HIV-infected persons commonly have cutaneous abnormalities; the prevalence approaches 100%.(1-3) Some of the conditions are unique and virtually pathognomonic for HIV disease, for example, Kaposi's sarcoma (KS). Patients with HIV disease often have several simultaneous or sequential cutaneous conditions with a progressively more intransigent clinical course, a key to suspecting underlying HIV infection.
In general, noninfectious cutaneous abnormalities are not prognostic of rapid progression of immunosuppression, but they may be specific markers of the stage of HIV disease. For instance, eosinophilic folliculitis virtually always occurs in persons with helper T cell counts below 200. Cutaneous abnormalities may worsen as HIV disease progresses (e.g., seborrheic dermatitis, xerosis), or they may appear anew as a fulminant process.
This chapter addresses cutaneous abnormalities in the following four groups: infectious, inflammatory, neoplastic, and hyperpigmented conditions.
| Infectious Cutaneous Conditions|
| Dermatologic Manifestations of Staphylococcus Aureus|
Staphylococcus aureus is the most common cutaneous bacterial infection in persons with HIV disease. Approximately 50% of HIV-infected persons are nasal carriers of S. aureus, explaining in part the high rate of infection.(4,5) Infection with S. aureus may occur before any other signs or symptoms of HIV infection. Morphologic patterns that may occur include: bullous impetigo, ecthyma, folliculitis, hidradenitis-like plaques, abscesses, cellulitis, and pyomyositis.(6)
| Bullous Impetigo|
Bullous impetigo is most common in hot, humid weather, presenting as very superficial blisters or erosions, most commonly seen in the groin or axilla. Because the blisters are flaccid, they are short-lived; often only erosions or yellow crusts are present. These lesions closely mimic cutaneous candidiasis.(7)
Ecthyma is an eroded or superficially ulcerated lesion with an adherent crust. Under this crust is often a plane of purulent material teeming with staphylococci. Removal of this crust is necessary to treat the lesion topically.
Folliculitis due to S. aureus occurs most commonly in the hairy areas of the trunk, groin, axilla, or face, especially in men who shave. Follicular pustules are the primary lesion. Gram's stain and culture confirm the diagnosis and allow selection of appropriate antibiotic therapy, such as dicloxacillin (500 mg 4 times daily). Often the follicular lesions of the trunk are intensely pruritic and may be mistaken for other pruritic dermatoses, such as scabies.(7) About 50% of HIV-infected persons with scabies have coexistent S. aureus folliculitis. Occasionally, follicular lesions extend more deeply, forming abscesses. Rarely, all follicles across several square centimeters are infected, forming a large, violaceous, hidradenitis-like plaque. The plaque may be studded with pustules and have deep tracts connecting infected follicles. These plaques may mimic KS, but overlying pustules are quite unusual in KS (Figure
1). Rarely, abscess of the muscle (pyomyositis) may occur.(6-10)
| Treatment of Cutaneous Staphylococcal Lesions|
The depth of the infection determines the treatment of cutaneous staphylococcal infections. Very superficial lesions, like bullous impetigo, often respond to a 7- to 10-day regimen of an appropriate antistaphylococcal antibiotic, such as dicloxacillin (500 mg given orally 4 times daily). Deeper lesions often require courses of treatment lasting for months. In addition, combinations of antibiotics, especially a penicillinase-resistant penicillin or first-generation cephalosporin plus rifampin (600 mg once daily), are often necessary to clear the infection.
Adjunctive topical therapy is helpful in beginning treatment and reducing recurrences. Washing the infected area once daily or every other day with an antibacterial agent (Hibiclens, Betadine, or benzoyl peroxide wash) helps remove crusts, dries lesions, and decreases surface bacterial concentration. Topical antibiotics (clindamycin 1% or erythromycin 2% solutions) applied twice daily may be used in chronically infected areas.(11)
Loculated abscesses must be incised and drained when fluctuant if antibiotics are to be effective. When cellulitis of any significance or symptoms of bacteremia are present, hospital admission for treatment with intravenous antibiotics is appropriate. Intranasal mupirocin may reduce carriage rate and prevent relapses. Chronic oral antibiotics may be required in some patients.(5)
| Infections Due to Bartonella: Bacillary Angiomatosis|
Bacillary angiomatosis, a treatable opportunistic infection, was initially reported as atypical subcutaneous infection in patients with advanced HIV disease(12) and as epithelioid angiomatosis.(13) The agents causing this infection, initially designated as Rochalimaea, have been reclassified as Bartonella. The term bacillary angiomatosis is being replaced by Bartonella infection because the infectious agents causing this condition have been identified as two species of Bartonella - B. henselae and B. quintana.(1,2,14) These bacteria, closely related to rickettsiae, are extremely difficult to culture. As proposed initially by Le Boit, Koehler, and others at the University of California, San Francisco, one of the agents causing bacillary angiomatosis, B. henselae, is associated with most cases of cat scratch disease. One epidemiologic study has demonstrated cat exposure and cat scratches as risk factors for acquiring bacillary angiomatosis.(15)
Bacillary angiomatosis initially was considered primarily a disorder of the skin, but systemic involvement is common. Visceral disease may include osseous lesions,(16) hepatic and splenic involvement,(17) lymph node disease, pulmonary lesions,(3) brain lesions,(18) and widespread fatal systemic involvement.
| Clinical Features|
The most characteristic cutaneous lesions of bacillary angiomatosis resemble pyogenic granulomas -- fleshy, friable, protuberant papules-to-nodules that tend to bleed very easily (Figure
2). In addition, deep cellulitic plaques and subcutaneous nodules may occur. Lesions number from a few to hundreds. Clinically, the skin lesions are frequently misdiagnosed as vascular tumors, especially KS. A prominent vascular proliferation that forms an elevated papule histologically characterizes the lesions (Figure
3). Neutrophilic leukocytes are prominent in the interstitium. Basophilic aggregates are found adjacent to the vascular lumina, representing collections of the bacterium. Diagnosis is confirmed by identifying the causative organism in affected tissue using silver stains or electron microscopy.
Systemic findings such as fever, night sweats, weight loss, and anemia are common in patients with bacillary angiomatosis. Reports describe mucosal lesions of the conjunctiva and upper respiratory tract.(3) Visceral lesions may be as or more common than cutaneous lesions. Involvement of the liver and spleen with or without skin lesions is the most commonly diagnosed form of visceral disease.(17) These patients present with abdominal pain, fevers, elevated levels on liver function tests, and hepatosplenomegaly. Liver and spleen biopsies may show large ectatic vascular spaces, a pattern called peliosis. Abundant bacilli are adjacent to these vascular spaces. Osseous lesions manifest as bone pain and may precede the appearance of skin lesions.(16) Routine radiographs reveal a lytic lesion at the site of pain. Bone scans rarely reveal additional asymptomatic lesions. Isolated lymph node enlargement is another presentation. The diagnosis of visceral disease is made on the basis of biopsy of the affected organ and examination with silver stains or electron microscopy. In the untreated patient, fatal widespread visceral disease may occur.(17)
Treating affected patients with erythromycin in full doses (500 mg orally 4 times daily) resolves the lesions, as does treatment with doxycycline (100 mg orally twice daily). Cutaneous lesions usually resolve in 3 to 4 weeks, but therapy should continue for at least 8 weeks. Patients with documented visceral disease should receive at least 4 months of therapy. Relapses can occur if treatment is not continued appropriately.(18) In vitro sensitivities as currently performed do not correlate well with clinical response. Unlike KS, bacillary angiomatosis lesions do not respond to radiation therapy.(19)
| Dermatologic Manifestations of Pseudomonas Aeruginosa|
Information on Pseudomonas aeruginosa infections in HIV-infected persons is limited to anecdotal evidence.(20) No studies of this infection have been conducted in HIV-infected patients, but we have diagnosed and treated several cases at San Francisco General Hospital that had in common neutropenia and advanced HIV disease.
