Special Interest Topics

Cutaneous Emergencies in the HIV Positive Patient

The Human Immunodeficiency Virus (HIV) is a member of the retrovirus family of enveloped RNA viruses. Retroviruses rely on an RNA-dependent DNA polymerase (reverse transcriptase) for their replication1. HIV is the causative organism in the development of acquired immune deficiency syndrome (AIDS).  Although a complete review of the pathogenesis of HIV is beyond the scope of this text, a basic comprehension of the mechanism of HIV infection is helpful in understanding its resultant clinical manifestations. Briefly, HIV initiates infection of cells bearing the CD4 receptor through the interaction of the gp120 envelope glycoprotein present on the surface of HIV particles.2,3 Binding of gp120 to CD4 on the surface of T helper (TH) lymphocytes, monocyte-derived macrophages (including tissue specific macrophages such as brain microglia), and dendritic cells (including Langerhans cells of the skin) results in a conformational change in gp120 that facilitates binding to the chemokine co-receptors CCR5 and CXCR4 and exposes the HIV gp41 envelope protein, allowing membrane fusion and viral entry into a given cell.3 Once it has entered a host cell, HIV initiates the synthesis of a double-stranded DNA molecule from its original RNA genome via reverse transcriptase activity; this may result in direct cellular lysis or altered activity of host cells, causing immune dysregulation and subsequent release of HIV virions into the bloodstream.4 Alternatively, viral DNA may be integrated into the host genome, where it can remain latent in cellular reservoirs (most commonly macrophages).  When a host cell infected with latent virus receives subsequent signals to proliferate, this concomitantly activates transcription of the original RNA virus, allowing for continued viral dissemination.4 Of note, following primary infection there is a rapid rise in HIV viral counts that typically precedes the production of HIV-specific antibodies between 1-3 months post-infection; it is these antibodies that are detected by HIV screening tests.2,5,6 As a result of their viremia, individuals newly infected with HIV are more infectious and are at increased risk of transmitting the virus to others before being identified as seropositive5,7.
The worldwide morbidity and mortality associated with the AIDS epidemic is substantial, and as such, a significant public health effort has been initiated to control both the spread of HIV and the progression of disease within infected individuals. HIV is transmitted through contact with blood, vaginal secretions or semen of an infected individual. Transmission most often occurs through sexual intercourse (including oral sex), IV drug use or via vertical mother-to-child transmission in the womb or during the perinatal period2,8. HIV can also be transmitted via blood transfusion, though improved screening measures make this mode of transmission increasingly rare.


PRIMARY HIV INFECTION

The acute manifestations of primary HIV infection are nonspecific, and a high degree of suspicion is required to establish the proper diagnosis. Since early diagnosis and treatment of HIV can help prevent serious sequelae in the source patient and further dissemination of HIV to sexual contacts, it is considered here as an emergency. Symptomatic primary HIV infection has been described as “mononucleosis-like” and most often presents with fever, fatigue and rash between 2 to 4 weeks after exposure9-11. Additionally, symptoms such as sore throat, lymphadenopathy, headache, arthralgias, myalgias, night sweats, nausea, vomiting and diarrhea are not uncommon2,9-11. Hematologic abnormalities including lymphopenia and thrombocytopenia are frequently seen on laboratory evaluation 2,5,12. Any patient who presents with this constellation of signs and symptoms therefore warrants a detailed sexual and drug use history, as well as a thorough physical exam to assist in the early diagnosis of new HIV infection.
The most common cutaneous manifestation of primary HIV infection (estimated to occur in up to 80% of new infections) is a macular or morbilliform eruption that is localized primarily on the upper trunk, but may also include the neck, face, extremities, scalp, palms and soles2,8,10,13,14. The eruption may resemble a primary roseola exanthema. The macules that compose this rash are typically non-confluent, range in size from 4-10 mm and are pink or red in color10,13. Notably, the exanthem is not painful, rarely pruritic and usually disappears within one to two weeks, occasionally inducing a fine desquamation as it resolves5,10,12,13. The histologic features of the rash are also nonspecific and mimic various viral and drug reactions; an absence of epidermal change and a sparse dermal perivascular infiltrate composed mainly of lymphocytes and histiocytes is seen.  Other skin findings that have been reported in association with primary HIV infection include a papulopustular and vesicular exanthem, urticaria, and desquamation of the palms and soles7,11,15.
In addition to its characteristic rash, the dermatologic findings common to primary HIV infection include mucocutaneous change. Specifically, anal and genital ulcers, as well as ulceration of the esophagus, buccal mucosa, palate and gingiva, have been reported in the absence of any other infectious causes10,12.  These characteristic ulcers have been described as 5-10 mm, round to oval in shape, with a white base surrounded by a red rim10. Enanthema of the soft and hard palates have also been noted.10,12,14 Lymphadenopathy is another visible early manifestation of acute HIV infection; it appears to present most prominently during resolution of the acute syndrome.2,9

Diagnosis

Early diagnosis of HIV infection is of paramount importance, as recognition of new infections helps to prevent inadvertent transmission. Traditionally, the diagnosis of HIV infection is made via a screening enzyme-linked immunosorbent assay (ELISA) followed by a confirmatory Western blot for antibodies against the p24 nucleocapsid antigen, and the gp120 and gp41 envelope proteins. For populations of patients in remote locations or who infrequently or reluctantly visit healthcare practitioners, however, a rapid antibody test may be preferred because, although it can be more user dependent (the presence or absence of a line must be interpreted and proper controls must be used), at least the answer can be given immediately without having to worry that the patient will not be able to be located.  One limitation of the traditional ELISA is that it is unable to identify a new HIV infection when the immune system has yet to mount an appreciable antibody response (the so-called “window of infectivity”).5,6 As a result, alternate tests are needed to establish a diagnosis of HIV when it is suspected in the acute phase before a screening ELISA becomes positive. Two tests are currently used to diagnosis acute HIV infection: the p24 antigen test and a quantitative HIV RNA test. Of these two, evaluation of HIV RNA appears to have greater sensitivity but also has a lower specificity and is more expensive; p24 antigen detection may therefore be a more practical test in a setting of limited resources.5,16 Whether p24 or HIV RNA assay is performed, an ELISA should be performed simultaneously to establish the chronicity of infection. These tests should all be performed in consultation with an infectious disease specialist.

