Cutaneous markers of HIV infection

Cutaneous Markers of HIV Infection DIMITRIS RIGOPOULOS, MD VASILIS PAPARIZOS, MD ANDREAS KATSAMBAS, MD Abstract. Despite the development of laboratory methods, dermatological symptoms are a basic index of the presence and physical course of HIV infection. HIV infection usually undergoes a long latent period, proceeds to a period of immunodeficiency-related symptoms, and ends in an advanced immunodeficiency state characterized by opportunistic infections and neoplasms. Occasionally, dermatological manifestations can be the first signs of asymptomatic disease, indices of advanced immunodeficiency, or symptoms of opportunistic infections or neoplasms. The variety of symptoms and signs for the skin during the course of HIV infection is a consequence of the progressing immunodeficiency and therefore indicates the underlying disorder. The use of these manifestations is a challenge for clinical praxis.

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cquired immunodeficiency syndrome (AIDS) was recognized as a new disease for the first time in 1981. Disease entities such as Pneumocystis carinii pneumonia and Kaposi’s sarcoma were the reason for this recognition. Despite the development of laboratory methods, dermatological symptoms were, in the past and still are, a basic index of the presence and physical course of the disease; human immunodeficiency virus (HIV) infection and AIDS are frequently related to a wide range of skin and mucosae manifestations. These manifestations occasionally can be the first signs of asymptomatic HIV infection, indices of advanced immunodeficiency, or symptoms of opportunistic infections or neoplasms. Dermatological signs in HIV/AIDS are sometimes related with atypical immunologic stimulation, sometimes to severe immunodeficiency or infections, and can be important prognostic markers regarding the evolution of the underlying disorder. HIV infection usually undergoes a long physical course with various manifestations, depending on the degree of immunological deficiency. Thus far, staging attempts have produced many different systems, with CDC-1993 being the most widely accepted (Appendix). According to this staging, the disease goes through a long latent period (stage A), then proceeds to a period of immunodeficiency-related symptoms such as oral mycoses, oral hairy leukoplakia (OHL), or recurrent herpes zoster appearance (stage B), and ends in an advanced immunodeficiency stage characterized by opportunistic infections and neoplasms (stage C). From the Department of Dermatology, University of Athens, A. Sygros Hospital, Athens, Greece. Address correspondence to Andreas Katsambas, MD, Department of Dermatology, A. Sygros Hospital, 5 Dragoumi Street, Kesariani, Athens, Greece. E-mail address: [email protected] © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010

During the asymptomatic HIV infection, the immunological response preserves a dynamic equilibrium against virus activity, and is also capable of defending against usual or opportunistic intruders; however, the atypical form of stimulation generates various skin and mucosae manifestations. In this stage, the CD4 lymphocyte count decreases, while CD8 count increases and CD4/CD8 ratio inverses. B-lymphocyte polyclonal activation results in ␥-globulin increase, accompanied by autoantibody production and subsequent autoimmune phenomena.1–3 Cytokine levels such as IFN-␥ and TNF-␣ increase while the IL-2 levels of CD4 lymphocytes and the IL-1 levels of dentritic cells and macrophages are decreased. At this stage, manifestations such as seborrhreic dermatitis, psoriasis, xeroderma, and pruritic papular eruption can be seen. As the infection advances, the immunological response weakens both in a quantitative and qualitative manner. The CD4/CD8 ratio decreases dramatically, the reversion of the type of immunological response is becoming typical, and the repertoire of immunological responses diminishes gradually. In advanced stages of HIV disease, manifestations such as seborrheic dermatitis and psoriasis coexist or are generated because of the appearance of opportunistic infections or other disorders. At these stages, OHL, chronic herpes simplex, recurrent herpes zoster, Kaposi’s sarcoma, etc, are also common. The variety of symptoms and signs from the skin during the course of HIV infection is a consequence of the progressing immunodeficiency and therefore indicates the underlying disorder. The use of these manifestations as clinical markers of the disease course is a challenge for clinical praxis. In our opinion, the criteria for such a use should be: •