Chronic ulcerations and macerated skin are susceptible to colonization by gram-negative bacteria, especially P. aeruginosa. One patient with advanced HIV disease and with chronic leg ulcers due to excoriation and folliculitis developed Pseudomonas overgrowth. He responded very slowly to intravenous antibiotic administration and local acetic acid soaks. Two other patients developed macerated toe webs that became colonized with P. aeruginosa.(21) One died of Pseudomonas sepsis, underscoring the potential danger of this usually benign condition for patients with advanced HIV disease. A third patient, while receiving zidovudine (AZT), developed Pseudomonas sepsis, including multiple subcutaneous nodules that became fluctuant and required surgical drainage.(22) A fourth patient, while receiving ganciclovir, developed buttocks lesions resembling ecthyma gangrenosum on two occasions; both required wide surgical excision. The last patient we have seen with P. aeruginosa infection had cellulitis develop from "hot tub folliculitis."
| Herpes Simplex Virus|
Early in the HIV epidemic, chronic persistent infection with herpes simplex virus (HSV) was recognized in patients with advanced HIV disease.(23) Today, this syndrome is a Centers for Disease Control (CDC)-defined index infection in establishing an AIDS diagnosis.(24)
As long as the host immune system is still reasonably intact, the course of genital and orofacial HSV recurrences may be similar to the course in non-HIV-infected patients. Clinicians should consider HSV in evaluating all ulcerative lesions, particularly perirectal ulcers and nonhealing ulcers anywhere on the body.
Lesions may appear as grouped blisters that rupture, crust, and heal in 7 to 10 days. More commonly, ulceration is the finding with no prior history of blisters. Once severely immunosuppressed, HIV-infected persons often experience chronic lesions that continue to expand and form large, crusted erosions 2 to 10 cm or larger in diameter (Figure
4). Lesions may be quite painful, especially if located perianally or periorally. Periungual infection is another characteristic manifestation of HSV-2 infection in the HIV-infected patient; all paronychial lesions should be cultured for HSV.(25)
A Tzanck smear taken from the edge of the ulcer, stained with Giemsa or methylene blue, when positive for multinucleated epithelial giant cells gives rapid diagnosis. Alternatively, fluorescent antibody testing or viral culture are diagnostic. If these are negative and clinical suspicion of HSV is high, clinicians should perform a biopsy of skin from the edge of the ulcer. A portion of the tissue should be cultured for viruses, which may be positive even when swab cultures are negative. In addition to routine histologic examination, clinicians should perform special stains and cultures for other possible infecting organisms, including spirochetes.
Oral acyclovir is extremely useful in managing HSV infections in HIV-infected patients. In the immunocompetent HIV-infected patient, either intermittent or chronic suppressive therapy may be used. The immunosuppressed patient with chronic ulcerative lesions should receive acyclovir (200 to 400 mg orally 5 times daily) until the ulcers heal, which may take several weeks. Then, chronic suppressive therapy should be instituted with acyclovir (400 mg orally twice daily) to reduce recurrences. The newer acyclovir analog antiviral agents are available with better absorption and higher bioavailability. Famciclovir (250 mg 3 times daily) and valaciclovir (100 mg twice daily) are alternatives.
| Spreading, Necrotizing, and Disseminated HSV Infections|
Untreated HSV lesions tend to enlarge slowly. New lesions at distant sites may appear, probably due to cross-contamination rather than to hematogenous spread. It is unusual for HSV infections to disseminate, even in severely immunosuppressed HIV-infected individuals.
HSV may rarely cause a necrotizing folliculitis that appears as 0.2- to 1.0-cm papules with firm central crusts. A biopsy is usually required to establish the diagnosis, because the site of infection is the epithelium along the hair shaft in the dermis.
| Acyclovir-Resistant HSV Infection|
Large chronic perianal, perioral, or periungual ulcers that fail to heal with acyclovir treatment are often due to thymidine-kinase-negative, acyclovir-resistant HSV-2.(26-32) Treatment with foscarnet(29-32) and continuous-infusion acyclovir(33) is beneficial. Unfortunately, recurrences may also be resistant to acyclovir and, rarely, foscarnet.(27) The correct management of acyclovir- and foscarnet-resistant HSV is difficult, but trifluridine ophthalmic solution may be tried.(34)
| Varicella Zoster Infection|
| Patients with Previous Varicella|
Varicella zoster virus (VZV) infection is commonly seen early in the course of HIV infection, particularly in healthy-appearing individuals, before the onset of other symptoms.(35-39)
Because most HIV-infected persons have had varicella previously, the initial manifestation of VZV infection is usually herpes zoster. During the course of HIV disease, herpes zoster often precedes thrush and oral hairy leukoplakia by about 1 year,(37) making it an important early finding and raising suspicion of HIV infection in persons at risk.
Unlike zoster in individuals without HIV infection, this dermatomal eruption may be particularly bullous, hemorrhagic, necrotic, and painful in HIV-infected persons. The duration of blisters and crusts is usually 2 or 3 weeks. The approximate duration of significant pain is also 2 or 3 weeks. Necrotic lesions may last for up to 6 weeks and heal with severe scarring. This dermatomal scarring is characteristic of HIV-infected patients and should be sought when evaluating at-risk individuals. In severe cases, and occasionally in severe cases in non-HIV-infected persons, excruciating and disabling pain may last for many months.
Recurrences have been reported in up to 25% of African HIV-infected persons with herpes zoster.(38) This number is about 5% higher than that seen in San Francisco.(40) As immune suppression advances, recurrent episodes may increase in severity.
Dissemination of VZV in HIV infection is fortunately uncommon.(41) VZV does disseminate more commonly in HIV-infected persons than does HSV, however, so all disseminated herpetiform eruptions should be considered VZV until proven otherwise, and high-dose acyclovir should be given. The clinical manifestations of disseminated VZV infection include typical widespread Tzanck-positive blisters with or without an associated dermatomal eruption. In addition, chronic disseminated VZV may present as widespread ecthymatous ulcers or hyperkeratotic verrucous lesions.(42-44) This verrucous pattern often appears with prolonged infection that has been treated with acyclovir.(45) VZV strains cultured from verrucous lesions in patients failing acyclovir therapy are often acyclovir-resistant, thymidine-kinase-negative mutants of VZV.(42-44)
A less common manifestation of VZV infection in HIV infection is persistent, chronic, localized herpes zoster. Patients may develop typical herpes zoster that either fails to clear with acyclovir therapy or immediately recurs after therapy. Although dissemination does not occur, lesions fail to resolve with increasing doses of acyclovir, and patients eventually develop chronic localized zosteriform thymidine-kinase-negative VZV infection. Children with HIV infection may frequently develop primary, recurrent and persistent VZV infection.(46)
The use of corticosteroids in therapy for VZV infection in HIV-infected patients is somewhat controversial. Elderly patients without HIV infection are often given relatively high doses of oral corticosteroids for several weeks to prevent post-zoster neuralgia, although the efficacy of this treatment is debated. Systemic steroid therapy for VZV infection usually is not recommended for HIV-infected patients because of a theoretic risk of additional immunosuppression.
Because acyclovir reduces the initial pain, speeds healing, and reduces the risk of VZV dissemination, all VZV-infected patients with HIV disease should receive acyclovir treatment and their therapy should be initiated as soon as possible. The patient's immune status and pattern of zoster determines the method of administration.
| Oral Acyclovir|
If the patient has a reasonably intact immune system and does not have clinical features of disseminated or visceral infection, and if lesions are not near the eye (trigeminal nerve), then oral acyclovir is probably adequate and beneficial. Recommended doses for treating VZV are much higher than those for HSV because of the relative insensitivity of VZV to this medication. A dosage of 800 mg orally 5 times daily for 5 days is recommended. Therapy should continue at least 5 days beyond the last day of blister formation. Some authors believe that intravenous administration is more effective than oral.(47) Fortunately, side effects from this drug are rare, even at these high doses. Famciclovir (500 mg) and valaciclovir (1000 mg) may be given only three times daily but must be dose adjusted in the setting of renal impairment.
| Intravenous Acyclovir|
Intravenous acyclovir (10 mg/kg 3 times daily) is indicated when the patient's immunosuppression is significant (CD4 < 200 plus additional immune repression, e.g., lymphoma), when disseminated or visceral lesions are present, and when VZV affects the ophthalmic branch of the trigeminal nerve (eyelid or tip of the nose especially). The possible increased risk for herpetic keratitis, retinal vasculitis, and uveitis supports intravenous treatment of persons with such VZV infections.(48) Only intravenous acyclovir is guaranteed to reach plasma levels adequate to inhibit all VZV strains.
Treatment should continue until the lesions are well crusted (usually about 7 days), after which full doses of oral acyclovir may complete the therapy. Treatment should continue for 10 to 14 days. Early and vigorous treatment may prevent the severe necrotic forms of zoster and help relieve the terrible pain that can occur. Acyclovir treatment does not appear to reduce the risk of postherpetic neuralgia.