Treatment

The rationale for using highly active antiretroviral therapy (HAART) for HIV is not to cure the patient, but rather to reduce the incidence of AIDS defining illnesses and their associated morbidity and mortality. This is achieved by restoring normal immune function via a reduction of viral load and a concomitant increase in CD4 T cell count. The most recent recommendations of the International AIDS Society-USA Panel include beginning HAART at a CD4 cell count of less than or equal to 500/uL; patients who wait until they have a CD4 count below 350 or become symptomatic typically have worse outcomes. Other indications to initiate HAART include a high viral load (> 100,000) or a rapid decrease in CD4 cell count (> 100 cells/uL per year), age greater than 60 or co-infection with hepatitis B or C. 17
Importantly, HAART is also recommended for symptomatic primary HIV infection to limit viremia or a rapid decline in CD4 cell count, as well as to preserve immune function and prevent further transmission. The panel also recommends considering HAART in asymptomatic patients with a primary infection irrespective of CD4 count, though deferring treatment remains an option in those patients with a CD4 cell count of > 500/uL. A large, multi-national cohort study has shown that HAART improves survival rates in all patients with HIV, arguing for initiation of HAART in all patients; however, the reduction in mortality is less for patients who have a higher CD4 count at diagnosis.17
The decision of what antiretroviral medications to begin should be based on HIV resistance patterns, adverse side effects of medication, a patient’s individual comorbidities, and the ease of dosingfrequency of dosing (if compliance is likely to be a problem). Usually 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a 3rd agent (a protease inhibitor, non-nucleoside reverse transcriptase inhibitor or an integrase inhibitor) are suggested; fixed dose or once a day regimens are preferred. The goal of therapy is to induce a viral load of less than 50 copies/mL as evaluated by polymerase chain reaction (PCR) at 24 weeks. Initiating therapy, monitoring a patient’s immune status and the decision to change a given regimen secondary to resistance, toxicity or convenience should be performed in consultation with an infectious disease specialist.17

HIV-ASSOCIATED DERMATOSES

HIV infection is associated with the development of atypical and uncommon dermatoses, as well as irregular or exuberant presentations of more common cutaneous disease. Two such conditions that may require prompt medical intervention, psoriasis and eosinophilic folliculitis, are discussed below.

Psoriasis

Psoriasis is an inflammatory dermatitis with multiple clinical manifestations, but classic psoriasis vulgaris is characterized by well circumscribed, erythematous plaques with a thick overlaying silver scale commonly located on the extensor surfaces of the arms and legs. In immunocompetent patients, the pathogenesis of psoriasis is thought to be secondary to localized inflammation secondary to unrestrained activity of Th1 and Th17 subsets of helper T lymphocytes. Interestingly, though psoriasis is thought to occur in HIV+ patients at approximately the same frequency as in the immuncompetent population (between 1-3%), its clinical features vary.18 ImportantlyNotably, psoriasis in HIV+ patients often follows an explosive course: preexisting psoriasis can flare with new HIV infection or clinical progression to AIDS, and abrupt onset of severe psoriasis often occurs with HIV-associated immune dysfunction, requiring emergent intervention. Though psoriasis vulgaris is also the most common form of psoriasis in HIV+ patients, inverse, erythrodermic, guttate, rupioid, pustular (including keratoderma blennorrhagicum) and sebopsoriatic variants are not uncommon.19,20 In particular, inverse and palmoplantar forms occur more frequently in patients who develop psoriasis after contracting HIV. ImportantlyFurthermore, multiple morphologies can often be simultaneously present on the skin of the same patient, and an extensive amount of body surface area can be involved.19,21-23 HIV+ patients with psoriasis also appear to be more prone to developing accompanying arthritis. Interestingly, spontaneous resolution of psoriasis in patients with end-stage AIDS is also recognized.24
Though HIV-associated psoriasis of varying severity can manifest at any CD4 T cell count, it often presents later in the course of disease when CD4 numbers decrease to below 100-350.21,25 This paradoxical worsening of a disease driven by T cells is thought to be secondary to a decrease in the CD4:CD8 T cell ratio late in the course ofadvanced HIV infection. Specifically, elevated CD8+ T cell counts and the absence of CD4+ T cells (including suppressor cells) may allow for unrestrained pro-inflammatory activity and the development of psoriasis even in the face of decreasing absolute T cell numbers.19 Furthermore, staphylococcal and streptococcal infections in these immunocompromised hosts may induce flares of psoriasis.20 Diagnosis of psoriasis can typically be done clinically, but histologic evaluation reveals proliferation of basal keratinocytes, acanthosis and desquamation of the stratum corneum. In HIV+ patients, there is a predominance of plasma cells, and the presence of T cells, dyskeratotic keratinocytes and leukocytoclasis is less common than in immunocompetent patients.18,19 The discovery of plasma cells on biopsy should therefore raise the suspicion of an associated HIV infection in patients with new onset or abruptly worsening psoriasis.
Therapy for psoriasis in HIV+ patients is challenging, as immunomodulating drugs—a mainstay of psoriasis therapy—may expose the patient to increased risk of opportunistic malignancy and infection. As a result, topical therapies including calcipotriene, corticosteroids, tazarotene and calcipotriol/betamethasone are considered first line for mild to moderate disease.25 Ultraviolet (UV) therapy and antiretrovirals are also thought to be safe and effective options for this subgroup of psoriatic patients. Second line treatment consists of oral retinoids such as acitretin, with .  Iimmunomodulating agents such as methotrexate, cyclosporine and biologic agents are reserved for the most severe and recalcitrant cases.25 These instances should be considered on a case-by-case basis, and close monitoring, as well as institution of antiretroviral and prophylaxis against infection, should be initiated when beginning immunosuppressant therapy.

