on cART. 27 However, the exact mechanism is unknown. Some HIV-positive patients with undetectable viremia and normal CD4+ T-cell counts also develop KS, 28 implicating mechanisms other than immunodeficiency in KS progres- sion, including chronic inflammation associated with HIV or other co-existant opportunistic infections. 23,24 Clinical observations strongly suggest that corticoste- roids not only increase the risk of KS, but can also exacer- bate existing KS. 21,27,29-31 Dexamethasone has been shown to stimulate proliferation of cultured KS cells in vitro . 32 KS cells possess an unusually high concentration of cortico- steroid receptors, which can be further upregulated with corticosteroid treatment in a positive feedbackmechanism. 32 Inflammatory cytokines also synergize with corticosteroids to induce proliferation of KS cells. 26,32 Recognition of these associations is important due to the frequent use of systemic corticosteroids in HIV-infected patients for illnesses such as PJP and cryptococcal meningi- tis. Before initiating steroids in these patients, it is important to perform a thorough examination of the skin and oral cavity to identify suspicious lesions. We would advocate that if suspicious lesions are present, corticosteroids should generally be held until the diagnosis has been ruled out by biopsy. Sexual history is also important, as men who have sex with men have a much higher risk of acquiring HHV-8 and subsequently, KS relative to other risk groups. 6,33 The association of steroid treatment with KS appears to have been demonstrated in our patient, who developed clinically evident disease of the oral cavity and progressive pulmo- nary distress after receiving prednisone for IRIS. Further, our patient improved after the discontinuation of steroids, although it is unclear to what degree this was due to anti- fungal therapy and cART. CLINICAL FEATURES AND DIAGNOSIS In contrast to other subtypes of KS, AIDS-related KS is generally more fulminant, with a higher incidence of wide- spread disease. Typical lesions are purple, red, or brown, highly-vascular papules, although many morphological variants exist. The most common sites of clinically appar- ent disease include the extremities, face, oral mucosa, and genitalia, although virtually any tissue in the body can be af- fected. 34 The presentation is variable, includingmild disease limited to the skin and more severe disease involving the lymph nodes and viscera. Although cutaneous disease pre- cedes dissemination in most cases, disseminated or visceral disease may be present in the absence of skin involvement. 34 Prior to the emergence of cART, most patients who devel- oped KS would eventually develop disseminated disease, most often of the oral cavity, GI tract, and respiratory tract, which is associated with a high mortality rate. The most important clinical mimic is bacillary angiomatosis (BA), which can present as multiple, red, vascular skin lesions and also involve visceral organs. 34,35 Although uncommon, BAhas a higher prevalence amongHIV-infected individuals than the normal population. 36
tions, which eventually led to the discovery of AIDS in 1982. While the causative agent of AIDS was determined in 1984, it was not until a decade later that the viral etiology of KS, the Kaposi sarcoma-associated herpesvirus (KSHV; or HHV-8), was identified. 5 Four subtypes of KS have been described, including classic, endemic, iatrogenic, and AIDS-related KS. Current estimates of the prevalence of KS among AIDS patients vary. A study in 1989 showed that the prevalence among homosexual men with AIDS was 21% and only 1% in AIDS patients who had contracted the virus by way of blood transfusion. 6 The cumulative incidence in HIV patients has since fallen from 14.3% in 1980-1989 to 1.8% in 1996-2006, mostly due to the emergence of cART. 7 RISK FACTORS AND TRANSMISSION OF HHV-8 Several epidemiologic studies indicate that sexual con- tact is the most commonmode of transmission for HHV-8. 6,8 Higher circulating viral loads have been associated with homosexual activity, increasing number of sexual partners, commercial sex work, and attendance at STD clinics. 8-11 Viral DNA has been detected in the semen and prostatic fluid of HIV-positive men, but higher viral loads in saliva relative to anal and genital tissue/fluid samples support saliva exposure as the most likely mode of transmission. 12,13 Salivary transmission is further supported by observation of horizontal transmission of HHV-8 among children and relatives in endemic regions. 14,15 Recipients of blood transfu- sions and solid organ transplants are also at greater risk of HHV-8 acquisition if the donor is seropositive for HHV-8. 16,17 Although all patients with KS are infected with HHV- 8, only about 0.03% of men and 0.02% of women infected with the virus will develop KS annually. 18 Immunosup- pression, either inherited, acquired, or iatrogenic, is a well- documented risk factor for the development of KS. Male gender, lower total lymphocyte count, lower CD4+ T cells, and a history of systemic and topical corticosteroid use have all been associated with development of KS. 19-21 PATHOPHYSIOLOGY OF KS AND CORTICOSTEROIDS HHV-8 is grouped in the human gamma-herpesvirus family, which also includes Epstein-Barr virus. Members of this family cause tumors in both humans and animals by induction of uncontrolled cellular proliferation. 22 Target cells for infection include endothelial cells, epithelial cells, macrophages, and B lymphocytes. A host of factors have been shown to activate latent virus, including inflamma- tory cytokines, immunosuppression, and tissue hypoxia. 23-25 Inflammatory cytokines, including IL-6, induce proliferation of KS cells in vitro through the gp130 protein pathway, 26 and increased inflammation associated with immune re- constitution inflammatory syndrome (IRIS) may explain the induction or KS tumors in patients recently started
J La State Med Soc VOL 166 September/October 2014 227
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