Kaposi+Sarcoma-+Understanding+the+AIDS+rash

= __**Kaposi’s sarcoma: Understanding the “AIDS rash"**__ =

 **__Introduction__**
= = = =  Kaposi’s (KA-po-she) sarcoma, hereby referred to as KS, is a cancerous disease caused by the viral agent Human Herpesvirus 8. The virus causes the formation of cancerous lesions in a wide array of areas, ranging from the skin and mouth, to the lungs and intestines. The virus, while originally being discovered in 1872, became most recognizable in the 1970s and 1980s with the rise of HIV/AIDS. The virus, and resulting tumors, is common in AIDS patients, as immunosuppression allows for increased viral expression. KS consists of five main types each containing varying levels of metastatic aggression, lesion dissemination, affected populace, and affected areas. While functionally incurable, if diagnosed early most forms of Kaposi ’s sarcoma can be managed with various forms of treatment. In many cases, Highly Active AntiRetroviral Therapy, or HAART, can halt lesion growth and possibly induce remission. This treatment however is not 100% effective. Altogether, Kaposi ’s sarcoma is a predominately systemic cancer caused by a retrovirus highly affiliated with HIV/AIDS. This project seeks to further research that relationship and bring to light information on this highly recognizable and highly common disease.

__**Types and history**__
 Kaposi ’s sarcoma (KS) was originally identified in 1872 by Hungarian dermatologist Moritz Kaposi. Moritz only described the symptoms however, and real research in to the cause of KS arose predominately with the advent of the AIDS virus. In the late 1970s and early 1980s, KS was predominately believed to be a symptom of the AIDS virus commonly referred to as the “AIDS rash”. This ideology soon began to fade as understanding of HIV/AIDS began to increase. Researchers began to notice that KS, while being highly linked to AIDS, was also present outside of HIV/AIDS patients. This, along with increasing success of antiretroviral drugs, led researchers to believe that the disease was viral in nature. In 1994 researchers from Columbia University successfully isolated small strands of viral DNA from infected human tissue. Over the next two years, these strands were expanded upon and linked together until the genome for a new virus was mapped. The virus was titled Human Herpesvirus 8 (HHV-8), though soon became known as Kaposi’s Sarcoma-associated Herpes Virus (KSHV). Research in to this virus yielded five different forms of KS expression, all caused by KSHV.

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__**The Five Formsmedia type="youtube" key="Zv2CFG_pjYY?version=3" height="248" width="404" align="right"**__ ====== __//Classic Kaposi sarcoma//__ – This form of KS is what was originally described in 1872. It is primarily diagnosed in aging Mediterranean or Eastern European men. This geographical distinction is correlated directly to increased KSHV population in the area. The increased presence of KSHV yields increased infection rates, and so these areas see statistically higher expression. Since these patients have no form of immunosuppression or immunodeficiency for KSHV to piggyback on, this form of KS is the least common and the least metastatically aggressive.

__//African cutaneous Kaposi sarcoma//__ – Similar in nature to Classic KS, African cutaneous KS infects primarily middle aged men in Sub-Saharan Africa. This form is slightly more aggressive than classic KS, as is has high levels of subcutaneous lesion formation. As in Classic KS, this form is unrelated to immunosuppression instead simply being related to high KSHV levels.

//__African Lymphadenopathic Kaposi Sarcoma__// – A highly aggressive from of the disease, this manifestation is mainly diagnosed in young children ranging from 3-10. Tumorogenesis occurs in the lymph nodes and causes rapid metastasis. As an added danger, Lymphadenopathic KS frequently does not form skin lesions seen in all other forms. This results in significantly smaller chances of early diagnosis. Statistically, once the lymph nodes are infected, there is very little chance of recovery. As in the Classic and African Cutaneous forms, African Lymphadenopathic KS is not linked to additional immunosuppression.