Other treatments for VZV consist mostly of analgesics and topical care of skin lesions. In mild cases, soap and water are adequate for bathing skin lesions, but in severe cases, compresses (2 or 3 times daily) help remove necrotic debris. Use of an antibiotic ointment after such treatment, such as silver sulfadiazine (Silvadene; Marion Merrell Dow, Kansas City, MO) or bacitracin, keeps the scabs soft, helps prevent them from sticking to dressings, and may also prevent secondary infection. Capsaicin cream (Zostrix; Genderm, Lincolnshire, IL), a substance P depletor,(49) may reduce both acute and chronic zoster pain. It may be applied to the lesions 5 times daily until the pain is controlled; rebound pain may occur when Zostrix use is discontinued.
| Patients Without Previous Varicella Zoster Virus Infections|
On initial exposure to VZV, a disseminated blistering eruption called varicella (chickenpox) usually occurs. This presentation is followed by lifelong immunity, but dormant virus can later reactivate dermatomally, causing herpes zoster. Not surprisingly, varicella occurs in HIV-infected persons. HIV-infected persons with no prior history of varicella may on exposure develop typical chickenpox. In HIV-infected children and adults, however, varicella may be severe, cause visceral disease, and be fatal.(50,51)The predisposition for visceral disease seems greater in children than in adults with HIV disease. Prior VZV infection and the presence of anti-VZV antibodies do not protect the HIV-infected person from developing clinical lesions of varicella. Recurrences or persistence of varicella can occur despite acyclovir therapy. One possible explanation is the difficulty in achieving adequate blood levels of acyclovir during oral therapy.(43)
The number of reported HIV-infected persons with varicella is small, so it is unclear which are the best treatment strategies. Clinicians should probably give acyclovir to all HIV-infected persons with varicella. Adults who are feeling well, have normal chest radiographic findings, and have no evidence of visceral disease may be treated with oral acyclovir (800 mg 5 times daily for 10 to 14 days). For pediatric use, oral doses from 1,000 to 3,000 mg/m2 may be used in HIV-infected children with uncomplicated varicella. This therapeutic approach must be used with extreme caution, and intravenous acyclovir must be instituted if healing is not prompt. Oral therapy with acyclovir may predispose patients to subsequent chronic cutaneous VZV infection due to suboptimal blood levels of the drug.(43) HIV-infected persons with varicella who are not given oral acyclovir should receive intravenous acyclovir (10 mg/kg every 8 hours). The clinical status of the patient determines the length of therapy. Acyclovir therapy should continue at least until the lesions are completely healed.
| Dermatologic Manifestations of Molluscum Contagiosum|
| Clinical Presentation|
Molluscum contagiosum is a superficial cutaneous viral infection manifested as 2- to 3-mm flesh-colored hemispheric papules. Characteristically, a faint whitish core is at the center of each papule, some of which may be slightly umbilicated. This eruption is seen commonly in immunocompetent young children (ages 3 to 8 years), whose lesions are scattered widely over the face, arms, and trunk. In adults, this mild infection is usually sexually transmitted and occurs in the pubic area. In the nonimmunosuppressed child, lesions tend to last 6 to 12 months and then spontaneously resolve when the host develops resistance to the virus. Genital molluscum in the non-HIV-infected adult may be chronic.
Molluscum contagiosum occurs in approximately 10 to 20% of HIV-infected persons.(35) Early in the infection, the lesions are usually mild and localized to the groin or face. Once CD4 counts fall below 200, however, lesions tend to proliferate. They often number greater than 100 and may involve the face, trunk, and groin; there is a predilection for the eyelids.(52) Extensive molluscum contagiosum is a cutaneous marker of advanced HIV disease (CD4 < 50). At this stage, molluscum may extend onto mucosal surfaces of the lips or conjunctiva. Patients with advanced HIV disease are rarely cured of their molluscum. The finding of subclinical, microscopic infection in apparently normal skin may explain failure to cure patients.(53)
| Treatment of Molluscum Contagiosum|
There are no known medical complications of molluscum contagiosum. It does not affect internal organs or even cause significant symptoms on the skin. The objective of treatment is therefore primarily cosmetic and preventive. Rarely, lesions become inflamed by rupture (simulating a secondary infection) or by the development of an associated dermatitis.
Light cryotherapy using liquid nitrogen can treat individual lesions. If this is not available, pricking the lesion with a large-gauge needle and removing the white core (molluscum body) may also be effective. Topical application of a tiny drop of cantharidin to each lesion for 3 to 6 hours will often induce sufficient inflammation to eradicate the lesions. Complete cure is difficult to achieve, and treatment is usually restricted to bothersome or distressing lesions. For refractory lesions, removal by curettage without cautery is very effective. Lesions of the lid margins should be removed by an ophthalmologist.
| Human Papillomavirus (Warts)|
Superficial cutaneous infection with human papillomavirus (HPV), or warts, occurs with increased frequency in immunosuppressed patients. Lesions may be extensive and resistant to therapy.
| Clinical Presentation|
In HIV-infected patients, warts usually look like those seen in nonimmunosuppressed patients. Reports describe the rare occurrence of very extensive infections mimicking epidermodysplasia verruciformis in HIV-infected individuals. The warts seldom cause symptoms, except when on the soles of the feet and around the fingernails.
| Treatment of Papillomavirus Lesions|
Treatment is primarily cosmetic; the exact same methods are used as in immunocompetent patients. In patients with symptomatic HIV disease, the results may be disappointing. Even in persons with normal immunity, relapse of warts after treatment is common. In advanced HIV disease, relapse is almost to be expected. Discomfort may limit the use of standard treatment. Liquid nitrogen cryotherapy can be applied every 1 to 4 weeks. Topical "anti-wart" medications containing salicylic and lactic acids dissolve keratin and help primarily by debulking the callous-like cap over the wart. They are applied daily under occlusion and may lead to complete disappearance of the lesions. In general, the treatment outlook for warts is poor in immunosuppressed patients. Referral to a dermatologist may be appropriate to help with these annoying lesions.
| Human Papillomavirus (HPV) and Sexually Transmitted Cancers|
Condyloma acuminata are of special significance in persons with HIV infection. Cervical dysplasia and carcinoma are clearly associated with HPV infection.(54) Like the cervix, the anorectal area has a "transformation zone." HPV infection is very common in the genital and perianal area of homosexual men, especially those practicing receptive anal intercourse. In these men, even when visible warts are not present, cytologic dysplasia can be seen on smears.(55-57) Cervical dysplasia is also extremely common in HIV-infected women.(58) In addition, bowenoid dysplasia is seen in biopsy material of wartlike lesions (bowenoid papulosis) from the genital area of homosexual men.(59) This pattern correlates closely with the presence of potentially carcinogenic HPV type 16. In the absence of visible warts, oncogenic HPV is detectable in swabs from the anal area of patients with HIV disease.(56) Reports also describe HPV in the anorectal carcinomas of homosexual men.(60) These data strongly support the concept that anorectal cancer, like cervical carcinoma, is a consequence of sexually transmitted disease. HPV may be the inducing agent and by itself may be sufficient to produce cancer. HIV infection may be a cofactor enhancing this effect.
Unfortunately, anorectal warts in HIV-infected men are difficult to eradicate.(61) Nonetheless, an attempt should be made to eliminate all warts, especially those that are potentially premalignant lesions. The degree of cytologic atypia seen on biopsied condylomata may identify at least a portion of those harboring HPV with malignant potential.(62) The future availability of HPV typing may guide therapy. Until that time, complete eradication of all anogenital warts in HIV-infected men and women should be the goal. If this is impossible, then careful evaluation and close follow-up are clearly necessary to identify any genital neoplasms at the earliest and most treatable stage. Female HIV-infected patients must have regular gynecologic examinations and Papanicolaou (Pap) smears.(63,64)
| Treatment of Genital Warts|
Genital warts in HIV-infected persons are treated exactly the same way as in uninfected persons. Topical treatment with podophyllin or trichloroacetic acid may be applied weekly. At least 6 to 10 weeks of treatment is a reasonable "trial" of efficacy. Liquid nitrogen freezing has a slightly greater response rate. Persistent lesions may be surgically debrided and the bases cauterized. (For other than the most routine warts, we recommend sending the removed tissue for pathologic evaluation to rule out dysplasia.) Recurrence is almost universal.
