complain of spontaneous bleeding. In acute-onset ulcerative gingivitis, ulcers occur at the tips of the interdental papilla and along the gingival margins, and often elicit complaints of severe pain. The ulcers heal, leaving the gingival papillae with a characteristic cratered appearance.

Fig. 17. Linear  gingival erythema

NUP may present as rapid loss of supporting bone and soft tissue. Typically, these losses occur simultaneously with no formation of gingival pockets, sometimes involving only isolated areas of the mouth. Teeth may loosen and eventually fall out, but uninvolved sites can appear healthy. Necrotizing stomatitis may develop, and areas of necrotic bone may appear along the gingival margin. The bone may eventually sequestrate. Patients with NUP and necrotizing stomatitis frequently complain of extreme pain and spontaneous bleeding.

Fig. 18. Necrotizing ulcerative periodontitis

Differential Diagnosis

The patient’s history and clinical appearance make the diagnosis. It is sometimes difficult to distinguish this type of periodontal disease from non-HIV-related periodontal disease. However, the complaints of severe pain, rapid onset, and rapid destruction in an often extremely clean mouth are unusual for non-HIV-related periodontal disease.

Treatment

Clinicians should refer patients to a periodontist or dentist for management. The following protocol has achieved reasonable success: plaque removal, local debridement, irrigation with povidone-iodine, scaling and root planing, and maintenance with a chlorhexidine mouth rinse (Peridex-R) once or twice daily. Studies show that the addition of chlorhexidine to this regimen produces significant improvement in periodontal condition. In cases of NUP, metronidazole (one 250-mg tablet four times daily), amoxicillin/clavulanate (Augmentin)(one 250-mg tablet three times daily), or clindamycin (one 300-mg tablet three times daily) should be added to the treatment regimen.

Different Course in HIV Infection

The microbiology  of periodontal disease in HIV-infected patients has not been fully described. Oral flora associated with LGE and NUP appear to be similar to those associated with periodontal disease seen ion-HIV-infected persons. Recurrences of acute episodes are common and response to conventional treatment may be poor. However, therapeutic strategies and frequent recall appointments can produce effective local treatment of LGE and NUP. There is as yet no known relationship between these conditions and the progression of HIV disease.

4.    NEOPLASTIC LESIONS

Kaposi’s sarcoma

Kaposi’s sarcoma (KS) may occur intraorally, either alone or in association with skin and disseminated lesions. Intraoral lesions have been reported at other sites and may be the first manifestation of late-stage HIV disease (AIDS). KS occurs most commonly in men but also has been observed in women.

Clinical Features

KS can appear as a red, blue, or purplish lesion. It may be flat or raised, solitary or multiple. The most common oral site is the hard palate, but lesions may occur on any part of the oral mucosa, including the gingiva, soft palate, and buccal mucosa, and in the oropharynx. Occasionally, yellowish mucosa surrounds the KS lesion. Oral KS lesions may enlarge, ulcerate, and become infected. Good oral hygiene is essential to minimize these complications.

Fig. 19. Kaposi’s sarcoma

Fig. 20. Kaposi’s sarcoma

Differential Diagnosis

KS must be distinguished from vascular lesions such as hematomas, hemangiomas, other vascular tumors, pyogenic granulomas, bacillary angiomatosis, and pigmented lesions such as oral melanotic macules. Diagnosis is made from histologic examination. There are usually no bleeding problems associated with a biopsy of oral KS. However, aspiration of a lesion prior to biopsy may be useful to rule out a hemangioma. Small, flat lesions are probably in early stages, and the histologic appearance is different from the larger, nodular lesions that are probably more advanced. Early lesions may be difficult to diagnose histologically because they resemble endothelial proliferation. KS may appear suddenly, within days of a normal oral examination, in previously uninvolved areas of the mouth.

Providers should ensure that a patient with KS receives evaluation and follow-up care for the underlying HIV disease.