//__Immunosuppression-associated Kaposi sarcoma__// – A relatively new form of the disease, Immunosuppression-associated KS is linked to medical immunosuppression. Most frequently caused by organ donation, this form of KS arises when KSHV is introduced to a subject at roughly the same time as immunosuppressants. In example, an organ carrying a small amount of KSHV may be transplanted into a new host. To reduce the chances of rejection immunosuppression drugs are administered. This drop in immune system functionality allows for the relatively small amount of KSHV to present a larger threat, and so give rise to full blown expression. The expression itself is similar to Classic KS, but in a much more random array of affected area. Tumors and lesions can occur systemically, but are most common in the area surrounding the transplant. This form has recently become increasingly common, mostly attributed to the increased usage of calcineurin inhibitors. Calcineurin inhibitors block the functionality of calcineurin, a protein devoted to activating immune system T-cells. With these T-cells blocked, KSHV is much less likely to be recognized and destroyed, and so spreads throughout the body faster. In the last 10 years, increased screening efforts for KSHV presence in organ donation has stabilized the incidence of this KS form.

__//AIDS-associated Kaposi sarcoma//__ – The most common and most aggressive form of KS, this form is typically referred to simply as KS. This form sees the fastest lesion growth and spreads rapidly to vital areas of the body. This speed is directly linked to the presence of the AIDS virus. Since AIDS causes the human immune system to be massively weakened, KSHV proliferates exponentially faster. This growth creates additional weakening, creating a positive feedback loop with KSHV growth rate. The disease manifests first in lesions on the skin and oral cavity, but quickly transitions to the stomach, lungs, intestine, muscle tissue, and lymph nodes. This form is most benefitted from HAART treatment, as it affects both the AIDS virus and the KSHV virus. However, once diagnosed, this form is predominately widespread enough to eliminate all chance of being cured.

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__**Physiological origin and transmission**__ ======  The physiological pathway involved in KS is an area of significant research. Interestingly enough, KS is not actually a sarcoma. Sarcoma is a term applied to mesynchymal tumors. KS however is a progenitus of lymphatic endothelium. Additionally, KS begins as a flat lesion with high angiogenesis. This varies from most sarcomas as angiogenesis is present before mass build up. This increased angiogenesis causes the increased proliferation of spindle cells. These cells are inflammatory in nature and promote lesion into the nodular stage. It is also these spindle cells that act as host and promoter for KSHV. KSHV augments lymphatic endothelial cells to create these spindle cells, which in turn promotes lesion growth. These spindle cells however are typically not clonal like most cancer promoters. They arise from and create KSHV. As the spindle cells proliferate, they cause more angiogenesis and inflammation. This draws more lymph endothelium and immune system response, which in AIDS patients especially, can be converted in to spindle cells. This increases the size and complexity of the lesion, as well as the overall presence of KSHV. KS is never witnessed in the absence of KSHV