The high frequency of appearance of the manifestation in HIV patients in comparison to immunocom0738-081X/04/$–see front matter doi:10.1016/j.clindermatol.2004.07.007

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petent persons. (Seborrheic dermatitis, OHL, Kaposi’s sarcoma). A well-defined and proved epidemiological correlation with low CD4 levels and/or high HIV-RNA load (OHL, chronic herpes). The improvement of the manifestation due to immunological improvement because of the contemporary antiretroviral therapy. The possible correlation to the rapid progression of HIV disease and decreased possibilities of survival (OHL, Kaposi’s sarcoma). An atypical form of the manifestation and/or its resistance to common therapeutic modalities (chronic herpes, recurrent or severe zoster).

Seborrheic Dermatitis The occurrence of seborrheic dermatitis (SD) in the general population varies between 2– 4%; however, its incidence in patients with HIV is significantly higher.4,5 Seborrheic dermatitis is the most common skin manifestation of HIV disease, occurring most frequently on the scalp, face, and chest. As the disease progresses, the clinical findings worsen and subside after highly-active antiretroviral treatment (HAART).5 It is considered that during the course of the disease, around 85% of patients will at least once manifest SD, although these data seem to have a close link to the type of the studied population and the duration of the follow-up.6,7 Hengge et al reported that 25.3% of HIV patients develop SD lesions prior to HAART.8 Shimizu et al9 reported SD lesions in 38% of Japanese hemophiliac HIV patients, and Jing et al10 reported SD lesions in 20.7% of Malaysian and Chinese HIV patients. In a study by Mirmirani et al,11 SD lesions were found at an increased frequency in seropositive women compared to a control group of seronegative women. In a number of studies, SD manifestations were found at every stage of HIV disease, from the first stages of the disease to the latest. Although the frequency, duration and severity of the rash are common findings at the first stages of the disease, they are basically related to later stages and decreased numbers of CD4 lymphocytes.12 In a study by Alessi et al,13 SD was found in 4.7% of early-stage patients and in 26.7% of full-blown-syndrome patients. Mathes et al6 reported a prevalence of 42% in AIDS-related-complex stage, but 83% in advanced AIDS patients. Disseminated forms of SD, characterized by sternum, back, axillae, and groin lesions, have been reported mainly in advanced disease.5,6,14 In a cohort study by Ippolito et al,15 72 asymptomatic patients were under observation from 1994 –95 up to 1998. It was concluded that patients suffering from SD had more possibilities of rapid progression to advanced disease. In conclusion, the exacerbation of SD, or its presentation in atypical and severe forms, are related to impending progression

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of HIV infection, and constitute a clinical index of deterioration of the underlying immunological disorder.

Psoriasis The frequency of common psoriasis in HIV patients is slightly higher than that in general population. Nevertheless, psoriatic arthritis has a higher frequency that is related to the presence of HLA-27. In extensive samples of patients, the percentage of psoriasis was around 1%, similar to that of the general population.16 In a study by Kaplan et al,12 the rate of psoriasis was 2%, while Wolfer et al17 report a 5% rate. Psoriatic lesions may appear before or after HIV infection. Rarely, psoriasis may be the first manifestation of HIV infection.18 De novo appearance of psoriasis or sudden worsening of pre-existing lesions in a person with a high-risk sexual behavior is an indication for undertaking a HIV test.19,20 The clinical course of psoriasis in HIV patients is reported to be deteriorating as immunodeficiency advances21; therefore, it could be a clinical index of progression of the HIV infection. Psoriatic lesions in the context of a modified immune response are commonly atypical. The frequent appearance of guttate form is reported, which normally is a post-streptococcal infection, or located in the genitourinary or auxiliary folds (inverse type), as well as in the palmar and plantar surfaces. Severe onychodystrophy, as well as generalized erythrodermic type,16,22 have been reported. Wolfer et al described the appearance of psoriasis in advanced disease with a CD4/CD8 ratio below 0.4.17 In a study by Obuch et al concerning 50 seropositive patients with psoriasis, psoriasis appeared after HIV infection in 2/3 of the patients and, more specifically, in older patients and in patients without any family history of psoriasis.21 Researchers report that amelioration of the lesions after remission of the disease from antiviral therapy (AZT) proves the correlation of these two diseases. Similar association of the development or progress of psoriasis with HIV viral load was also confirmed by Fisher et al.23 Generally, it is assumed that in diseases associated with increased keratinocyte activity such as SD, psoriasis, Reiter syndrome, Grover’s disease, Darrier’s disease, etc, HIV infection acts as an inflammation triggering factor, provoking appearance or deterioration of the lesions. Therefore, similar manifestations, which are influenced by growth factors and cytokine deregulation, could be used as a clinical index of the degree of progression of the underlying disorder.24 –27 The same patient can suffer both psoriasis and Reiter syndrome, which supports the hypothesis that these two diseases can be part of the manifestation range of the same disease.16 In a study of 50 HIV patients with psoriasis, in 1/3 of the cases, it was estimated that psoriasis appeared before HIV infection (group I) and in 2/3 of the cases after