Treatment

Treatment is determined on the basis of the number, size, and location of the oral KS lesions. The choice of therapy depends on the effect of treatment on the adjacent mucosa, pain associated with treatment, interference with eating and speaking, and the patient’s preference. It is important to perform thorough dental prophylaxis before initiating therapy for KS lesions involving the gingiva. Response to therapy is improved if all local plaque and calculus are removed. Local application of sclerosing agents may reduce the size of oral lesions.

Local treatment is appropriate for large oral KS lesions that interfere with eating and talking. Oral KS can be treated surgically or with localized intralesional chemotherapy. Surgical removal is suitable for small, well-circumscribed lesions such as gingival or tongue lesions. Surgical removal can be performed under local anesthesia with a blade or with the carbon dioxide laser. Intralesional vinblastine is useful for treating small lesions, particularly on the palate or gingiva. Several studies have documented the effectiveness of one or two injections of 0.1 to 0.2 mg per ml solution of vinblastine. Posttreatment pain is fairly common, but systemic effects are rare. The pain usually disappears several days after therapy.

Radiation therapy may be indicated for large, multiple lesions. A single dose of 800 cGy or an equivalent fractionated dose is frequently used and produces a good response. Side effects include xerostomia and mucositis, although both conditions usually improve with cessation of radiation therapy.

5.    LYMPHOMA

Clinical Features

Diffuse, undifferentiated non-Hodgkin’s lymphoma (NHL) is a frequent HIV-associated malignancy. Most are of B cell origin, and Epstein-Barr virus occurs in cells from several cases. Lymphoma can occur anywhere in the oral cavity, and there may be soft tissue involvement with or without involvement of underlying bone. The lesion may present as firm, painless swelling that may be ulcerated. Some oral lesions may appear as shallow ulcerations.  Oral NHL may appear as solitary lesions with no evidence of disseminated disease.

Differential Diagnosis

Oral NHL may be confused with major aphthous ulcers and rarely as a pericoronitis associated with an erupting third molar. Diagnosis of NHL must be made by histologic examination of biopsy specimens.

Treatment

After diagnosis of the oral lesions, the patient must be referred for further evaluation for disseminated disease and its subsequent treatment.

6.    OTHER ORAL LESIONS ASSOCIATED WITH HIV DISEASE

Oral Ulceration

Oral ulcers resembling recurrent aphthous ulcers (RAUs) in HIV-infected persons are reported with increasing frequency.  The cause of these ulcers is unknown. Proposed causes include stress and unidentified infectious agents. In HIV-infected patients, the ulcers are well circumscribed with erythematous margins. The ulcers of the minor RAU type may appear as solitary lesions of about 0.5 to 1.0 cm. The herpetiform type appear as clusters of small ulcers (1 to 2 mm), usually on the soft palate and oropharynx. The major RAU type appears as extremely large (2 to 4 cm) necrotic ulcers. The major RAUs are very painful and may persist for several weeks.

Diagnosis

The ulcers may present a diagnostic problem. Herpetiform RAUs may resemble the lesions of coxsackievirus infection, and major RAUs may require biopsy to exclude malignancy, such as lymphoma, or opportunistic infection, such as histoplasmosis. The ulcers usually occur oonkeratinized mucosa; this characteristic differentiates them from those caused by herpes simplex.

Treatment

The RAU type ulcers usually respond well to topical steroids such as fluocinonide (0.05%) ointment mixed with equal parts Orabase applied six times daily or clobetasol (0.05%) ointment mixed with equal parts Orabase applied three times per day. Dexamethasone elixir (0.5 mg/5 ml) used as a mouth rinse and then expectorated two to three times daily is helpful for multiple ulcers and for those where topical ointments are hard to apply. For HIV-infected persons with oral and gastrointestinal aphthous-like ulcers, systemic steroid therapy (prednisone 40 to 60 mg/day for 7 to 10 days) has been reported as helpful. The risks of steroid therapy, however, must be considered before administration to individuals in this population. Thalidomide (50 to 200 mg) has been used in Europe and is the subject of clinical trials in the United States (ACTG 251).