The presence of external genital warts in women and perirectal warts in homosexual or bisexual men is usually associated with internal warts. Pelvic examination, Pap smear, and colposcopy are recommended in women, and anoscopy in men.
| Acute HIV Exanthem and Enanthem|
In acute primary HIV infection, a rash may develop in addition to a mononucleosis-like illness. The frequency of the rash in acute HIV infection may be as high as 50%.(65-72) The rash may be exanthematous or pityriasis rosea-like, usually does not itch, is distributed over the upper trunk and proximal limbs, and may involve palms and soles. A collarette of scale may be present at the periphery of the lesions. An associated enanthem of oral erythema or superficial erosions may be present. Dysphagia or retrosternal pain due to oral and esophageal ulcerations may be the prominent complaint of patients.(73) The exanthem and enanthem spontaneously resolve within 1 to 2 weeks.
These features are similar to other viral exanthems and are not specific for HIV infection. Clinicians should consider this syndrome when diagnosing at-risk individuals exhibiting symptoms of acute viral syndrome. Detection of HIV antigen(74) by enzyme immunoassay may confirm the diagnosis of acute HIV infection in HIV-antibody-negative persons.
| Cutaneous Mycobacterial Infection|
Reports describe increased frequency of infections with Mycobacterium avium-intracellulare and Mycobacterium tuberculosis in patients with HIV disease. These infections may be disseminated, unusual, and severe.(75,76) Cutaneous lesions caused by these organisms, however, are unusual. They commonly present as chronic sinuses over involved lymph nodes (scrofula), chronic ulcerations, or hemorrhagic macules.(2,77) All biopsies from HIV-infected patients should be examined with appropriate stains to rule out mycobacteria in the tissue. When present, organisms are usually abundant.(78)
In most cases, acid-fast bacilli (AFB) in skin lesions indicate disseminated mycobacterial disease, usually from M. avium-intracellulare. Rarely, however, abscesses or sporotrichoid lesions due solely to mycobacteria may represent localized disease.(79) M. avium-intracellulare causes most cases of isolated lymph node or sporotrichoid disease. Treatment with effective antimycobacterial agents may cure HIV-infected patients with localized disease.
M. haemophilum rarely causes mycobacterial infection in immunosuppressed persons. Typically, it presents with cutaneous abscesses or ulcerations and tenosynovitis or arthritis. In the few descriptions of HIV-infected patients with this infection, lesions were widespread and blood cultures and/or pulmonary studies demonstrated disseminated disease. Clinicians should suspect this organism if skin or joint lesions yield AFB on smears, yet standard AFB cultures are negative. Hemin supplementation of culture media may result in positive cultures.(80,81)
Rarely, M. kansasii can cause cutaneous lesions in HIV-infected persons. The histology may be that of a spindle cell proliferation resembling KS. Unless special stains for mycobacteria are ordered, a misdiagnosis may result.(82)
Reports describe two HIV-infected patients with localized M. marinum infection that appeared to respond to appropriate therapy.(78,83) Bacille Calmette-Guérin immunization is probably contraindicated in immunocompromised HIV-infected persons because disseminated M. bovis infection may result.(84)
In at least one case, an asymptomatic HIV-infected U.S. Army recruit given vaccinia immunization developed widespread infection with the virus.(53) In general, however, HIV-infected individuals tolerate live-virus immunization.(85)
| Fungal and Yeast Infections|
| Superficial Infections|
Superficial yeast and fungal infections can be broken down into the following three groups: thrush; intertriginous infections; and nail, paronychial, and foot infections.
The most common form of yeast infection in HIV-infected persons is thrush. Angular cheilitis -- fissuring, maceration, and erythema of the corners of the mouth -- may accompany thrush. Treatment includes clotrimazole troches for oral thrush and an anticandidal agent such as nystatin (e.g., Mycolog ointment) or an imidazole cream for the affected lateral lips.
| Intertriginous Infections|
Either Candida or Tinea may cause intertriginous infection and may involve the groin, axillary vault, or inframammary areas. In these areas, candidiasis presents as a vivid red, slightly eroded eruption in the depths of the folds. The surface is wrinkled and a white membrane may coat the eroded surface. A hallmark of this rash is satellite pustules extending out centrifugally from the eroded areas. In males, the scrotum is often involved. Patient complaints of a burning pain may be as numerous as those related to pruritus.
Tinea in the groin is usually pruritic. The scrotum is spared. The depth of the folds may be clear, and a well-demarcated, annular patch expands down the upper thigh. In more extensive cases, the lesions may extend through the pubic hair onto the lower abdomen and buttocks. Rarely, Tinea of the groin may extend to cover large areas of the body.(86)
Both Candida and Tinea are diagnosed by potassium hydroxide examination of scales taken from the active border or a satellite pustule. Topical treatment is usually adequate and involves the application twice daily of an imidazole cream (clotrimazole, miconazole, or ketoconazole). Candidal lesions may be moist, so drying soaks with Burow's solution 1:20 may be initially helpful. Eroded lesions in intertriginous areas are very tender, so topical solutions may burn. Treatment should be continued for 21 to 28 days. Because relapses are common, intermittent prophylactic treatment may be required.
In our experience, most HIV-infected patients referred for a refractory intertriginous eruption have seborrheic dermatitis or psoriasis of the groin. This condition presents as variably pruritic erythematous patches with a fine scale. There are no satellite pustules and no central clearing. Scrotal involvement occurs, but it is not erosive or tender, unless infected with bacteria.
Rarely, Tinea causes groin rashes that persist because of using the wrong medication (e.g., nystatin), using a strong steroid with the antifungal agent (e.g., Lotrisone; Schering, Kenilworth, NJ), or trying to treat with oral ketoconazole alone. Tissue levels of oral ketoconazole may be insufficient due to poor absorption, if gastric acid production is low.(87) Addition of a topical imidazole is dramatically beneficial.
| Candida Infection of the Nails|
Both Candida and Tinea may infect the nails. Candida almost always affects the tissue around the fingernails, frequently presenting as a paronychia (inflammation of the tissues surrounding the nail). Findings include tenderness, erythema, and bogginess of the proximal nail fold. Pressure on the inflamed nail fold may express purulent material. Infection tends to be chronic, in which case the cuticle is lost and the nail plate may become ridged or dystrophic. Onycholysis (separation of the nail plate from the nail bed) may also occur. The nail plate itself is usually not invaded, so nail thickening, opacity, and crumbling are unusual.
Chronic frequent exposure to water is a significant predisposing factor in candidal nail infection. Dishwashers, bartenders, and homemakers are at increased risk. Topical imidazole in solution or 2 to 4% thymol in chloroform twice daily is the initial therapy. The onycholytic nail must also be trimmed away so that the medication can be applied at the most proximal area of onycholysis. In refractory cases, fluconazole (100 mg daily), itraconazole (200 to 400 mg daily), or ketoconazole in doses of 200 mg to 400 mg daily for 2 to 4 weeks is helpful.
| Tinea Infection of the Nails, Feet, and Hands|
Tinea infection of the nails, feet, and hands is common in HIV-infected persons, but because it is also common in the non-HIV-infected population, it is not a specific marker of HIV infection. Tinea of the nail, in contrast to Candida, involves primarily the nail plate, favors the toenails over the fingernails, and does not cause acute paronychia. Nails become opaque and thickened, and may split or crumble. An associated Tinea infection of the soles or toe webs is common, manifested by chronic maceration, scaling, blistering, and/or thickening of the skin. Occasionally, the palms are involved in a similar manner. Tinea is especially likely if two feet and one hand are affected. Occasionally, Tinea will spread to hairy areas, especially the face and lower legs, causing a chronic plaque-like folliculitis that is easily mistaken for a chronic bacterial infection. Previous use of topical steroids may induce this pattern and mask the correct diagnosis.
Tinea of the palms and soles is improved with topical imidazole therapy twice daily. Fingernail infection can be treated with griseofulvin, fluconazole, or itraconazole. The exact dosing for the two imidazoles is unknown, but probably is 100 to 200 mg (fluconazole) and 200 to 400 mg (itraconazole) daily. Treatment may be restricted to 1 week per month to reduce cost. Once treated, fingernail infection has a long disease-free period. Toenail infection is common and chronic and does not require therapy unless it causes discomfort. Fluconazole and itraconazole will likely be effective, but at a high cost for this largely cosmetic condition. Toenail infection is probably more likely than fingernail infection to relapse. Because relapse is common, constant use of topical antifungals is often necessary.
| Deep (Systemic) Fungal Infections|
Systemic infections reported in patients with symptomatic HIV disease include: cryptococcosis, histoplasmosis, sporotrichosis, aspergillosis, candidiasis, coccidioidomycosis, actinomycosis, and phaeohyphomycosis.(87-99) Only the first four present significant dermatologic problems.