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__**Kaposi’s Sarcoma-associated Herpesvirus (KSHV)**__ ======  KSHV is a large DNA virus composed of a linear DNA strand roughly 165 kb long. It is a member of the lymphotropic/herpesvirus family. KSHV primarily attacks immune system B-cells and lymphatic endothelium, converting both in to KS spindle cells. It accomplishes this is two different ways. The first manner of attack and expression is known as latent infection. This attack strategy is very limited and slow, but serves as a way to create a foundation to build off of. Once the virus has penetrated in to the cell, the DNA enters the nucleus and transitions from linear to circular formation. Here it will duplicate several times and exhibit very little functionality. Because the host DNA is left intact and the viral DNA is exhibiting limited functionality, the immune response to this type of infection is almost negligible. Studies have shown that this method of infection is highly benign, until introduced to lymphatic endothelium. When this cell type has been attacked, it begins to undergo massive structure changes. The actin cytoskeleton is completely overhauled to create a structure severely similar to KS spindle cells. This method of attack allows for small amounts of KSHV creation while remaining mostly unnoticed by the immune response. Additionally, it creates precursors to KS spindle cells. The next method of infection is known as lytic replication and builds off of the first infection type. Once certain cell conditions are met, the mainly benign viral DNA in the cell nucleus begins full expression. These trigger conditions are unknown in living human subjects. Once the viral DNA has been activated, it completely takes over cell function, creating invasive and infectious versions of the virus. Once the cell has been exhausted of materials for virus creation, the DNA causes cell death. The viruses created then move out into the surrounding cells and blood stream infecting immune system b-cells. These cells then help facilitate the conversion of pre-spindle cells into KS spindle cells. These KS spindle cells, now sharing DNA with infected B-cells, now become highly resistant to immune response. Once the spindle cells become immune resistant they proliferate and begin the aforementioned feedback loop.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">**__KS Transmission__**
<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> Since KS is directly caused by KSHV, KS transmittance is caused by KSHV transmittance. The virus is transmitted through saliva and any form of fluid exchange. This encapsulates all forms of kissing and sexual acts but also breast feeding. This means that transmittance is predominately sexual. Interestingly enough, heterosexual coupling has significantly lower rates of transmission than homosexual coupling. This increase in transmission is attributed to the higher statistical infection percentage of gay men and also to the sexual acts of gay males themselves, citing gay intercourse and “deep kissing” as a more susceptible manner of transmission for all sexually transmitted diseases. This is predominately due to the absence of vaginal antibodies and the presence of inflammation and small amounts of blood in anal intercourse. <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> KSHV can also be transmitted by organ donation and blood transfusion. This incidence is significantly rarer than sexual transmittance however, and recent screening efforts have made this less common than in the past. <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> Finally, in lesser developed countries with warm wet climate, specifically sub-Saharan Africa, KSHV is theorized as being capable of surviving for short amounts of time in stagnant pools of water. This manner of transmittance, along with genetic inheritance of latent viral DNA and heavy AIDS exposure, is a possible explanation of why Africa has such large expression of KSHV.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">**__Symptoms__**
<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> The symptoms of KS are highly variable depending on how aggressive the cancer is and where the lesions are occurring. To describe the symptoms, KS is broken down in to five zones.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">//__Skin Lesions__// <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">Skin and subcutaneous lesions while being an eye-sore, are mostly benign. The most prevalent symptom is the lesion itself, disfiguring the individual with a large red/black growth. They are typically associated with itchiness and slight pain when scratched intensely. In advanced cases, skin lesions may begin to seep or ooze, ultimately ending in tissue necrosis. Lesions that reach this advanced stage must be excised or else risk causing additional tissue death.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">//__Oral Cavity Lesions__// <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">Oral cavity lesions are present in roughly 35% of KS cases. These lesions, like skin lesions, are mostly harmless. Symptoms stem from the high incidence of damage caused by chewing, resulting in bloody gums, infection, and loss of teeth. If allowed to grow, oral lesions may interfere with the ability to chew and swallow, and may impair speech.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">//__Respiratory Tract Lesions__// <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">While being spared the cosmetic damage of outer lesions, patients suffering from respiratory lesions are awarded numerous other symptoms. Small lesions can cause shortness of breath, coughing and fever. As the lesion progresses, it can cause severe chest pain, bloody phlegm, and eventually lung failure. Due to the covert nature of respiratory lesions, they are often first noticed as a response to these symptoms.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">//__Gastrointestinal Tract Lesions__// <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">Gastrointestinal lesions, being typically only present in advanced cases of KS, provide some of the worst symptoms associated with KS. While occasionally benign, these lesions initially cause pain and nausea and diarrhea. As the lesion swells, side effects worsen to include bloody stool, vomiting, vomiting blood, weight loss, nutrient deficiency, and full intestinal blockage. If these later symptoms are allowed to accumulate, nutrient deficiency, intestinal blockage and vomiting blood can become fatal side effects.