Eosinophilic folliculitis

Eosinophilic folliculitis (EF) is an extremely pruritic, follicular-based eruption of erythematous papules that is most commonly seen in HIV+ patients with low CD4 counts.26-28 It has been reported as the primary presentation of HIV but more commonly serves to identify patients at risk for severe opportunistic infections; its . The presence of EF therefore indicates that urgent intervention is required to identify and/or treat an associated HIV infection.29 The characteristic lesions of EF are 3-5 mm papules located primarily on the upper trunk, head, neck and proximal extremities that are often excoriated or crusted as a result of associated pruritus. 27-29 Rarely, EF can present as erythematous plaques or urticaria.30 A relative peripheral eosinophilia and elevated IgE levels may also be noted on laboratory studies.28 The condition has a stark male predominance and has rarely been reported in women.27-29 Interestingly, EF is associated with CD4 cell counts less than 250/uL; however, the initiation of antiretroviral therapy (ART)HAART also appears to be a trigger of EF in these same patients.26,27 This tends to occur between 3 and 6 months after initiating HAART.27
The differential diagnosis for EF includes multiple pruritic dermatoses, such as scabies, papular urticaria, dermatitis herpetiformis and, arthropod assault, as well asand bacterial folliculitis.31 In order to establish a diagnosis, skin biopsy of a papule is often helpful, though care must be taken to section the specimen appropriately so that an involved follicle can be evaluated. Histologic examination reveals a mixed perivascular or perifollicular infiltrate of eosinophils and lymphocytes with occasional neutrophils, often with rupture of the associated sebaceous gland.26,28,30 Notably, infectious organisms are absent on both H&E and special stain examinations.  A scabies preparation is also helpful to exclude this condition in patients who are immunosuppressed although typically scabies, even in severely immunosuppressed patients, spares the face.
The pathogenesis of EF remains unknown, though it is thought to occur secondary to the skewing of the immune system toward a Th2 phenotype in the context of extreme immunosuppression and immune dysregulation. Many common environmental antigens, including skin flora and medications, have been suggested to potentiate a hypersensitivity reaction that leads to the clinical appearance of EF.
Treatment of EF is challenging, and no consensus exists on the optimal treatment for this condition. Of foremost importance is the initiation of HAART, which, though it may potentiate EF when initiated in those with low CD4 cell counts, ultimately helps resolve the condition by restoring normal immune system function.27,30,32 Among other therapeutic modalities, UVB therapy two to three times per week appears to most reliably provide improvement within 3 to 6 weeks, though weekly maintenance treatments are usually required.32 High potency topical steroids applied twice daily may also be effective, but given their side effects of skin atrophy, hypopigmentation and telangiectasias, an effective alternative topical therapy such as tacrolimus may be a better option28,33.  Systemic therapies including itraconazole (begun at 200 mg/day), metronidazole (250 mg three times per day) and isotretinoin (0.3 to 1 mg/kg/day) have also been used to treat EF, with varying degrees of success.32 Symptomatic control of pruritus can be achieved by using antihistamines such as cetirizine or doxepin, as well as through the application of topical lotions containing menthol.31,32


INFECTIOUS COMPLICATIONS OF HIV INFECTION

Given the global immunosuppression associated with HIV infection and the depletion of CD4+ T helper cells, patients who are HIV+ are at an increased risk of both common and opportunistic infections.  The most common and life-threatening infections are discussed below.

TUBERCULOSIS AND OTHER MYCOBACTERIAL INFECTIONS

Co-infection with HIV and Mycobacterium tuberculosis is a significant public health issue, as these two organisms have synergistically detrimental effects on individuals afflicted with both. Namely, weakening of the immune system by HIV allows latent M. tuberculosis infection to become active. In turn, tuberculosis (TB), which has become increasingly resistant to a greater number of pharmacologic therapies, is a leading infectious cause of death worldwide in HIV+ individuals.34-36 HIV infection often prevents timely diagnosis of TB because of the atypical presentation of active TB in the immunosuppressed; HIV also promotes immune anergy and makes tests such as the tuberculin skin test less sensitive for diagnosis. 34,35
Although cutaneous TB is rare, it appears to be more common in patients co-infected with HIV and therefore deserves special mention.37 While scrofuloderma (suppurative, subcutaneous nodules of TB originating from an underlying nidus of infection such as a lymph node) can be seen in the context of immunosuppression, the more common appearance of cutaneous TB in patients with HIV/AIDS, particularly with CD4 cell counts

< 100/uL, is the disseminated miliary form, a.k.a. tuberculosis cutis miliaris acuta generalisata.36,37 Cutaneous miliary TB typically appears as macules, papules and crusted ulcers, but papulovesicles, pustules, purpura and subcutaneous nodules are also possible manifestations.36-39 The distribution of these multiple lesions most often includes the buttocks, trunk, thighs and extensor extremities. Other clinical signs of TB include fever, weight loss and productive cough.
Diagnosis of cutaneous TB can be made via scraping of a lesion and visualizing acid-fast bacilli (AFB) under microscopy after Ziehl-Neelsen staining. Biopsy may be necessary, and reveals a superficial dermal infiltrate of neutrophils, histiocytes and/or lymphocytes, though granuloma formation is uncommon given patients’ weakened immune response. Special stains are often necessary to visualize AFB. Most importantly, physicians must simply be alert to the possible diagnosis of disseminated cutaneous TB in any HIV+ individual who presents with multiple non-specific skin lesions.37
Treatment of tuberculosis includes quadruple therapy with isoniazid, rifampicin, pyrazinamide and ethambutol, though sensitivities should be performed given increasing TB drug resistance; alternative medications may be required. HAART is also indicated in these patients, but there is considerable interaction between anti-tuberculosis and antiretroviral medications; therefore treatment should be undertaken with an infectious disease specialist.35,38
Infection with other non-tuberculosis mycobacteria can also produce cutaneous findings. M. kansasii, M. haemophilum, and M. avium/M. intracellulare (the MAI complex) rarely cause cutaneous disease but are more likely to do so in immunocompromised hosts, including those with HIV. The clinical manifestations of these assorted mycobacteria are variable, and include firm red nodules, erythematous papules, pustules, ulcers, abscesses, sinus tracts, verrucous lesions and firm annular plaques.40,41 It is therefore important for physicians to consider these atypical infections as a potential cause of persistent, non-specific skin lesions in patients with HIV. Importantly, in the context of an unclear clinical diagnosis, biopsy sections should be cultured broadly and evaluated with special AFB stains so as not to miss the diagnosis of a mycobacterial infection.42 As with tuberculosis, therapy and management should be performed in consultation with an infectious disease specialist, and evidence of a disseminated infection should be sought and managed as necessary.