Cryptococcosis is common in patients with advanced HIV disease and usually presents as meningitis. Cutaneous lesions may precede or occur simultaneously with central nervous system (CNS) disease. Approximately 6% of patients with HIV disease and cryptococcosis have skin lesions. Lesions appear anywhere on the body but are most common on the head and neck; they typically present as pearly 2- to 5-mm translucent papules that resemble molluscum contagiosum.(89,90,95,97) Diagnosis is established by skin biopsy and culture. Cryptococcosis in the skin is an indication of disseminated infection, so appropriate work-up, especially of the CNS, is mandatory.
Disseminated histoplasmosis is becoming an increasingly common problem in HIV-infected patients living in histoplasma-endemic areas; it occurred in more than 5% of patients with advanced HIV disease in one series from Houston, Texas.(96) Most cases probably represent reactivation of previous histoplasmosis infection rather than dissemination of newly acquired infections. This fact explains cases seen in New York City, Los Angeles, and San Francisco -- nonendemic areas -- among individuals who previously lived in areas endemic for the disease. Skin involvement occurs in about 10% of patients with advanced HIV disease with disseminated histoplasmosis.(96,99)
The cutaneous lesions are not specific and present as erythematous macules, papules, maculopapular dermatitic lesions, pustules, acneiform lesions, ulcerations, and plaques. Histologic analysis of the skin may demonstrate granulomas; organisms are easily seen with special stains (e.g., methenamine silver). Therefore, skin biopsy is a good way to establish the diagnosis of disseminated histoplasmosis. Bone marrow biopsy and culture are positive in 69% of cases, and blood culture is positive in 27% of cases.(96)
About 10% of patients with disseminated histoplasmosis present with sepsis, disseminated intravascular coagulopathy, and pulmonary, CNS, and renal failure. This syndrome is usually fatal.
In non-HIV-infected persons, sporotrichosis most commonly presents as a disease of the skin and draining lymphatics. Rarely, sporotrichosis may disseminate. Disseminated sporotrichosis associated with HIV infection apparently begins as an asymptomatic pulmonary infection that spreads hematogenously to the skin and joints. Skin biopsies and cultures establish the diagnosis. Multiple widespread cutaneous ulcers and subcutaneous nodules are present.(91,92)
Localized or disseminated sporotrichosis may be treated with amphotericin B. To avoid the difficulties associated with amphotericin B use, itraconazole at a dose of 400 mg daily or higher may be attempted in a patient with localized or non-life-threatening disease. SSKI is not recommended for HIV-infected patients with disseminated sporotrichosis.
Cutaneous Aspergillus can occur as primary or secondary infection. The latter is from hematogenous spread or from direct invasion of underlying structures. Primary cutaneous aspergillosis is associated with local skin injury (from tape, intravenous catheter sites) and neutropenia. Lesions can appear as erythematous indurations with overlying pustules, hemorrhagic ulcers, or molluscum contagiosum-like lesions. Treatment includes systemic antifungal therapy (amphotericin B and/or itraconazole) along with surgical debridement and removal of predisposing agents (tape and catheters).(98)
| Cutaneous Manifestations|
Cutaneous presentations of primary and secondary syphilis in HIV-infected persons are usually similar to those in non-HIV-infected persons. In two reported cases of patients with advanced HIV disease who had cutaneous lesions of secondary syphilis, one had a true negative treponemal (FTA-ABS) and both had negative nontreponemal (VDRL) serologies.(100,101) Skin biopsies of cutaneous lesions demonstrated spirochetes and established the diagnosis. The patients' HIV infection apparently delayed development of serologic evidence of Treponema pallidum, resulting in negative tests. Thus, in the HIV-infected person, a negative serologic test may not be adequate to rule out secondary syphilis. Another report documents palmoplantar keratoderma as a manifestation of secondary syphilis in an HIV-infected person.(102) His immune response to T. pallidum was atypical.
| CNS Manifestations|
Syphilitic infection of the CNS may occur early, even in the primary or early secondary stage, among both non-HIV-infected and HIV-infected persons. Clinical CNS disease may be manifest as early as a few months after infection.(103) Recommended therapies may not be adequate to treat or prevent this complication in non-HIV-infected persons. Early CNS relapse (even after standard treatment regimens) may be more common in HIV-infected individuals,(103-107) possibly because of a combination of impaired cell-mediated immunity due to HIV and suboptimal CNS levels of medication. Clinicians should carefully follow HIV-infected patients who have been treated with standard therapies for early syphilis. If CNS signs or symptoms develop, clinicians should perform appropriate evaluation for early CNS relapse, including lumbar puncture and VDRL of the cerebrospinal fluid (CSF). The CDC recommends that a CSF examination precede and guide therapy in all HIV-infected patients with latent syphilis present for longer than 1 year or for unknown duration.(108)
Because of reports of early CNS relapse, the CDC has issued special guidelines for the treatment of syphilis in persons with HIV infection.(108) They recommend that patients with early syphilis be treated with 2.4 million units of benzathine penicillin given intramuscularly at a single session. We recommend weekly intramuscular injections of penicillin G benzathine (Bicillin; Wyeth-Ayerst, Philadelphia, PA) 2.4 million units for 2 or 3 weeks. Even patients with early syphilis, however, require CSF examination if there are any clinical findings suggesting CNS involvement. For penicillin-allergic patients, hospitalization, desensitization to penicillin, and treatment with penicillin are recommended. Erythromycin is not recommended.(109) Quantitative nontreponemal tests are repeated at 1, 2, and 3 months and thereafter at 3-month intervals until a satisfactory serologic response occurs. If an appropriate fall in titer does not occur (two dilutions by 3 months for primary or by 6 months in secondary), the clinician should reevaluate and perform CSF examination.
For latent syphilis of longer than 1 year or of unknown duration, CSF examination is recommended for all HIV-infected patients. Benzathine penicillin should not be used to treat asymptomatic or symptomatic neurosyphilis in HIV-infected individuals.
Patients with neurosyphilis should be treated for at least 10 days with either aqueous crystalline penicillin G (2 to 4 million units intravenously every 4 hours) or with procaine penicillin G (2.4 million units intramuscularly daily) plus probenecid (500 mg orally 4 times daily). The correct therapy for HIV-infected persons with late latent syphilis and a normal CSF examination is not known. Weekly injections of benzathine penicillin (2.4 million units for 3 consecutive weeks) is suggested. Frequent serologic reevaluation is recommended to document the adequacy of therapy. Serologic response may be slower than in patients with early syphilis.
Two reports have documented Pneumocystis carinii cutaneous infection of the external auditory canal.(110,111) In these cases, polypoid lesions obstructed and protruded from the ear canals. Histology showed a dermal nodule composed of angiocentric perivascular amphophilic foamy material identical to that seen in P. carinii lung infection. Silver stain identified organisms. Neither patient had clinical pneumonia at the time of presentation, but one later developed P. carinii pneumonia (PCP). Both patients received trimethoprim-sulfamethoxazole (TMP-SMZ) and their cutaneous lesions healed.
| Inflammatory Conditions|
| Papulosquamous Diseases: Xerosis and Ichthyosis|
HIV-infected patients commonly complain of increasing dryness of the skin (xerosis).(78,112) Typically, the xerosis is most prominent on the anterior lower legs, but it may be quite widespread. In the winter, the xerosis is more severe and may be associated with dermatitis, manifesting as itching and dryness with areas of erythematous papules and fine scale on the posterior arms and lower legs. Patients with an atopic diathesis (hay fever, asthma, or previous atopic dermatitis) are predisposed to this type of xerotic eczema. Excessive or frequent bathing with deodorant or antibacterial soaps is a frequent precipitating factor and should be discontinued. Patients should apply mild topical steroid ointments (1.0 to 2.5% hydrocortisone or 0.025% triamcinolone) to the dermatitic areas three times a day and should cover all dry areas of the body with a moisturizing lotion or cream (e.g., Eucerin, Lubriderm, Moisturel) after bathing and at bedtime. In HIV-infected patients, xerosis remains active to some degree, especially in the winter months.