Idiopathic Thrombocytopenic Purpura

Reports have described idiopathic thrombocytopenic purpura (ITP) in HIV-infected patients. Oral lesions may be the first manifestation of this condition.

Clinical Features

Petechiae, ecchymoses, and hematoma can occur anywhere on the oral mucosa. Spontaneous bleeding from the gingiva can occur, and patients may report finding blood in their mouths on waking.

Differential Diagnosis

The clinician must distinguish ITP from other vascular lesions and KS. Because of potential bleeding risk, the clinician should obtain blood and platelet counts before performing other diagnostic procedures.

Salivary Gland Disease and Xerostomia

Salivary gland disease associated with HIV infection (HIV-SGD) can present as xerostomia with or without salivary gland enlargement. Reports describe salivary gland enlargement in children and adults with HIV infection usually involving the parotid gland. The enlarged salivary glands are soft but not fluctuant. In some cases, enlarged salivary glands may be due to lymphoepithelial cysts. Schiodt et al. found that 9 of 12 patients (11 adults and 1 child) with HIV-SGD had salivary gland enlargement. Three had xerostomia. Labial salivary gland biopsy revealed histologic features similar to those in Sjogren’s syndrome. In HIV-SGD, however, the lymphocytic infiltrate is predominantly CD8 cells, unlike that in Sjogren’s syndrome, which is predominantly CD4 cells.

No evidence of Epstein-Barr virus or cytomegalovirus has been found in biopsies of salivary glands. One report describes an association between HIV-SGD and HLA-DR5 and HLA-B35 cell-surface antigen.

The etiology of HIV-SGD is as yet unknown but the enlarged parotid glands can be a source of annoyance and discomfort.

Xerostomia is sometimes seen in individuals with HIV-SGD. HIV-infected patients may also experience dry mouth in association with taking certain medications that can hinder salivary secretion, such as ddI, antidepressants, antihistamines, and antianxiety drugs.

Management

Removal of the enlarged parotid glands is rarely recommended. For individuals with xerostomia, the use of salivary stimulants such as sugarless gum or sugarless candies may provide relief. Candies that are acidic should be avoided as frequent use may lead to loss of tooth enamel. The use of salivary substitutes may also be helpful. An increase in caries can occur, so fluoride rinses (that can be bought over the counter) should be used daily, and visits to the dentist should occur two to three times per year.

Diagnosis of HIV infection

HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA.

Tests used for the diagnosis of HIV infection in a particular person require a high degree of both sensitivity and specificity. In the United States, this is achieved using an algorithm combining two tests for HIV antibodies. If antibodies are detected by an initial test based on the ELISA method, then a second test using the Western blot procedure determines the size of the antigens in the test kit binding to the antibodies. The combination of these two methods is highly accurate (see below).

Antibody tests

Window period

Antibody tests may give false negative (no antibodies were detected despite the presence of HIV) results during the window period, an interval of three weeks to six months between the time of HIV infection and the production of measurable antibodies to HIV seroconversion. Most people develop detectable antibodies approximately 30 days after infection, although some seroconvert later. The vast majority of people (97%) have detectable antibodies by three months after HIV infection; a six-month window is extremely rare with modern antibody testing. During the window period, an infected person can transmit HIV to others although their HIV infection may not be detectable with an antibody test. Antiretroviral therapy during the window period can delay the formation of antibodies and extend the window period beyond 12 months. This was not the case with patients that underwent treatment with post-exposure prophylaxis (PEP). Those patients must take ELISA tests at various intervals after the usual 28 day course of treatment, sometimes extending outside of the conservative window period of 6 months. Antibody tests may also yield false negative results in patients with X-linked agammaglobulinemia; other diagnostic tests should be used in such patients.