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HIV infection (group II).28 Group I had a lower average age of onset (19 years versus 36 years) and positive family history, to a greater extent. Clinical types diagnosed are as follows: plaque psoriasis (78%), inverse (37%), gutted (29%), palmoplantar (8%), erythrodermic (14%), and pustular (8%). Palmoplantar and inverse psoriasis was more common in group II. Severe psoriasis was diagnosed in 25% of patients. Psoriasis tends to worsen as immunodeficiency advances, but does not affect survival.29

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results of their former study, reporting 47% AIDS progression in 24 months and 67% in 4 years. Begg et al accepted high prognostic value for rapid disease progress for OHL and other oral diseases, especially in low CD4 counts (below 200/␮L).48 Furthermore, Husak et al linked OHL to poorer prognosis, even in patients with CD4 counts above 300/␮L.43 According to the findings of Margotta et al, OHL and other skin or mucosa manifestations strongly related to HIV disease constitute, by their appearance, an index of therapy failure.49

Oral Hairy Leukoplakia (OHL) OHL, a lesion of oral and tongue mucosa, is due to Epstein-Barr virus infection (EBV).30,31 EBV proliferates in epithelial cells due to underlying immunodeficiency, being an opportunistic infective agent.30 The detection of OHL is therefore a characteristic of underlying immunodeficiency, either due to HIV infection or other disease.32,33 In seropositive patients, it appears in any stage of the disease, with a frequency of approximately 25%.34 The high incidence of OHL in seropositive patients is an index of high suspicion for HIV infection.35 In a study by Feigal et al36 in San Francisco, the incidence of OHL was estimated at 20%. Eyeson et al,37 in a study of 203 HIV patients, found a 9.9% incidence and correlation with higher HIV virus load. CeballosSalobrena et al38 reported OHL in 26.6% of a 154-patient group, most of them intravenous drug users. In another study, by Samet et al,39 OHL was found in 23% of 95 patients. Patton et al40 reported a similar percentage (26.5%) in a 238-patient group. According to researchers, OHL incidence was related to sex, with a higher incidence in men, and with CD4 levels below 200. The same investigators correlated later OHL manifestation to higher HIV virus load.41 Shiboski also reports association to sex and lower OHL incidence in women.42 In Germany, in a long-term follow-up study concerning a group of 456 patients, Husak et al diagnosed OHL in 15.6% of patients, and correlation of its appearance with low CD4 counts (median CD4 count: 235/␮L).43 Generally, OHL has been linked to advanced HIV disease, with low CD4 counts and higher HIV-RNA load. Taking into account that OHL appears also at early stages, its presence constitutes a rather weak index of immunodeficiency status.44 On the contrary, its relation to HIV infection activity is confirmed by its recession after immune reconstitution due to HAART treatment.45,46 This correlation is also reflected clinically, making OHL a clinical indicator of disease activity.35 In 1987, Greenspan et al30 linked OHL to rapid disease progression, and concluded that OHL has an important prognostic value. In their study, the possibility of developing AIDS in HIV carriers manifesting OHL was 48% in 16 months and 83% in 31 months. The same researchers, in a subsequent study,47 confirm the