Dry and thickened skin, as is seen in acquired ichthyosis, is seen in patients with advanced HIV disease. Thickening of the palms and soles may be present as well.(1,2) Acquired ichthyosis has been seen in association with a wasting syndrome. Treatment is the same as for xerosis.
| Seborrheic Dermatitis|
Seborrheic dermatitis is a mild eruption, usually affecting the scalp and central areas of the face, that occurs in up to 5% of the non-HIV-infected population. The etiology of common seborrheic dermatitis is not understood. There is no evidence that increased numbers of Pitysporium ovale play an etiologic role in this condition. The skin eruption waxes and wanes, may be mildly itchy, and responds quickly to mild topical corticosteroid therapy. Flare-ups of this condition often occur when the afflicted individual is recovering from a severe illness or surgery. Increased severity of seborrheic dermatitis is present in certain neurologic conditions, particularly Parkinson's disease.
| Incidence in HIV Disease|
Early in the HIV epidemic, many patients with symptomatic HIV disease had particularly severe seborrheic dermatitis. One study found an 83% point prevalence of seborrheic dermatitis associated with advanced HIV disease and a 42% point prevalence with symptomatic HIV disease.(113) Other studies have reported rates in patients with advanced HIV disease ranging from 25 to 45%.(114-116) These percentages are far above those expected in a population on the basis of flare-ups from severe illness alone. Seborrheic dermatitis in HIV-infected individuals has a broad clinical spectrum, ranging from typical seborrheic dermatitis to a widespread form more like inverse psoriasis or sebopsoriasis.
| Clinical Manifestations in HIV Disease|
Clinically, typical HIV-related seborrheic dermatitis occurs predominantly on the scalp, usually with mild involvement on the face (particularly in the brows, around the eyelashes, down the nasolabial folds, and in and around the ears). Occasionally, seborrheic dermatitis will also occur on the center of the chest, particularly in individuals with a lot of chest hair, and in the axillae and groin. The dermatitis usually manifests as poorly defined, faint pink patches, with mild-to-profuse fine, loose, waxy scales. In a small percentage of patients, the seborrheic dermatitis is more extensive and is present on the scalp and large areas of the face. The intertriginous lesions are clinically identical to those seen in Reiter's syndrome and psoriasis concurrent with HIV infection.
A small percentage of patients present with the most severe form of seborrheic dermatitis, which consists of typical severe seborrheic dermatitis of the face and scalp, plus extensive involvement of the intertriginous areas. The axillae and groin are bright red and covered by a fine scale. The eruption moves out from the intertriginous areas onto the trunk and neck and may involve large areas of the body. Like classic seborrheic dermatitis, pruritus is generally mild. This severe form of seborrheic dermatitis may also be seen in non-HIV-infected persons, although it is quite unusual. This form may be called sebopsoriasis or inverse psoriasis -- a cross between seborrheic dermatitis and psoriasis -- and may be the presenting manifestation of HIV infection (Figure
Mild seborrheic dermatitis in HIV-infected patients is managed in the same manner as in non-HIV-infected patients: mild topical steroids (e.g., 1% hydrocortisone), tar shampoos, and often twice daily application of topical imidazole cream (clotrimazole or ketoconazole), which is used for its anti-inflammatory rather than its antifungal effects. Patients are very slow to respond to treatment with topical imidazoles alone. In our experience, topical imidazoles do improve the ing skin disease and others have stable skin disease is unknown.
| Clinical Manifestations in HIV Disease|
The clinical appearance of psoriasis is similar in HIV-infected and noninfected individuals. The incidence of severe involvement of the axillae and groin (sebopsoriasis), however, is increased in HIV-infected patients.(7) In addition, psoriatic erythroderma is not rare in these patients.(117) In our experience, drug reactions and psoriasis are the first and second most common causes, respectively, of an erythroderma in patients with advanced HIV disease. As in routine psoriasis, pruritus may be a serious problem for the HIV-infected patient with psoriasis. With scratching, secondary infection of excoriated psoriatic plaques with S. aureus may occur. Erythrodermic psoriasis in HIV-infected patients may be a sign of S. aureus septicemia, and the psoriasis may improve dramatically with only intravenous antibiotics.(118)
At least one series reported a poor prognosis for psoriatic HIV-infected patients. Many of them developed CDC-defined index disease for AIDS soon after diagnosis of psoriasis. Their average life span was 12 months.(119) This has not been our experience at San Francisco General Hospital, where survival has been unaffected by the presence of psoriasis.(7)
Therapy for psoriasis in otherwise healthy persons is imperfect, due in part to limited understanding of the condition's pathogenesis. Topical steroids, anthralin, ultraviolet light (UVB) with or without tar, psoralens plus ultraviolet A (PUVA), the retinoids, and immunosuppressives (especially methotrexate) are all useful. HIV-infected patients present additional challenges to an already inadequate armamentarium.
In general, psoriasis responds poorly to less than medium- or high-potency topical steroids. Use of potent topical steroids over large areas of the body, however, leads to systemic absorption, adrenal suppression, and possibly immunosuppression, obviously undesirable effects in patients with HIV infection. Topical steroids may also reduce local immunity, increasing the likelihood of cutaneous infections.
We have used tar plus UVB (Goeckermann therapy) with marginal success. Several patients did develop KS while receiving this therapy, and other authors have reported the appearance of KS or worsening of HIV disease with UVB therapy.(117,119) KS, like psoriasis, is known to develop in areas of inflamed or traumatized skin (Koebner phenomenon); whether this is a cause and effect relationship is unknown.
PUVA reduces T cell numbers in atypical infiltrates in the skin and may even eliminate circulating atypical T lymphocytes. PUVA is also a cutaneous carcinogen. The safety of PUVA in HIV-infected patients has yet to be established, but two of four patients treated in one series developed KS while receiving this therapy.(117) Short-term treatment with PUVA has been used in early HIV disease without obvious complications.(120-122)
Standard low-dose methotrexate therapy has been associated with progressive immunosuppression or rapid demise (or both) when used in some HIV-infected persons.(117) We have used methotrexate in a few HIV-infected psoriatic patients without apparent complications.(123,124) HIV testing for all psoriatic patients should be considered before methotrexate or PUVA therapy is started. Methotrexate use in HIV-infected individuals is of high potential risk and should be considered a last resort.
Many HIV-infected patients with severe psoriasis have responded favorably to etretinate, a retinoid given in standard doses.(117,125) The frequency of past or current liver disease due to hepatitis B infection in patients with HIV disease has limited etretinate's usefulness, but most patients we have treated responded to therapy with this agent. Some individuals have found side effects limiting.(119)
At least nine patients reported to date have had significant improvement of their psoriasis associated with AZT therapy.(119,126-128) The response is described as dose related. Highly active antiretroviral therapy (HAART) should be encouraged in all HIV-infected patients with psoriasis if appropriate. The efficacy of HAART for psoriasis in HIV disease is unstudied.
| Reiter's Syndrome|
Classic Reiter's syndrome (RS) consists of the triad of arthritis, conjunctivitis, and urethritis. Incomplete forms (e.g., arthritis and other findings) have been recognized. Reiter's syndrome occurs predominantly in genetically predisposed (HLA-B27 positive) men, commonly following genitourinary or gastrointestinal infections. Like psoriasis, RS may appear in HIV-infected patients.(117,129) Usually, symptoms of HIV infection and RS appear simultaneously or the HIV infection is symptomatic before the onset of RS. Patients may initially present, however, with classic cutaneous lesions of RS before manifesting clinical symptoms of HIV infection.
Whether the incidence of RS is increased in HIV infection, or whether HIV infection merely permits the expression or exacerbates the features of RS, is unknown. Certainly, the postulated precipitating events for RS, namely, genitourinary sexually transmitted diseases and gastrointestinal infectious illnesses, are common in HIV-infected persons. In addition, many HIV-infected persons are young men -- the population at risk for RS. The finding that the majority of HIV-infected patients with RS or psoriatic arthritis are HLBA-27 positive suggests that HIV is a cofactor in those persons genetically predisposed to RS.(130)
| Clinical Manifestations|
The classic cutaneous lesions of RS occur in HIV-associated RS as well and may help to establish the diagnosis. The palms and especially the soles develop superficial pustules that dry, forming keratotic papules. These coalesce until the soles are diffusely thickened and scaled, a condition called keratoderma blennorrhagicum (Figure
6). The nails are commonly affected; extensive subungual debris may appear, the nails may be horizontally ridged, and during severe flares, the nail plate may be so dystrophic as to appear absent. These nail findings may also be seen in psoriasis.
In the groin and axillae, red plaques identical to those seen in seborrheic dermatitis and psoriasis can be present. Skin biopsies from lesions of RS and psoriasis show identical histologic features. Biopsies are therefore not useful in distinguishing between these two conditions.