Three instances of delayed HIV seroconversion occurring in health-care workers have been reported; in these instances, the health-care workers  tested negative for HIV antibodies greater than 6 months postexposure but were seropositive within 12 months after the exposure. DNA sequencing confirmed the source of infection in one instance. Two of the delayed seroconversions were associated with simultaneous exposure to hepatitis C virus (HCV). In one case, co-infection was associated with a rapidly fatal HCV disease course; however, it is not known whether HCV directly influences the risk for or course of HIV infection or is a marker for other exposure-related factors.

ELISA

The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the first screening test commonly employed for HIV. It has a high sensitivity.

In an ELISA test, a person’s serum is diluted 400-fold and applied to a plate to which HIV antigens have been attached. If antibodies to HIV are present in the serum, they may bind to these HIV antigens. The plate is then washed to remove all other components of the serum. A specially prepared “secondary antibody” — an antibody that binds to human antibodies — is then applied to the plate, followed by another wash. This secondary antibody is chemically linked in advance to an enzyme. Thus the plate will contain enzyme in proportion to the amount of secondary antibody bound to the plate. A substrate for the enzyme is applied, and catalysis by the enzyme leads to a change in color or fluorescence. ELISA results are reported as a number; the most controversial aspect of this test is determining the “cut-off” point between a positive and negative result.

Western blot

Like the ELISA procedure, the western blot is an antibody detection test. However, unlike the ELISA method, the viral proteins are separated first and immobilized. In subsequent steps, the binding of serum antibodies to specific HIV proteins is visualized.

Specifically, cells that may be HIV-infected are opened and the proteins within are placed into a slab of gel, to which an electrical current is applied. Different proteins will move with different velocities in this field, depending on their size, while their electrical charge is leveled by a surfactant called sodium lauryl sulfate. Some commercially prepared Western blot test kits contain the HIV proteins already on a cellulose acetate strip. Once the proteins are well-separated, they are transferred to a membrane and the procedure continues similar to an ELISA: the person’s diluted serum is applied to the membrane and antibodies in the serum may attach to some of the HIV proteins. Antibodies that do not attach are washed away, and enzyme-linked antibodies with the capability to attach to the person’s antibodies determine to which HIV proteins the person has antibodies.

There are no universal criteria for interpreting the western blot test: The number of viral bands that must be present may vary. If no viral bands are detected, the result is negative. If at least one viral band for each of the GAG, POL, and ENV gene-product groups are present, the result is positive. The three-gene-product approach to western blot interpretation has not been adopted for public health or clinical practice. Tests in which less than the required number of viral bands are detected are reported as indeterminate: a person who has an indeterminate result should be retested, as later tests may be more conclusive. Almost all HIV-infected persons with indeterminate western blot results will develop a positive result when tested in one month; persistently indeterminate results over a period of six months suggests the results are not due to HIV infection. In a generally healthy low-risk population, indeterminate results on western blot occur on the order of 1 in 5,000 patients.:However for those individuals that have had high-risk exposures to individuals where HIV-2 is most prevalent, Western Africa, an inconclusive western blot test may prove infection with HIV-2.

The HIV proteins used in western blotting can be produced by recombinant DNA in a technique called recombinant immunoblot assay (RIBA).

Rapid or point-of-care tests

Rapid antibody tests are qualitative immunoassays intended for use as a point-of-care test to aid in the diagnosis of HIV infection. These tests should be used in conjunction with the clinical status, history, and risk factors of the person being tested. The positive predictive value of Rapid Antibody Tests in low-risk populations has not been evaluated. These tests should be used in appropriate multi-test algorithms designed for statistical validation of rapid HIV test results.

If no antibodies to HIV are detected, this does not mean the person has not been infected with HIV. It may take several months after HIV infection for the antibody response to reach detectable levels, during which time rapid testing for antibodies to HIV will not be indicative of true infection status. For most people, HIV antibodies reach a detectable level after two to six weeks.

Although these tests have high specificity, false positives do occur. Any positive test result should be confirmed by a lab using the western blot.

Fig. 21. A woman demonstrates the use of the OraQuick rapid HIV test.