Herpes Zoster (HZ) The appearance of herpes zoster is reported as more frequent, more severe, and of longer duration in HIV patients in comparison to immunocompetent persons.50 –53 Friedman-Kien et al found HZ occurrence of up to 8% in AIDS-related Kaposi’s sarcoma patients.54 Buchbinder et al estimated a 17-fold relative risk for HZ in seropositive homosexual HIV patients in comparison to seronegative homosexuals.55 Veenstra et al reported the incidence of HZ at 51.51 per 1000 person-years in seropositive patients, in comparison to 3.31 per 1000 personyears in a seronegative control group.56 HZ appears more frequently in patients with low CD-4 counts, proving an opportunistic infection tendency and a clinical index of underlying immunodeficiency. In a study by Veenstra et al, CD4 count was found to be an indicator of HZ risk in an inverse ratio.56 The findings of Brambilla et al57 and Engels et al58 were similar although, generally, HZ appearance occurs even in high CD4 counts.59 Atypical and complicated HZ forms are more common in HIV patients, and such cases are proportional to the status of the immune system. In underlying immunodeficiency, disseminated or generalized HZ, multiple recurrences, systemic infection with visceral dissemination, and CNS involvement such as encephalitis, meningitis, myelitis, and polyneuritis are reported.60 – 62 HZ dissemination outside the affected dermatome is more frequent in seropositive persons compared to seronegative persons.52 According to Tappero et al, disseminated and recurrent HZ is a characteristic of advanced disease.59 Recurrent HZ appears in 20 –30% of HIV patients.63 According to Buchbinder et al, recurrences occur in 20% of patients, and disseminated, multidermotomal form is not rare.55 The chronic course of HZ is common almost exclusively in advanced HIV disease. Chronic forms with icthyasiform necrotic lesions or verruciform hyperkeratotic lesions, often disseminated to more than one dermatome, have been also reported.49,50 Therefore, the presence of the atypical, disseminated, or systemic form of HZ is of high suspicion of advanced HIV/AIDS disease.

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Despite the aforementioned conclusions, HZ prognostic importance in the course of the HIV disease remains controversial, and its appearance is not a skin marker of deterioration. In relatively few studies, HZ is correlated to rapid disease evolution and unfavorable prognosis. Melbye et al, in a long follow-up study with 112 seropositive patients, support HZ prognostic value.64 In a study by Lindan et al, with a 2-year follow-up in 460 seropositive women, the history of HZ constituted an independent baseline predictor of mortality.65 Van Griensven et al, in an epidemiological study of 286 seropositive homosexual men, found correlation of HZ to high-risk status, determined by CD4 levels and HIVRNA load66; however, HZ is rather the result, and not an early index, of immunocompromise. Furthermore, McNulty et al did not find an association between HZ and disease progress in a 146 seropositive patient group.67 Similar results have been reported by Chaisson et al,68 in a series of 2081 patients, Veenstra et al,56 in 966 homosexuals (Amsterdam cohort study), Glesby et al,69 in 1044 patients, and Buchbinder et al.55 Furthermore, Alliegro et al ascertained that, in 48 patients suffering from HZ (in a group of 1198 HIV patients), only fever was an independent predictor factor of the progress of HIV disease.70 In conclusion, HZ infection is a potential skin marker in HIV disease only in disseminated, chronic, or systemic forms. These forms are expected frequently in advanced disease and correlate theoretically to shorter survival.