FUNGAL INFECTIONS
Candidiasis
Candida species, in particular Candida albicans, are the most frequent cause of fungal disease in patients with HIV.43 Typically, candidal disease presents as infection of the oropharynx, esophagus or anogenital region, though intertriginous involvement of the skin is not uncommon.43,44 Disseminated infections are rare in HIV-associated candida, however, in part due to a relatively more functional humoral immune system.43 Candida infections present at moderate-to-advanced stages of HIV infection (with CD4 cell counts

< 200-300/uL), and often signify progressive disease and poor clinical outcomes.17,43,45
There are four main manifestations of oropharyngeal candidiasis: pseudomembranous, erythematous/atrophic and hyperplastic forms, as well as angular cheilitis.43 Pseudomembranous oral candidiasis (OC) presents as creamy white plaques present on multiple oropharyngeal surfaces, including the tongue, palate and buccal mucosa; these lesions can be easily scraped away. Erythematous and atrophic lesions are common in older patients with HIV and present as red ulcers and erosions; they can often be found under oral accessories such as dentures.45 The hyperplastic form and angular cheilitis are far less common and appear as thick yellow plaques or erythema and painful fissuring at the angles of the mouth, respectively. Patients with active oral candida infections may note altered taste, and complaints of pain on swallowing should alert the physician to potential esophageal involvement, as well. 45Vulvovaginitis, enteritis and gastritis are also possible mucocutaneous manifestations of candida infection.43 Cutaneous candidiasis is marked by pink-red, thin plaques and patches with surrounding satellite pustules, found most commonly in skin folds, including the groin, inframammary and axillary regions.43
The diagnosis of candidiasis is often a clinical one, though KOH preparations demonstrating budding yeast and pseudohyphae, fungal culture and biochemical tests can aid in diagnosis when uncertainty exists.43,45 In adults, treatment of oral candidiasis can be achieved by administering oral fluconazole at a dose of 100-200 mg/day until the patient has remained asymptomatic for 1-2 weeks; alternatively, a single dose of 750 mg can be given. Clotrimazole troches and nystatin solution are other topical alternatives for treatment of oral candidiasis, while itraconazole, voriconazole or posaconazole can be used as alternatives to fluconazole in unusually refractory cases or for esophageal involvement when systemic therapy is indicated.43-45 Cutaneous candidiasis is typically responsive to Nystatin or topical azoles including ketoconazole or clotrimazole 43

Cryptococcus and Other Invasive Fungal Infections

Infection with the encapsulated yeast Cryptococcus Nneoformans is a common occurrence in patients with AIDS, occurring in between 6-13% of patients, typically with CD4 cell counts below 200/uL.4,46 Cryptococcal infection occurs following inhalation of the organism, which is found in soil or grass contaminated with pigeon droppings; from this primary pulmonary focus, the organism can disseminate hematogenously.46,47 Most often this dissemination manifests as meningitis associated with central nervous system involvement, but cutaneous involvement occurs in approximately 6-20% of patients with disseminated disease, as well.4,46 Notably, pPrimary cutaneous disease secondary to external inoculation is overwhelmingly rare.46
The primary lesions of cutaneous cryptococcal disease are protean in appearance, but most often present as umbilicated papules and nodules, often with a central hemorrhagic crust.4,48 Other potential morphologies include violaceous and crusted papules, plaques and nodules, scaly plaques and less commonly ulcers or draining sinuses.4,46 These lesions occur primarily on the face and neck, though involvement of the extremities and trunk also occur at a reduced frequency.4 The differential diagnosis of these lesions includes molluscum contagiosum, Kaposi’s sarcoma, basal cell cancercarcinoma and nummular eczema.4,46 However, iIdentification of an antecedent flu-like illness or symptoms indicating multi-organ system involvement, such as neurologic changes or pulmonary symptoms, may assist the astute dermatologist in making the correct diagnosis of cryptococcal infection.
Diagnosis can easily be established on biopsy with routine histology. Two primary histopathologic appearances manifest in the case of cryptococcal infection,: granulomatous or gelatinous, though individual biopsy specimens can also exhibit an overlap of these two patterns. In the granulomatous form, multiple histiocytes can be seen phagocytizing budding yeast that are surrounded by clear halos; t.  The gelatinous form exhibits fungal organisms surrounded by a pool of mucin. These organisms can be found in a variety of distributions, from subepidermal foci to involvement of the entire dermis.4 PAS stains may aid in identification of encapsulated yeast organisms. In instances where the diagnosis remains in question even afterdespite biopsy, other methods of identification can be used including culture on Sabouraud dextrose agar or identification of cryptococcal capsular polysaccharide antigen in serum.46,48 Microscopic or serologic examination of cerebrospinal fluid may also help in establishing the diagnosis in patients with concomitant meningitis or neurologic symptoms.48
Treatment of disseminated cryptococcal infection in immunocompromised patients includes intravenous amphotericin B; adjunct therapy with fluconazole or flucytosine is often administered. Lifelong prophylactic therapy is subsequently indicated, most often with daily oral fluconazole.