Interpreting antibody tests

ELISA testing alone cannot be used to diagnose HIV, even if the test suggests a high probability that antibody to HIV-1 is present. In the United States, such ELISA results are not reported as “positive” unless confirmed by a Western Blot.

The ELISA antibody tests were developed to provide a high level of confidence that donated blood was NOT infected with HIV. It is therefore not possible to conclude that blood rejected for transfusion because of a positive ELISA antibody test is in fact infected with HIV. Sometimes, retesting the donor in several months will produce a negative ELISA antibody test. This is why a confirmatory Western Blot is always used before reporting a “positive” HIV test result.

Rare false positive results due to factors unrelated to HIV exposure are found more often with the ELISA test than with the Western Blot. False positives may be associated with medical conditions such as recent acute illnesses and allergies. A rash of false positive tests in the fall of 1991 was initially blamed on the influenza vaccines used during that flu season, but further investigation traced the cross-reactivity to several relatively non-specific test kits. A false positive result does not indicate a condition of significant risk to health. When the ELISA test is combined with Western Blot, the rate of false positives is extremely low, and diagnostic accuracy is very high.

HIV antibody tests are highly sensitive, meaning they react preferentially with HIV antibodies, but not all positive or inconclusive HIV ELISA tests mean the person is infected by HIV. Risk history, and clinical judgement should be included in the assessment, and a confirmation test (Western blot) should be administered. An individual with an inconclusive test should be re-tested at a later date.

 

Other tests used in HIV treatment

The CD4 T-cell count is not an HIV test, but rather a procedure where the number of CD4 T-cells in the blood is determined.

A CD4 count does not check for the presence of HIV. It is used to monitor immune system function in HIV-positive people. Declining CD4 T-cell counts are considered to be a marker of progression of HIV infection. A normal CD4 count can range from 500 cells/mm3 to 1000 cells/mm3. In HIV-positive people, AIDS is officially diagnosed when the count drops below 200 cells/μL or when certain opportunistic infections occur. This use of a CD4 count as an AIDS criterion was introduced in 1992; the value of 200 was chosen because it corresponded with a greatly increased likelihood of opportunistic infection. Lower CD4 counts in people with AIDS are indicators that prophylaxis against certain types of opportunistic infections should be instituted.

Low CD4 T-cell counts are associated with a variety of conditions, including many viral infections, bacterial infections, parasitic infections, sepsis, tuberculosis, coccidioidomycosis, burns, trauma, intravenous injections of foreign proteins, malnutrition, over-exercising, pregnancy, normal daily variation, psychological stress, and social isolation.

This test is also used occasionally to estimate immune system function for people whose CD4 T cells are impaired for reasons other than HIV infection, which include several blood diseases, several genetic disorders, and the side effects of many chemotherapy drugs.

In general, the lower the number of T cells the lower the immune system’s function will be. Normal CD4 counts are between 500 and 1500 CD4+ T cells/microliter, and the counts may fluctuate in healthy people, depending on recent infection status, nutrition, exercise, and other factors. Women tend to have somewhat lower counts than men.

Management

There is currently no cure or effective HIV vaccine. Treatment consists of high active antiretroviral therapy (HAART) which slows progression of the disease  and as of 2010 more than 6.6 million people were taking them in low and middle income countries. Treatment also includes preventive and active treatment of opportunistic infections.

Antiviral therapy

Current HAART options are combinations (or “cocktails”) consisting of at least three medications belonging to at least two types, or “classes,” of antiretroviral agents. Initially treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). Combinations of agents which include a protease inhibitors (PI) are used if the above regime loses effectiveness.