Herpes Simplex (HSV) Herpes simplex is a profound opportunistic manifestation in HIV disease. Herpes simplex chronic infection of longer than1-month duration in HIV patients is a criterion for the existence of AIDS (AIDS-Condition) and was included by the CDC to the definition of the syndrome in 1987 (Appendix). In HIV patients, HSV infection can manifest in a more persistent, ulcerative form and can be accompanied with intense pain and fever. In these patients, recurrences or asymptomatic HSV shedding occurs 3–5 times more frequently than in immunocompetent persons.71 The degree of immunodeficiency determines the frequency of recurrences and severity of the disease.71,72 This frequency increases dramatically when CD4 count is below 50/␮L.72 The tendency for self-limitation of lesions depends on the immune status, and in immunocompromised hosts is very low.73 Therefore, HSV tendency for chronicity is associated with advanced immunodeficiency, and appears to be a clinical index of the progress of the disease course.74 In advanced HIV disease, due to severe immunodeficiency, herpetic infection is more likely to proceed to chronicity with deep, painful ulcers.75 Dissemination in

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oropharynx and esophagus,76,77 herpetic whitlow,78 – 80 atypical, hypertrophic, or nodular skin lesions, 81,82 and resistance to acyclovir treatment,83– 85 have also been described. Similar conditions appear to be indisputable indexes of underlying immunodeficiency. HSV infection in HIV patients is considered to be by itself, an aggravating factor for HIV disease. Interaction between the two viruses has been described in various in vitro studies, which documented multiple mechanisms of HSV-induced HIV replication;86 –91 however, only a few in vivo studies exist. Schacker et al,92 as well as Mole et al,93 ascertained that HIV-RNA load was increased during HSV infection manifestations. In a study by Serrwadda et al,94 HIV load was increased in HIV patients seropositive to HSV-2, compared to seronegative. In a recent study by Suligoi et al,95 correlation of HSV to more rapid progression of HIV disease was found in a 359-patient group. If active HSV infection is a skin marker of rapid progression of HIV infection, chronic suppressive therapy should be beneficial to survival rates; however, results from relative studies are conflicting,96 –99 and correlation of HSV to aggravating prognosis is not yet strong.

Candidiasis From the initial description of early cases,100 candidiasis of mucosae has been associated with HIV disease. From the beginning of the AIDS epidemic, it was determined that oropharynx candidosis is a marker of dysfunction of the immunological system, and is also a prognostic marker for the development of other resulting infections.101 Candidiasis of the esophagus or of the lungs and bronchi is considered an indicator disease for AIDS. Candidiasis in HIV patients is strongly related to deficiency of anti-candida defense mechanisms, both topical and systemic, due to the induced immunodeficiency related to HIV infection.102–105 Changes of the standard levels and the efficiency of topical factors, such as secretory IgA globulin, lactoperoxidase, lactoferin, and lysozyme have been proven in HIV patients, and are potentially related to the development of candidosis.102,106 Oropharyngeal candidosis is extremely common in HIV patients, while in seropositive women, vulvovaginitis due to candida is not a rare finding.107 Candidiasis of the mucous membranes is frequently the first clinical symptom of HIV infection.108 Recurrences are frequent, and constitute an indicator of debility growth and maintenance of adequate immunological response.107 Prevalence of oral candidiasis in HIV patients ranges, between different studies, from 30% to 80% according to the population, the follow-up period, and the level of immunodeficiency. In a study by McCarthy