Although less common, infection with other invasive fungi such as Histoplasma capsulatum (histoplasmosis), Blastomyces dermatitidis (blastomycosis) and Coccidioidomyces immitis (coccidiomycosis) must also be considered in HIV+ patients with cutaneous manifestations, especially those who live in or have recently traveled to endemic areas.
Histoplasmosis is found primarily in the Ohio and Mississippi River valleys, Bblastomycosis in the Midwest and southeastern United States, and coccidiomycosis is most common in the southwestern United States.49 For all of these diseases, infection occurs primarily after inhalation and entry through the lungs; cutaneous manifestation therefore represents disseminated disease in the majority of patients, as primary cutaneous disease secondary to inoculation is rare.47,49
Like Cryptococcus, cutaneous histoplasmosis often presents on the face, and has a protean appearance.  Red macules, necrotic papules, nodules and pustules, eruptions reminiscent of acne and rosacea and even ulcers have all been reported in association with histoplasmosis.50 Oral manifestations are also common, presenting most often as painful ulcerations or granulomatous lesions. 51 Blastomycosis can also present in a variety of forms, including papules, pustules, ulcers and granulomatous masses.52,53 Similarly, cutaneous coccidiomycosis manifests typically on the face as papules, pustules or nodules. If given time to expand and coalesce, these lesions can eventually transform into abscesses, ulcers and verrucous or scarred plaques.50 Given the non-specific nature of these cutaneous findings and the considerable overlap in presentation between the various fungal organisms, these species must always be considered in HIV+ patients who present with any of the aforementioned cutaneous findings. Biopsy and serologic testing are indicated to quickly establish the appropriate diagnosis.49 Treatment of all of these organisms begins with amphotericin B, with azole therapy (typically with itraconazole or fluconazole) initiated after clinical stabilization. Patients subsequently require lifelong prophylaxis to prevent recurrence.47,49

Cutaneous bacterial infections that can be emergencies:

Staphylococcus Aureus
Methicillin R-resistant Staphylococcus Aaureus (MRSA) is a rapidly emerging pathogen that has a higher prevalence of both colonization and skin and soft tissue infection in people infected with HIV.  MRSA colonization is more highly associated with HIV infected patients who have low CD4 counts, are intravenous drug users and in men who have sex with men (54-57).  Staphylococcus Aaureus presents in the skin most frequently with folliculitis or furunculosis and can lead to more severe systemic infection.  Although folliculitis and furunculosis are rarely emergencies, given the risk of bacteremia and internal abscesses, it is important to identify and treat cutaneous MRSA infections in HIV patients.  Antibacterial washes such as 4% chlorhexaidine can be used to decolonize the skin and treat mild folliculitis. When indicated, antibiotic therapy for cutaneous bacterial infections should be guided by cultures to assure the proper antibiotic choice.  Furuncles and abscesses should be drained when possible.  Antibiotic choices should be based on regional differences in susceptibilities.  Since MRSA presents commonly with furunculosis, proper MRSA coverage (typically trimethroprim-sulfamethoxazole, a tetracycline or clindamycin) should be started empirically while waiting for cultures if antibiotics are to be used. Dosing guidelines for skin and soft tissue infections should be followed but, and patients should be followmonitored closely for clinical resolution as they may need more extended duration due to immunodeficiency. 

Bacillary Angiomatosis
Bacillary Aangiomatosis (BA) is a bacterial infection caused by Bartonella henselae or Bartonella quintana.  BA is nearly exclusively a manifestation of immunosuppression.58 BA presents with papules and nodules that grow slowly in the skin and often ulcerate.  The skin lesions often look distinctly vascular and can be mistaken for multiple pyogenic granulomas or Kaposi sarcoma. A high index of suspicion is vital, especially if an ulceration is cultured with conventional swab and does not yield a typical staphylococcal infection.  Since BA can be an emergency with fever, fatigue and disseminated lesions involving the liver, spleen, bone and CNS, it is important to be able to recognize BA in the skin. BA is typically seen in patients with CD4 count below 100 cells/microliter. 58 Therefore a diagnosis of BA should prompt a thorough workup for other diseases of extreme immunodeficiency such as PCP pneumoniaPneumocystis carinii pneumonia.  Diagnosis of BA can be made with histology showing a vascular proliferation with protuberant cuboidal cells and staining of the organisms positive with Warthrin-sStarry or Silver stains. Polymerase Chain Reaction (PCR) and immunoglobulin M detection can also be done where available.59 Therapy is typically with erythromycin (500 mg every 6 hours typically for 2 months).  T, tetracyclines are often used as a second line agent again for 2 monthsor trimethoprim-sulfamethoxazole.60  

Syphylis
Syphylis is a bacterial infection caused by Treponema Ppallidum, which is most often sexually transmitted. The initial cutaneous manifestation of syphilis is the primary chancre that is commonly found in the perineum.  In immunosuppressed HIV patients, the primary chancre may be deeper and longer lasting and there may be multiple chancres.61   In addition, syphilis may predispose to easier transmission of HIV due to the chronic open wound with HIV shedding from the wound.62,63
Secondary syphilis is usually characterized by scaling papules and plaques on the trunk and , palms and soles but can include scattered ulcerations and condyloma lata.  Later findings inof cutaneous syphilis include large ulcerations (gummas).  The risk of transition to neurosyphylis may be higher in patients with HIV, and therefore promptly recognizing and treating syphilis in HIV patients is vital.64 Non-treponemal tests such as Rrapid Pplasma Rregaagin (RPR) and Vvenereal Ddisease Rreference Llaboratory (VDRL) can be falsely positive or negative in patients with HIV but are still the preferred first line tests.  Biopsies of skin lesions with special stains as well as dark field examination and specific treponemal tests can help confirm diagnosis.65

Cancrum Oris (Noma)
Noma is a gangrenous infection of the oral cavity that typically effects young children.  The infection typically starts with an ulceration on the gingiva which spreads to involve the mucous and cutaneous lips.  Noma is thought to be caused by a combination poor nutrition and immunosuppression such as HIV.  It is often polymicrobial and very challenging to treat.  Noma can lead to significant morbidity and mortality due to inability to eat and drink. Therapy is based on augmenting nutritional status and targeted therapy toward HIV as well as treating the infection based on cultures with antibiotics.  Reconstructive surgery is also very important once the infection has been treated.66

Viral infections
Cutaneous viral infections are common and can manifest as typical self-limited infections in patients with HIV especially if they have a normal CD4 count.  This section will review the atypical manifestations in patients with HIV and lowered immunity.  Viral infections in immunosuppressed patients often present as more severe, disseminated or chronic infections than in immunocompetent patients. 