When to start antiretroviral therapy is subject to debate. The World Health Organization, European guidelines and the United States recommends antiretrovirals in all adolescents, adults and pregnant women with a CD4 count less than 350/µl or those with symptoms regardless of CD4 count. This is supported by the fact that beginning treatment at this level reduces the risk of death. The United States in addition recommends them for all HIV-infected people regardless of CD4 count or symptoms; however it makes this recommendation with less confidence for those with higher counts.  While the WHO also recommends treatment in those who are co-infected with tuberculosis and those with chronic active hepatitis B. Once treatment is begun it is recommended that it is continued without breaks or “holidays”. Many people are diagnosed only after treatment ideally should have begun. The desired outcome of treatment is a long term plasma HIV-RNA count below 50 copies/mL.  Levels to determine if treatment is effective are initially recommended after four weeks and once levels fall below 50 copies/mL checks every three to six months are typically adequate.  Inadequate control is deemed to be greater than 400 copies/mL.  Based on these criteria treatment is effective in more than 95% of people during the first year.

Benefits of treatment include a decreased risk of progression to AIDS and a decreased risk of death. In the developing world treatment also improves physical and mental health. With treatment there is a 70% reduced risk of acquiring tuberculosis. Additional benefits include a decreased risk of transmission of the disease to sexual partners and a decrease in mother-to-child transmission. The effectiveness of treatment depends to a large part on compliance. Reasons for non-adherence include poor access to medical care, inadequate social supports, mental illness and drug abuse. The complexity of treatment regimens (due to pill numbers and dosing frequency) and adverse effects may reduce adherence. Even though cost is an important issue with some medications, 47% of those who needed them were taking them in low and middle income countries as of 2010  and the rate of adherence is similar in low-income and high-income countries.

Specific adverse events are related to the agent taken. Some relatively common ones include: lipodystrophy syndrome, dyslipidemia, and diabetes mellitus especially with protease inhibitors. Other common symptoms include diarrhea,  and an increased risk of cardiovascular disease. Newer recommended treatments are associated with fewer adverse effects. Certain medications may be associated with birth defects and therefore may be unsuitable for women hoping to have children.

Treatment recommendations for children are slightly different from those for adults. In the developing world, as of 2010, 23% of children who were ieed of treatment had access. Both the World Health Organization and the United States recommend treatment for all children less than twelve months of age. The United States recommends in those between one year and five years of age treatment in those with HIV RNA counts of greater than 100,000 copies/mL, and in those more than five years treatments when CD4 counts are less than 500/µl.

 

 

 

 

References:

1.      Danilevskiy M.F. et al. “ Diseases of the mucous membrane of the mouth.” – K.: “Medytsyna”, 2010.

2.      Bruch J.M. Clinical oral medicine and pathology/ J.M. Bruch, N.S. Treister// London.:Humana Press, 2010

3.      Cawson R. E. Cawson’s essentials of oral pathology and oral medicine. Seventh edition/ Cawson R. E. et. al. //Elsevier science limited, 2002.

4.      Slootweg P. Dental pathology – a practical introduction/ P.J. Slootweg// Berlin.: Springer, 2007.

5.      Da Silva J.D. Oxford American Handbook of Clinical Dentistry (Oxford American Handbooks in Medicine) / J.D. Da Silva et al.// Oxford University Press, 2007.

6. http://www.cdc.gov/flu/
7. http://www.who.int/mediacentre/factsheets/fs211/en/index.html
8. http://en.wikipedia.org/wiki/Influenza

9. http://www.medicinenet.com/infectious_mononucleosis/index.htm
10. http://en.wikipedia.org/wiki/Infectious_mononucleosis
11. http://www.cdc.gov/ncidod/diseases/ebv.htm

12. http://www.cdc.gov/hand-foot-mouth/
13. http://children.webmd.com/guide/hand-foot-and-mouth-disease-topic-overview
14. http://en.wikipedia.org/wiki/Hand,_foot_and_mouth_disease

15. http://www.ncbi.nlm.nih.gov/pubmed/9413529

16. http://www.cfsph.iastate.edu/DiseaseInfo/disease.php?name=foot-and-mouth-disease

17. http://www.fwi.co.uk/articles/12/09/2007/105713/foot-and-mouth-symptoms.htm

18. http://en.wikipedia.org/wiki/Foot-and-mouth_disease

 

 

Information was prepared by Sukhovolets I.O.