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et al, 92% of the patients with CD4 lymphocytes below 300/␮L developed oral candidiasis during their disease.105 Ceballos-Salobrena et al38 predicted prevalence of the disease of up to 34.4%, Kumarasamy et al109 up to 45%, Wang Jing et al10 up to 35.9%, while Singh et al110 predicted up to 14.3% of patients in the early stages of HIV infection and up to 49.2% in patients a later stages. Although candida infection can appear at any stage of HIV infection, immunodeficiency and decrease of CD4 lymphocytes definitely prove an increased possibility for the existence of the disease.111,112 Patton et al found correlation of candidiasis not only with CD4 to be as low as 200 ␮L, but also with an increased HIV viral load.40,41 The adoption of HAART in the treatment of HIV infection and the resulting immune reconstitution has lead to a decrease of candida infections. Ulrich et al found a decrease from 36.8 % to 20.2% after HAART administration;113 Birnbaum et al45 and Greenwood et al46 reported similar findings. On the other hand, candidiasis is strongly related to unfavorable prognosis, aggravation of HIV infection, progress of AIDS, and death, despite the fact that its prognostic value is restricted to a lower number of CD4 lymphocytes. Klein et al reported that 59% (13/22) of HIV patients with oral candidiasis developed occasional manifestations in a short period of time in comparison with 0% (0/20) in the control group.101 Smith et al,114 in a larger group of patients (912) and with a longer follow-up period (42 months), published the same findings as many others.115–117 Begg et al confirmed the worse prognosis of oral candidiasis, in patients with CD4 lower than 200/␮L.46 Correlation of oral candidosis’ diagnostic importance to CD4 counts is found in Maden et al,118 and Nielsen et al112 studies. On the contrary, it is not certain that HAART treatment can change the prognostic importance of oral candidiasis in the physical evolution of HIV infection. In the study by Ceballos-Salobrena,38 patients were under HAART treatment, while Margiotta et al49 consider its appearance as failure of treatment. Clinical failure of HAART, however, is usually followed by viral and immunological failure, a fact that by itself defines a deterioration of the prognosis.

Pruritus, Pruritic Papular Eruption, and Eosinophilic Folliculitis Pruritus is one of the most prominent symptoms reported during HIV infection. It may or may not be accompanied by different eruptions, and it can be a manifestation of systemic or cutaneous disease. Skin infections, photodermatitis, xeroderma, drug eruptions, insect bites, psoriasis, and seborrheic dermatitis are among the causes of pruritus. Hepatitis B or C, chronic renal failure, lymphomas, and psychiatric disorders are also associated with pruritus. Idiopathic pruritus is di-

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agnosed by result and is commonly an indicator of the subjacent HIV immunodeficiency.119 Furthermore, puritus can be the first clinical symptom of HIV infection.120,121 Pruritus can be related with atopy as a result of the immune disorder with changes of the cytokine levels and with the inversion of the type of the immune response with domination of Th-2 and with eosinophilia.122 Papular dermatitis, or as is usually referred to in the literature, pruritic papular eruption (PPE), is a common atypical papular pruritic eruption appearing in HIV patients. Etiology and the exact pathogenesis of eruptions of the type of PPE remain unclear and controversial.122 The most constant finding in HIV patients with PPE is hypereosinophilia in the lesions or/and in peripheral blood,123,124 although eosinophilia is a usual finding in advanced HIV infection125 and commonly accompanies pruritic skin diseases such as drug eruptions, eosinophilic folliculitis, atopic dermatitis, or prurigo nodularis (Fitz. new. 28). In the laboratory investigation of PPE, decreased levels of IL-2 and IFN-gamma, and increased levels of TNF-␣ are mentioned.24,124,126 PPE is correlated to latent HIV infection, decreased CD4 lymphocytes (⬍100/␮L), and high HIV viral load, and constitutes a marker of underlying immune disorder.110,124,127,128 Eosinophilic folliculitis (EF) is a chronic skin disease in patients with advanced HIV infection. The most common histological finding is the high eosinophilic infiltration129,130 with accompanying blood eosinophilia,131 as in PPE. PPE is considered by some researchers to be a form of EF.132 Pathogenesis of EF remains obscure. The involvement of an infectious factor has been proposed, but not proven,44 as the rush of EF does not respond to antibiotic treatment.131 Demodex folliculorum, which does not function as an antigen in immunocompetence, probably triggers the production of special anti-demodex IgE antigens, which, connected with mast-cells and Langerhans cells in the skin, result in the formation of pruritic follicular lesions.129 Lesions usually appear at later stages of HIV infection, with CD4 counts ⬍250/␮L.129,131 At these levels, immune disorders, which constitute the substrate of the manifestation, are frequent and intense. During HAART, EF may appear or recur with higher levels of CD4 and low viral load, probably due to the “syndrome of immune reconstruction.” Idiopathic pruritus, PPE, and EF are correlated with advanced HIV immunodeficiency and can coexist with other symptoms or indicators of HIV infection; however, their appearance is not related with prognosis aggravation and faster progress of the disease to AIDS. Although their diagnostic significance is important as indicative of the underlying immunodeficiency, their prognostic value as skin markers remains obscure.