Oral and genital mucosa can also be involved. The glans penis may be covered by a dry, sharply marginated eruption called circinate balanitis. In the uncircumcised patient, lesions are more moist and may mimic candidiasis. On gross examination, the arcuate nature and sharp border of the lesions and a negative test for yeast (using a potassium hydroxide preparation) help to establish the diagnosis of circinate balanitis. Evanescent and often asymptomatic oral erosions may be present. A geographic tongue (i.e., showing migratory white patches) may also be found in patients with RS.
Therapy for the cutaneous lesions of HIV-associated RS is identical to that for psoriasis. Methotrexate is relatively contraindicated, but etretinate at the standard doses may be useful in severely affected patients.(124,125)
| Eosinophilic Folliculitis of HIV Disease|
Bacteria do not cause all folliculitides in HIV-infected patients. Culture-negative folliculitis commonly reveals eosinophils on biopsy.(131) Cases in which the biopsy shows eosinophils within or around the follicle have been called eosinophilic folliculitis of HIV infection.(88,132) This disorder typically occurs in HIV-infected persons with helper T cell counts below 200, so it is an important cutaneous marker of a specific stage of HIV disease. The eruption waxes and wanes. Intensely pruritic, edematous, urticarial papules and pustules appear in crops on the trunk or face or both (Figure
7). Cultures and histologic examination for infectious agents are negative, but a relative peripheral eosinophilia may be present.
Therapy can be difficult. We have used continuous astemizole (10 mg daily) with limited success, but concurrent imidazole or erythromycin therapy is contraindicated with astemizole because of the risk of cardiac arrhythmia. Ultraviolet phototherapy, as used for the pruritus of renal disease, is also beneficial in clearing the eruption and reducing the pruritus. Itraconazole in a dosage of 200 to 400 mg daily is sometimes beneficial in the treatment of HIV-associated eosinophilic folliculitis. Permethrin 5% (Elimite) used every other day from the waist up has been beneficial in some patients: Permethrin kills the mite Demodex, which theoretically may be the driving etiologic agent in eosinophilic folliculitis. The condition usually recurs once therapy stops.
| Atopic Dermatitis|
Atopic dermatitis may appear in both children and adults infected with HIV. In one series, 50% of infants with advanced HIV disease had atopic dermatitis.(133) Hemophilic children infected by blood transfusion may have flare-ups of previously quiescent atopic dermatitis.(134) Adults with a previous history of atopic disease may also note recurrence of atopy in advanced HIV disease.(135) They may develop atopic dermatitis when previously they had only respiratory atopic symptoms. Treatment recommendations are the same as for non-HIV-infected patients: use of topical steroids and lubricants, sedating antihistamines, and avoidance of water and soap.
| Hypersensitivity Reactions in HIV-Infected Patients|
Helper T cells and antigen-presenting cells are targets of HIV and have been proposed as crucial in the development of many hypersensitivity reactions. These reactions should be infrequent in HIV-infected persons whose T cells are depleted, but the fact that they occur frequently in HIV-infected patients suggests that normal numbers of T cells are not necessary for many hypersensitivity reactions to take place.
| Drug Reactions|
TMP-SMZ is used frequently in managing PCP. The incidence of adverse reactions to the drug is very high; in one study, 62% of HIV-infected patients with PCP could not complete their course of therapy because of adverse reactions.(136) Most reactions occur in the second week of therapy and are typical maculopapular/morbilliform reactions. They begin in the groin and pressure areas and quickly generalize. Cutaneous eruptions occurred in 48% of treated patients. In this group, 33% had resolution of the skin rash during therapy, and the remaining patients had progressive toxicity, which necessitated discontinuation of the drug. The rash did not always recur when the patient was rechallenged with the same therapy.
The use of systemic corticosteroids in treating PCP has substantially reduced the rate of drug eruption from TMP-SMZ. In persons with HIV infection and PCP, the overall incidence of skin eruptions from TMP-SMZ is about 10 times that in a non-HIV-infected population. The reasons for this difference are unknown. Similar mechanisms may account for the high incidence of similar eruptions in patients with Epstein-Barr infection given ampicillin.
Other drug-induced hypersensitivity reactions in HIV-infected patients are urticarial reactions, exfoliative erythroderma, fixed-drug eruption, erythema multiforme, and toxic epidermal necrolysis. These reactions are most often due to antibiotics, especially TMP-SMZ and the penicillins. These reactions may take up to 8 weeks to clear. Multiple sequential reactions are not unusual.(137) Eruptions due to acyclovir, ketoconazole, amphotericin B, AZT, DDI, DDC, D4T, 3TC, and the protease inhibitors are uncommon.
| Insect Bite Reactions|
Urticarial pruritic papules are a common morphologic lesion in HIV-infected patients. This lesion is clinically specific but etiologically nonspecific. In occasional patients, this lesion is associated with insect bites and is called papular urticaria. In HIV-infected patients in San Francisco, except for scabies mites, fleas most commonly cause papular urticaria. In the southern United States, mosquitoes may be the primary offender.(138,139) A skin biopsy of the lesion can confirm the diagnosis of insect bite reaction. Oral antihistamines combined with protection from biting insects leads to improvement in the lesions.
Scabies in HIV-infected persons usually presents with the typical pattern of pruritic papules with accentuation in the intertriginous areas, genitalia, and finger webs. With advancing immunosuppression, the infestation may exaggerate, becoming more widespread and refractory to treatment, and sparing the characteristic areas.(140) Gamma-benzene hexachloride (lindane) applied from the neck down for 8 to 24 hours is usually curative. There is anecdotal evidence, however, that lindane may result in increasing peripheral neuropathies in HIV-infected patients, particularly in those with CD4 < 200.(141) We have seen HIV-infected patients with scabies who have not responded to gamma-benzene hexachloride therapy. In these patients, we find 5% permethrin cream (Elimite, Herbert Laboratories), used in the same method as lindane, is safe and effective.(129) Elimite is considered safe for persons over 2 months of age, so it can be used in most HIV-infected pediatric patients.
The diagnosis of scabies in an HIV-infected patient in a nursing home or in a nursing home nurse often heralds the outbreak of an epidemic of scabies in that facility. Management of scabies in this setting is different than management of a single patient or household. Extraordinary measures are required to control such epidemics. Often all patients, staff, and visitors must be simultaneously treated. Extremely aggressive housekeeping procedures and fumigation must be undertaken to eliminate fomite transmission of infestation. Public health and dermatologic consultations are suggested.
In rare cases, true crusted (Norwegian) scabies may occur in patients with advanced HIV disease.(142-145) Norwegian scabies is nonpruritic and appears as thick crusts over some areas of the body. These crusts teem with mites and are highly contagious. To avoid infection of nursing personnel, patients with Norwegian scabies should be isolated until therapy is complete. Treatment is difficult. Elimite repeated at least weekly until cutaneous manifestations clear is recommended. Additionally, Ivermectin 6% precipitated sulfur ointment daily may be added to the Elimite therapy. Ivermectin orally has been successful in treating Norwegian scabies but is unavailable for this indication in the United States.(146) As a portal of entry for bacterial pathogens, this form of scabies can lead to sepsis and death.(144)
Reports rarely describe photosensitivity in HIV-infected persons.(147) Such reactions are not unusual, however. Erythematous patches and plaques appear during periods of increased sun exposure, primarily on exposed body parts, especially the dorsa of the hands, extensor forearms, side of the neck, and face. The photosensitivity is usually due to the shorter ultraviolet spectrum (UVB). Frequently prescribed photosensitizing medications (nonsteroidal anti-inflammatory drugs and TMP-SMZ) used in HIV-infected patients may play a role in their photosensitivity. Discontinuation of the photosensitizer may not lead to resolution of the photodermatitis, however. Photosensitive patients benefit from topical steroids, sun protection, and sunscreens. Some patients with severe skin eruptions respond to PUVA therapy.
| Porphyria Cutanea Tarda (PCT)|
Porphyria cutanea tarda (PCT) has been described in many HIV-infected persons, suggesting an association between the two.(148-150) Some patients have the familial form and others the sporadic form of PCT. Many patients who are genetically susceptible to PCT develop the disease only after exposure to hepatotoxic agents (ethanol) or drugs that interfere with uroporphyrinogen decarboxylase (iron or estrogens, for example). Hepatitis may also precipitate clinical PCT. Hepatitis C has been associated with PCT.(151) Why patients capable of developing PCT do so after HIV infection is unknown, but in many cases, patients have been exposed to one or more of the above mentioned precipitating factors.