Herpetic Infections
Herpes Ssimplex virus (HSV) typically affects mucous membranes including the mouth, eyes, perianal areas, perineum and penis. This is because these areas are most likely to have micro-abrasions that can serve as portals of entry for the virus.  HSV typically presents clinically with grouped vesicles that then progress to grouped crusts and erosions as the vesicles rupture. In HIV patients with lowered immunity, the lesions will often be long standing or never fully resolve without therapy.67 The resultant lesion is a non-healing ulcer, often in a typical location for HSV (perianal, perioral).  These lesions can also become vegetative and exophytic and requirerequiring a high index of suspicion to diagnose.
HSV can present in an emergent fashion when cutaneous lesions disseminate hematogenously.  Disseminated HSV can lead to widespread cutaneous erosions that can lead to secondary bacterial infection and sepsis.  HSV can also disseminate widely (especially to the central nervous system or liver) leading to significant morbidity and possible mortality in severely immunosuppressed patients.68 Diagnosis is typically with viral culture or more rapid tests such as PCR and direct fluorescent antibody. Therapy is based on how widespread the disease isthe extent of involvement. 

Varicella Zzoster virus (VZV) can be the first manifestation of new HIV infection.  VZV is typically a self-limited widespread infection withcharaceterized by vesicles on a macule of n erythematous base (“dew drops on a rose pedtal”) especially in non-immunized people.  In immunized patients who have been immunized or hadthose with prior infection, their immunity typically prevents them from getting widespread or exuberant VZV is rare.  Instead, these patients mayso they present with viral reactivation in one or two contiguous dermatomes.  In HIV patients with lowered immunity, VZV may start as a typical reactivation within a dermatome (shingles).  DHowever, due to the lowered immunity, the cutaneous manifestations can be exuberant, last longer then the typical 1-2 weeks or widely disseminate.  Disseminated VZV is defined by having many lesions outside of the original dermatome or multiple non-contiguous dermatomes due to hematogenous spread.  Disseminated VZV can lead to significant morbidity and mortality especially with involvement of the CNS, liver or lungs.69 Therefore disseminated VZV in a previously vaccinated or infected individual should prompt a workup for immunosuppression including HIV testing. 

Cytomegalovirus (CMV) is another type of herpes virus   that is typically self limited in a normal host. In immunosuppressed HIV positive patients, CMV can present as chronic ulcers (often oral or perianal) that are rarely emergent.  Rarely digital necrosis has been reported in HIV positive patients associated with CMV infection but the role of the CMV is not fully understood.70 CMV is usually treated with gancyclovir but should be guided by an experienced infectious disease specialist.

Molluscum contagiosum
Molluscum contagiosum is caused by a DNA pox virus and most typically manifests as small flesh colored papules with a central umbilication.  Although molluscum is not a life -threatening infection, the virus can over grow extensively in HIV patients.  This overgrowth can lead to nodular lesions which can obstruct vision, become purulent and disfiguring.71 Exuberant molluscum inflammation can also be a manifestation of immune reconstitution inflammatory syndrome (IRIS,  (discussed later in this chapter).

Viral infections can also be a precursor lesion to carcinomatous change.  Chronic infection with human papillomavirus (HPV) infection that is recalcitrant to therapy and exuberant should raise suspicion for transition to verrucous carcinoma.  Biopsy should be performed in immunosuppressed patients with especially recalcitrant warts especially around the perineum.

Drug Reactions
Many medications used for the treatment of HIV and for AIDS-associated opportunistic infections are associated with cutaneous toxicities and can cause serious reactions, many of which are emergencies.  Although the majority of cutaneous drug reactions are morbilliform, urticarial or nonspecific reactions, clinicians need to be aware of the concerning features associated with more serious drug reactions. Patients with HIV have allergic reactions at a higher rate than the general population.  Allergic reactions in HIV patients are likely to be multi-factorial, and severe drug reactions need to be caught early to minimize morbidity and mortality.72,73 This is potentially difficult because of the multiple medications or combination regimens that are used to treat these patients making it difficult to identify the culprit medication. 
The serious drug reactions that can occur include Stevens-Johnson Ssyndrome (SJS), toxic epidermal necrolysis (TEN), drug hypersensitivity syndrome (DHS) or drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). There are a few clinical signs and symptoms which can alert the clinician that one of these serious drug reaction might be occurring:  high fever, skin pain, mucous membrane involvement, facial swelling, and internal organ involvement suggested by laboratory abnormalities.  Table 5.2 provides a list of common medications used in the setting of HIV that may cause a serious drug reaction, including anti-retrovirals and antibiotic regimens.

Drug Hypersensitivity Syndrome
Drug hypersensitivity syndrome (DHS) has also been named “Drug Reaction with Eosinophila and Systemic Symptoms” (DRESS).  DHS is characterized by the triad of fever, skin eruption, and internal organ involvement in the setting of exposure to a medication.74 Patients will typically have a high fever (38-40C), malaise, facial edema and lymphadenopathy.  If suspected, laboratory testing should be performed to evaluate for internal organ involvement and should include a complete blood count (CBC) with differential looking for atypical lymphocytosis and eosinophilia, evaluation of liver abnormalities with special attention to transaminases, alkaline phosphatase, prothrombin time, and bilirubibuin, evaluation of kidney function with urinalysis and BUN and creatinine, and fecal occult blood test to look for inflammatory colitis if gastrointestinal symptoms are present. Liver abnormalities are present in about 50% of patients, and severe hepatitis and liver failure can occur.75 Skin biopsy results in these situations are generally non-specific but may provide allow the clinician to evaluate for underlying vasculitis, if suspected.  In addition, because autoimmune thyroiditis occurring within 2two months of the onset of symptoms can causemay result in hypothyroidism;, so , thyroid function tests should be checked in that period of timeperformed.75
In the setting of HIV, abacavir hypersensitivity is a well-described, serious, and potentially fatal drug hypersensitivity reaction that can occur in both children and adults and affected approximately 5 to 8% of people.76,77 It typically starts within the first eight weeks of therapy and is characterized by two of the following:  morbilliform rash, lymphadenopathy, fever, malaise, myalgias, gastrointestinal symptoms, and respiratory symptoms.  Upon re-challenge, patients may experience hypotension and similar but worsened symptoms within hours which can result in death; because of this severity, hypersensitivity to abacavir is considered an absolute contraindication to future use.78 Testing for HLA-B*5701 is recommended as positivity suggests a strong genetic predisposition for this hypersensitivity reaction.79 Treatment of this syndrome includes prompt discontinuation of the medication.  The use of systemic steroids also is recommended, at a dose of 1-2 mg/kg/day if symptoms are severe and should be used until laboratory abnormalities resolve.  First degree relatives also should also be counseled to avoid these medications because of the increased risk to them.  There are many other medications implicated in DHS including medications commonly used in HIV such as trimethoprim-sulfamethoxazole, dapsone and nevirapine.80