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Bacillary Angiomatosis Bacillary angiomatosis is a rather rare manifestation that is strongly related to HIV infection. LeBoit et al133 introduced the term for the first time. It is an opportunistic infection caused by gram-negative bacteria Bartonella (ex Rochalimea) quintata and Bartonella henselae.134 Almost 100 cases have been reported in the literature, mainly involving HIV patients in the United States, and less frequently, in Europe. In Germany, in a multicenter study of 23 medical centers during 1990 –1998, among 17,000 HIV patients, the reported incidence of bacillary angiomatosis was estimated to be at 0.12%.135 The disease appears in advanced immunosuppresion, with CD4 counts below 200/␮L.136 Bacillary angiomatosis affects skin or liver (peliosis), and potentially causes bacteremia and infiltration of other visceral organs. The appearance of the disease classifies the patient in stage B of the CDC staging of HIV infection (Appendix). Due to serious damage to the liver, late diagnosis is life threatening. Despite the above, it is not clarified if the appearance of bacillary angiomatosis is related to a more unfavorable prognosis of HIV infection.

Kaposi’s Sarcoma (KS) Kaposi’s sarcoma (KS) is one of the clinical entities that lead to the definition of AIDS as a new disease in 1981.137 Its opportunistic behavior and the correlation of KS with immunosupression were already known because of its appearance in transplanted patients;138 –142 with HHV-8 detection,143 the opportunistic character of the manifestation was clarified. Although in the general population, KS is rather rare, appearing sporadically in Mediterranean areas, the Caribbean, and central Africa,144 –147 in HIV infection, it is the most prominent neoplasia. Its incidence in HIV patients, at the beginning of the disease, was estimated at a level of 30 – 40%, affecting mainly homo- or bi-sexual men. Since the mid 1980s, a gradual decrease of its appearance was noticed and after 1992, its incidence did not exceed 10 –11% of the patients, a fact that was attributed to the change of high-risk behavior between homosexuals.148 –151 The establishment of HAART in 1996 lead to a greater decrease of HIV infection incidence.152,153 Franceschi et al154 report a decrease of the incidence of KS in AIDS patients, from 2.5 per 100 person-years between 1986 – 1992, to 1.0 per 100 person-years between 1997–98. KS can appear at any stage of HIV infection but is more frequent in advanced immunosupression, in patients with lower CD4 lymphocyte counts, or high rates of HIV-RNA.155–158 KS constitutes part of the definition for AIDS, and a patient with KS is classified as stage C, according to the CDC definition. As a multisystemic neoplastic disease,

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it is life threatening and is related to low survival rate. KS frequently affects visceral organs (lungs, gastrointestinal system) either early or late, contributing to an important prognostic factor of a faster evolution to death. In these situations, the evolution of KS159 is the evolution of AIDS. In the ACTG staging of the AIDSrelated KS159, CD4 below 200/␮L, disseminated or visceral sarcoma, and the presence of general symptoms are factors of poor prognosis for survival. Hermans et al, in an extensive study (1394 patients with AIDS/KS), confirmed its prognostic value in HIV/ AIDS disease.160 Brodt et al161 concluded that KS accelerates the evolution of HIV disease, despite the number of CD4 lymphocytes. Spano et al concluded that sole visceral Kaposi’s is an independent prognostic survival marker, while the antiviral treatment, without protease inhibitor, does not affect survival rate.162 Before the adoption of HAART, monotherapies with chemotherapy had only a palliative role in advanced sarcoma without improvement of the prognosis.163 Although the prognostic value of KS is thought to be high even after HAART,164 data seem to alter according to antiviral treatment. As KS establishes a characteristically opportunistic manifestation, improvement of the immune system because of HAART contributes to its substantial confrontation, decreasing also its prognostic importance. In case of the primary stages of skin sarcoma, HAART can lead to complete remission without any antineoplastic treatment.165 Benefits in the survival rate have been found, even in late stages of KS, combining HAART and chemotherapy.166 According to Tam et al,167 HAART decreased mortality rate by 81%. In conclusion, KS is considered to be a high-suspicion marker for an underlying immunosupression, imposing HIV infection testing. Its significance as a prognostic skin marker is important, although it has been reduced after HAART administration.