| Pruritic Papular Eruptions|
Pruritic papules are common in HIV infection(152) and are due to various causes. Reports describe S. aureus folliculitis, eosinophilic folliculitis, demodicidosis mites,(153) insect bite reactions, and granulomas with no identifiable infectious agent (e.g., granuloma annulare) as causes of itching in the setting of HIV. Evaluation requires a skin biopsy. Most patients with pruritic papular eruptions have folliculitis. Our approach is to search for staphylococcal infection by abrading and culturing an unruptured pustule (if present), followed by empiric treatment for staphylococcus with a semisynthetic penicillin (e.g., dicloxacillin) or a first-generation cephalosporin for 1 to 2 weeks. Some patients improve with this regimen, particularly those with positive cultures from the pustules. Most other patients with folliculitis have eosinophilic folliculitis and are managed as noted previously. We think there is no specific and unique "papular eruption of HIV infection." Most patients with this diagnosis have eosinophilic folliculitis.(155) Rarely, pruritus with no primary skin lesions may be the presenting sign of HIV disease.(156)
| Dermatologic Manifestations of Neoplastic Disorders|
| Kaposi's Sarcoma|
KS is a neoplasm of endothelial cells involving the skin and, at times, other internal organs. KS is common among HIV-infected persons, but there is not an equal incidence in all risk groups. Most KS patients are homosexual men. In one series, 46% of homosexual men with advanced HIV disease had KS at the time of their initial diagnosis. The incidence in heterosexual injection drug users is only 3.8%.(157) The prevalence of KS has declined over the past 10 years among patients with advanced HIV disease in San Francisco. After a peak incidence of 65% in 1982, only 20% of patients with advanced HIV disease developed KS in 1987.(158) In homosexual men in Vancouver, Canada, the strongest predictor for the development of KS was an elevated number of sexual contacts in high-risk areas (San Francisco, Los Angeles, and New York).(159) Several homosexual men have been identified who developed KS but who are uninfected with HIV by all current testing methods.(160) These data support the involvement of a sexually transmitted infectious agent. Herpes virus 8 (HHV-8) has been associated with KS (see Human Herpesvirus 8 and HIV-Associated Neoplasms).(161-167)
| Clinical Presentation|
KS may affect any portion of the cutaneous surface. Initially, it appears as red-to-brown flat macules (Figure
12) Papules, nodules, and tumors may also be present or develop later. Lesions tend to arise along the lines of cleavage, forming oval papules. Numbering from one to hundreds, they range in size from several millimeters to over 10 cm and may be widespread, grouped, or zosteriform.
KS may affect mucosal surfaces and internal organs with or without involving the skin. Visceral involvement occurs in 72% of patients with advanced HIV disease and KS, most often affecting the gastrointestinal tract (50%), lymph nodes (50%), and lungs (37%).(168)
| Natural History and Prognosis|
The natural history of HIV-associated KS is not uniform, but the prognosis is poor. The average survival of patients is 18 months.(168) Most individuals have generalized, slowly progressive disease; others have stable KS. Even more rarely, the disease may resolve spontaneously.(169) Poor prognostic findings include generalized disease and coexistent opportunistic infections; the latter are the most common cause of death.(168)
Biopsy of an affected organ (the skin being the most accessible, if it is involved) establishes the diagnosis. Clinicians should select a palpable lesion, preferably one that has been present for at least several weeks, and avoid a site of prior trauma. A 3.5- to 4.0-mm punch biopsy should be taken from the center of the lesion. Despite their vascular nature, lesions usually do not bleed excessively if the following precautions are followed:
Avoid foot and lower leg lesions avoided if possible
Inject xylocaine with epinephrine 1:100,000 at least 5 minutes before the biopsy
Extend the biopsy into the subcutaneous fat
Suture all wounds
Except for those on the lower extremity, biopsy sites in KS lesions heal at the normal rate, and the incidence of infection for this type of surgical wound is not increased. The most common errors resulting in biopsy material that is not diagnostic are the following: choosing the wrong lesion, taking the biopsy sample from the edge of a lesion, crushing the tissue, and taking too small a punch biopsy (<3 mm).
Someone skilled in evaluating HIV-associated KS lesions should perform pathologic interpretation of biopsies. Early lesions may be subtle and difficult to distinguish from the vascular reactivity associated with prior inflammation or stasis dermatitis. Changes may be focal, and so multiple sections are often required before finding a diagnostic area. Diagnostic pathologic findings must always be present to make the diagnosis of KS, especially in persons who exhibit no other evidence of HIV infection or who are HIV-seropositive but not immunosuppressed. Consultation should be sought if there is any question. It is best to avoid pathologic diagnoses that are equivocal, that is, "possible KS." If medical management requires certainty about the diagnosis (e.g., chemotherapy is indicated), clinical diagnosis should be made only rarely, because skin lesions are so accessible and biopsies are so easy to perform.
Therapy aims at controlling symptoms, reducing edema, eliminating pain, and clearing lesions, but it is not thought to be curative. If treatment is necessary or elected, clinicians commonly use radiation and systemic alpha-interferon or chemotherapy. Cutaneous lesions may be improved with local cryotherapy(170) or intralesional injections of vinblastine, 0.2 to 0.6 mg/mL.(171-173) The correct technique and its implications are described elsewhere.(150) See Treatment of HIV-Associated Kaposi Sarcoma for a more thorough discussion of treatment.
| Other Cutaneous Carcinomas|
Other cutaneous carcinomas are not unusual in HIV-infected patients. Fair-skinned patients with significant prior sun exposure are at risk for basal cell carcinomas (BCCs) and squamous cell carcinomas.(174-176) BCCs commonly present on the back or chest as nonhealing scaling patches that may erode or bleed. They tend to behave similarly to BCCs in uninfected persons. Standard therapies are effective and associated with a similar recurrence rate to that seen in immunocompetent persons. Squamous cell carcinomas are associated with more sun exposure and are more common on the head and neck. Complete excisional surgery is recommended. Occasionally, HIV-associated lymphoma of either T or B cells will present in the skin.(12,77,176,177)
| Mucocutaneous Pigmentation Due to Zidovudine|
| Common Sites|
In dark-skinned persons (Hispanics and blacks), treatment with AZT may result in hyperpigmentation of the nails, oral mucosa, and skin.(178-180) The hyperpigmentation appears to be related to increased melanogenesis in the areas of hyperpigmentation and not to drug deposition. Tests for adrenal insufficiency are normal in these patients. An animal model has confirmed the findings in humans.(13)
The initial manifestation of hyperpigmentation in nails is usually a bluish discoloration of the lunulae (proximal white portions) of the nails, most prominently on the thumbnails. This appears about 1 month after AZT therapy begins. In addition, hyperpigmented longitudinal nail bands may appear. In very dark-skinned black persons, the whole nail plate may turn black, beginning proximally and growing distally, and eventually involving the whole nail. Usually all nails are affected, but changes are more marked on the fingernails, especially the thumb. The pigment in the nail plate stains like melanin when examined histologically.
In patients receiving AZT, we have also observed bilateral black pigmentation of the lateral mid-tongue. The pigmentation occurs in the same location as hairy leukoplakia, but the relationship (if any) between the two is unclear; only one of three patients had leukoplakia when the pigmentation appeared.
Cutaneous hyperpigmentation may also be noted, especially in areas exposed to the sun or rubbed by clothing (e.g., the belt line). There may also be an enhanced ability to tan.
| Factors Affecting Hyperpigmentation|
The degree of hyperpigmentation of the nails and skin is related to dosage of AZT. Patients note a decrease in hyperpigmentation when the dose is decreased, and the pigmentation clears if the drug is discontinued. Cutaneous hyperpigmentation on the face may be improved by avoiding sun exposure and using a high sun-protection-factor sunscreen (SPF 15 or higher). Bleaching the skin with 2 to 4% hydroquinone cream is also useful when combined with a sunscreen.
|| ||Berger TG, Jacobson MA, Becker B, et al. Nasal carriage rate of Staphylococcus aureus (SA) in AIDS and ARC patients [abstract]. In: Twenty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy. Houston, 1989.|
|| ||Weaver D, Weissbach N, Kapell K, et al. Topical trifluridine (TFT) treatment of acyclovir-resistant (ACV-R) herpes simplex disease. ICAAC Abstract 1991;507:183.|
|| ||Archibald CP, Schechter MT, Craib KJP, et al. Evidence for a sexually transmitted cofactor for Kaposi's sarcoma in a cohort of homosexual men [poster]. Presented at the VI International Conference on AIDS. San Francisco, 1990;Th.C.630.|