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Stevens-Johnson Ssyndrome (SJS) and toxic epidermal necrolysis (TEN) are other forms of severe hypersensitivity reactions that occur in the setting of HIV and are characterized by widespread blistering and sloughing of the skin and mucous membranes with mortality rates ranging from 5 to 30% (typically depending on amount of body surface area involved and time to treatment). 81 These drug reactions are discussed in detail in other chapters.often considered on the same spectrum, with the distinction between the two being the percentage involvement of total body surface area:  SJS involves

<10% of the total body surface area, TEN involves >

30% of the total body surface area, and an overlap is between 10-30%.82 With SJS and TEN, there is often a prodrome of fever, cough, and malaise followed by the skin manifestations.  The gastrointestinal tract and respiratory system can be involved in up to 30% of cases.  If SJS or TEN is suspected, a complete history and physical examination with careful inspection of mucosal surfaces including the eyes, mouth, genitalia, and anus is mandatory.  In addition, laboratory evaluation including liver function tests, urinalysis, basic metabolic panel to evaluate for electrolyte abnormalities and kidney dysfunction, complete blood count, and a chest x-ray are essential tests to be ordered.  A skin biopsy can be helpful because histopathologic evaluation would reveal full thickness epidermal necrosis with orthokeratotic stratum corneum, supporting the diagnosis.73,82-84

Many HIV medications have increased risk of inducing SJS/TEN. Nevirapine is a non-nucelleoside reverse transcriptase inhibitor for which severe life-threatening cutaneous rashes have been reported at a rate of 0.5 to 1%.85,86 Severe hepatotoxicity has been describedassociated with the severe drug reactions and should be monitored for regularly.  A review of the literature identified several anti-retrovirals as potential culprit medications, which are included in Table 5.1.87
In addition to the anti-retroviral medications, serious drug reactions can occur with the use of sulfonamides as antibiotic therapy or for Pneumocystic jiroveci prophylaxis.  The incidence of TEN due to trimethoprim-sulfamethoxazole was about 4-fold compared to the general population and was 8.4 cases per 100,000 exposures.88 Similarly, tuberculosis drugs can play a role in serious drug reactions as concomitant infection is not rare in this population.89
SJS and TEN are most often caused by medications in HIV positive patients, but severe forms of erythema multiforme and SJS have been described in association with infections including herpes simplex virus and Mycoplasma pneumoniae, especially in pediatric populations; these and should also be considered if an inciting medication is not apparent.90-96 Mycoplasma PCR and evaluation of HSV via PCR, direct-fluorescence antibody, or viral culture can be performed if the timing of the drug reaction (patient has been on a medication for several years) or clinical scenario of mucosal predominant involvement, preceding cough and shortness of breath or other information suggests an alternate diagnosis.90,91,97
Treatment of SJS/TEN is discussed in detail in other chapters.includes immediate cessation of the suspected medication, supportive care including careful wound care, hydration and nutritional support. Evaluation by ophthalmologic services for eye involvement also is critical as long-term complications can result, and potential urological or gynecological support if genital mucosa is involved.98 Transfer to burn centers may be necessary for management of the full thickness skin desquamation that can occur.  Extremely close monitoring for secondary infection given the disruption in the skin barrier is important.  The use of corticosteroids in the setting of SJS and TEN is controversial because it can lead to an increase risk of secondary infections, sepsis, and gastrointestinal bleeding especially in TEN.98 Some clinical centers use intravenous immunoglobulin in the setting of SJS and TEN as there has been evidence of a benefit in mortality when used at doses of 2-3 grams per killogram divided over 2-4 days.82,99 Evaluation for underlying IgA deficiency and kidney function need to be evaluated prior to giving this medication because any IgA in the formulation could lead to anaphylaxis in deficient patients.  Patients who have had this reaction should not be re-challenged to the culprit medication, and first degree relatives also should be counseled to avoid these medications due to increased risk.  Similar to DHS, certain medications have a higher risk of SJS in patients with certain HLA subtypes.

Acute Generalized Exanthematous Pustulosis
Acute generalized exanthematous pustulosis (AGEP) is a rare severe drug reaction characterized by a fever above 38C and a cutaneous reaction with non-follicular sterile pustules on an edematous and erythematous base.  The onset of the reaction after drug administration can vary from 2 day to 3 weeks, depending on prior sensitization.  The onset is typically extremely abrupt, starting on the face and extending to the trunk then to the lower limbs.  In addition, patients may have petechial purpura.100 Laboratory studies should be performed and will reflect neutrophilia.  Liver and kidney functions should also be evaluated due to possible involvement in these organs.  In the setting of HIV infection, tThe anti-retrovirals reported to cause this in a HIV positive patient were two differentcondition are the protease inhibitors, ritonavir-boosted darunavir and atazanavir.  , and pProtease inhibitors have also been reported to be culprit medications when used forin post-exposure prophylaxis.101-103 As Ooverlap between AGEP and SJS/TEN or DRESS also has been reported so, clinicians should have a high index of suspicion when the constellation of symptoms with high fever and internal organ involvement is present especially when a higher risk medication is used.104
It also is important to note that a subgroup of patients with very low CD4+ counts (less than 50) also may exhibit drug reactions to every drug they are provided, which can pose a significant problem because these patients are on multiple new medications.105 To help prevent these reactions, some of which are dangerous as outlined above, and enable the use of medications, a slow prednisone taper over 12 weeks while individual medications are added individually can help.106
In summary, it is important for clinicians to have a high index of suspicion when HIV positive patients present with cutaneous drug eruptions and .  Cclues to a potentially serious underlying drug reaction include high fever, skin pain, facial swelling and lymphadenopathy, and mucous membrane involvement.  General laboratory tests should be obtained to evaluate for underlying internal organ involvement.  If a serious drug reaction is suspected, immediate cessation of the culprit medication is essential.