Other Skin Diseases A large range of skin and mucosal diseases has been reported in relation to HIV infection. Infections due to a variety of pathogens (folliculitis, erysipelas, fungal infections, and HPV infections), diseases characterized by increased keratinocyte proliferation, autoimmune diseases (Grover’s disease, Sjogren syndrome, and bullous diseases), neoplasms (squamous cell cancer of the anus), and other miscellaneous skin diseases (xeroderma, atopic dermatitis) are influencing clinical course and frequency of HIV infection. Despite these, such common skin diseases are not typical, highly suspicious for HIV immunosupression, and are not clearly associated with the prognosis of the disease. Such common dermatoses are of prognostic value only in association

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with the levels of the immune ability and they do not constitute independent prognostic skin markers. On the contrary, as indicative conditions of underlying immune disturbance, they can be important markers for the diagnosis of HIV infection. In the background of the modified immune response, skin manifestations can alter: Y Y Y Y Y Y

The The The The The The

degree of intensity of the symptoms extent of the rushes ordinary sites at which they appear duration of the symptoms frequency of the relapses, as well as response in ordinary treatment modalities.

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Appendix 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults (Taken from Morbidity and Mortality Weekly Report 1992;41 (No. RR-17)

CD4ⴙ T-Lymphocyte Categories Y Y Y

Category 1: greater than or equal to 500 cells/mL Category 2: 200 – 499 cells/␮L Category 3: less than 200 cells/␮L

Clinical Categories

Any modification of these characteristics is considered to be a main factor, which can lead to diagnostic approach of the immune disturbance and the diagnosis of HIV infection.

Category A

Modifications of Prognostic Importance of Clinical Manifestations

Category B

The adoption of HAART in the treatment of HIV infection has altered the course of the disease. HAART decreases the levels of the viral proliferation and permits the partial immune reconstruction, even in patients with very low CD4 lymphocytes. With HAART, the frequency of the opportunistic infections has decreased significantly. In the asymptomatic HIV infection, the most important indicator for treatment initiation is the laboratory findings, such as the number of CD4 lymphocytes and the viral load. The follow-up of the patients and the evaluation of treatment are based on these markers; however, clinical markers are still important. Because of poor prognosis manifestations, initiation of treatment in strongly recommended apart from the laboratory markers, while their appearance in patients under treatment is considered as treatment failure and is a reason for its modification. According to the guidelines, initiation of treatment is recommended at CD4 counts between 200 and 350, while the viral load may (CDC) or may not (British guidelines) be taken into account. Introduction of treatment according to the laboratory findings is controversial and is revised frequently. On the contrary, the evaluation of the clinical markers is everlasting and has not been changed in the last decade. According to these data, the importance of the clinical prognostic markers is limited only when the laboratory follow-up is easy. Furthermore, laboratory research is available mainly in developed countries, while in a significant part of the world, prognosis of the disease is based mainly on clinical criteria.

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Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection

Bacillary angiomatosis Candidosis, oropharyngeal (thrush) Candidosis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting greater than 1 month Hairy leukoplakia, oral Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess Peripheral neuropathy

Category C Y Y Y Y Y Y Y Y Y Y

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Candidosis of bronchi, trachea, or lungs Candidosis, esophageal Cervical cancer, invasive* Coccidiomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (greater than 1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (greater than 1 month’s duration); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary

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Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Isosporiasis, chronic intestinal (greater than 1 month’s duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary* or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent* Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV

*Added in the 1993 expansion of the AIDS surveillance case definition.

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