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">//__Lymphatic Lesions__// <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">While creating few symptoms of their own, lymphatic lesions are the most dangerous. Lymphatic lesions represent damage to the immune system and allow for rapid transmittance of KS to other areas in the body. The damage caused to the immune system lowers the body’s responsiveness to other symptomatic outputs of KS, functionally making every other symptom more severe. The combination of increased lesion growth and increased symptomatic output makes lymphatic lesions the most dangerous form of lesion

<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">__**Diagnosis**__
<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> Diagnosis for KS is ultimately rather simple. Often, patients will have visible skin or oral lesions. These lesions are biopsied and tested for the presence of KSHV. If the patient is suspected to have KS but does not have visible lesions, an X-ray or CT scan may be taken. Tumors found in this manner are typically biopsied using endoscopic techniques. Again the tissue is tested for the presence of KSHV. <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> In a clinical setting, there are also targeted tests aimed at specific antibodies linked to KSHV. These tests check for the presence of KSHV while simultaneously gauging the patient’s ability to transmit or become infected with KSHV. Developing this testing procedure and providing it in a public setting is pivotal in checking the rise of KS. Alternatively, this test can be used to track in more detail the exact pathways involved with KSHV infection.

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<span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;">**__Prognosis and Treatment__** ====== <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> Prognosis of KS is a rather tricky beast. While fundamentally incurable until a vaccine for KSHV is developed, if caught within the early stages, KS can be managed. When treated with HAART, 35-45% of patients will see decreased lesion size and even remission. HAART stands for Highly Active Antiretroviral Therapy and is primarily applied to inhibit the advancement of the HIV/AIDS virus. Since KSHV is also a viral agent, HAART affects both AIDS and KSHV. HAART itself includes a wide array of drugs. This wide array of drug types is what allows HAART to be effective, as multiple pathways can be addressed simultaneously. As an example, HAART in KSHV and AIDS patients frequently employs the use of protease inhibitors while simultaneously implementing reverse transcriptase inhibitors. Protease inhibitors block the ability of protease, a component vital to both HIV and KSHV viral replication. Alternatively, reverse transcriptase inhibitors block the function of any reverse transcriptase enzymes, the molecule that reads and facilitates viral gene expression and proliferation. By combining these two drugs, HAART attacks two separate pathways for KSHV and AIDS expression. By attacking multiple pathways at once, a smaller rate of adaptation is witnessed. However, depending on the level of immune system damage, HAART treatment may only treat KSHV for a few years. This is caused by adaptation to the used drugs, and once active, is difficult to halt. Treatment has to be augmented but primarily this only slows the return of the disease. While many patients are capable of living with repressed KS, over half of infected patients will begin to lose response to treatment in five years. <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> In addition to the HAART process, localized areas of KS can be treated with radiation. This treatment is typically not as effective with AIDS patients as HAART, but on localized areas in non-immunodeficient patients, can exhibit up to 40% remission rate. This treatment is less prevalent in AIDS patients due to the increased immune suppression caused by radiation therapy. Radiation therapy, when used in non-immune suppressed patients, can effectively control KS expression at a significant rate. <span style="background-color: transparent; color: #000000; font-family: serif; font-size: 16px; text-align: start; text-decoration: none; vertical-align: baseline;"> The last main form of treatment is cryosurgery. Due to the increased presence of KS lesions in swollen and inflamed tissue, surgery is typically not an outright option. To combat this, cryosurgery is implemented. Cryosurgery is directing extremely low temperatures at damaged tissue in order to avoid an inflammatory response. In KS, liquid nitrogen or dimethyl ether is used to freeze off skin lesions. This treatment is effective at repairing cosmetic damage as well as halting slower spreading KS. This treatment is fundamentally limited however by the nature of cryosurgery. Cryosurgery is significantly more problematic and costly if the area being treated is underneath the skin or deeper inside the body. This obstacle functionally limits cryosurgery usage to external lesions.

__**References**__
<span class="wiki_link_ext">KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine <span class="wiki_link_ext">Immunological Variables as Predictors of Prognosis in Patients with Kaposi's Sarcoma and the Acquired Immunodeficiency Syndrome <span class="wiki_link_ext">Kaposi Sarcoma Treatment (PDQ®): Treatment - Patient Information [NCI <span class="wiki_link_ext">Kaposi's Sarcoma - Medline Plus <span class="wiki_link_ext">Guidelines for the Use of AntiretroviralAgents in HIV-1-Infected Adults and Adolescents

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