Malignancies
Malignancies are an increasingly recognized complication of HIV infection in all settings.  There were five traditional AIDS defining cancers including Kaposi sarcoma, cervical cancer, and three types of non-Hodgkin’s lymphoma related to infection with the Ebstein-Barr virus, including primary central nervous system lymphoma, immunoblastic lymphoma, and Burkitt lymphoma.107-109 These are common and seen often, although some controversy about cervical cancer being AIDS-defining exists because it also can be commonly seen in HIV-negative individuals.  Interestingly, all five of these tumors are associated with chronic oncogenic viral infection.  There also are a wide variety of cancers that have been found to be more common in the setting of HIV, which have been termed non-AIDS-defining cancers including Hodgkin’s lymphoma, lung cancer, and hepatocellular carcinoma can occur.109 Many of these malignancies are chronic and overall indolent, but some of them present as emergencies and may havewith cutaneous features as their presenting signs.
HIV-associated Kaposi sarcoma (KS) is caused by human herpesvirus 8 and is primarily a disease of men who have sex with men.  It classically presents as asymptomatic red-purple to brown papules, plaques, or tumors involving the head, neck, palate, chest, and extremities.110 In children, often prominent lymphadenopathy often is the presenting sign, and tissue pathology is essential to establish diagnosis and rule out infection or lymphoma.111 Skin biopsy may be necessary to differentiate KS from other vascular proliferations such as bacillary angiomatosis or lymphoma/leukemia cutis, and typically can presentreveals a spindle cell proliferation with slit-like vascular spaces, increased red blood cell extravasation, and i.  Immunohistochemical stains with HHV8 will confirm the diagnosis.  When it presents iIn advanced stages, there can be accompanying there may be associated lymphedema, as well as aerodigestive tract, pulmonary, or gastrointestinal involvement. In the advanced stage, this i Internal involvement can be a poor prognostic factor and be indicative of rapid decompensation.112,113 The cornerstone of treatment and avoidance of this emergency is early detection and antiretroviral therapy.110,114,115 In some advanced or emergent cases, collaboration with oncology and administration of doxorubicin/danorubicin chemotherapy may be important.
Cervical and anal cancer related to underlying human papilloma viral infection also is an AIDS-defining malignancy.  Invasive cervical cancer was included as an AIDS-defining illness in 1993, and there is now good evidence that precursor lesions also are increased in women with HIV.108,109,116-118 Although these changes can be slow-growing and chronic in nature, the extent of disease can become emergent as it interferes with underlying bowel and bladder dysfunction or metastasis.  In most clinical situations, treatment of these diseases is the same as in immunocompetent women, although HIV positive women and men often present with more advanced disease at presentation.  Digital squamous cell carcinoma, also related to underlying HPV infection, can lead to amputation, which has significant morbidity.119 Metastatic disease also can ultimately lead to death.

Immune Reconstitution Inflammatory Syndrome
Immune reconstitution inflammatory syndrome (IRIS) is a condition that is characterized by the paradoxical clinical deterioration that has been noted to occur in patients with HIV days to months after starting HAART and is due to the restoration of pathogen-specific immune responses.120,121 Opportunistic pathogens may grow unchecked in immunosuppressed patients.  When the immune system recovers there may be an exuberant inflammatory response to these previously silent infections.122,123 Approximately 10-25% of individuals who start HAART experience this syndrome, and the skin is the most common organ system involved with 52-78% of the manifestations involving the skin.122 The presenting symptoms and dermatologic manifestations can be variable and include entities such as seborrheic dermatitis, psoriasis, acne vulgaris, folliculitis, molluscum contagiosum, and tinea versicolor or tinea capitis.  More serious presentations can occur when there is a significant opportunistic infection, or co-infection, and the inflammatory response can be detrimental.  It can sometimes be difficult to differentiate Frequently, differentiating this reaction from a medication reaction can be difficult.  The opportunistic diseases most commonly associated with IRIS include mycobacterial diseases, including tuberculosis, Mycobacterium avium complex disease, leprosy and a wide range of other nontuberculous mycobacterial diseases; deep fungal infections, especially cryptococcal meningitis; herpes viruses, including cytomegalovirus (CMV) retinitis, herpes zoster and herpes simplex; Kaposi Sarcoma (KS) and progressive multifocal leukoencephalopathy (PML).41,71,124-134 The diverse clinical manifestations and clinical sequelae of IRIS have been well documented.  Early identification of HIV and institution of HAART may help prevent both IRIS the unmasking and worsening orf pre-existing opportunistic infections by IRIS.  For less dangerous dermatologic manifestations, general treatment guidelines as previously outlined in this chapter can be used.

Summary
In conclusion, there are many cutaneous manifestations of HIV and AIDS.  Clinicians should be able to recognize and thus treat HIV early to prevent both serious illnesses and the spreadtransmission to other hosts..  The cutaneous manifestations of HIV are often the most clinically evident since they can be seen easily.  This chapter has reviewed the appearance of the initial eruption, dermatoses, infections, malignancies and inflammatory reactions which should alert the clinician to recognize undiagnosed HIV and also helpas well as provide appropriate management in patients with known infection.


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