Fever and rash in patients with HIV

INTRODUCTION — Before the introduction of effective combination antiretroviral therapy, dermatologic manifestations affected up to 80 to 90 percent of individuals infected with the human immunodeficiency virus (HIV) [1-4]. The frequency of cutaneous manifestations was illustrated in a review of 684 patients with HIV who were followed for almost three years; 540 patients (79 percent) were given one or more (average 3.7) dermatologic diagnoses [3,5]. Importantly, a higher number of mucocutaneous diseases in patients with HIV has been shown to correlate with poor prognosis and a shorter time to the development of AIDS [6,7].

Rash can occur as a manifestation of HIV infection, another infection, some neoplasms, and frequently as a reaction to a drug. The defect in cell-mediated immunity that results from HIV infection predisposes infected individuals to certain bacterial, fungal, mycobacterial, and viral infections, many of which have skin manifestations. In addition, many immune reconstitution inflammatory syndrome-associated events are dermatological and warrant consideration in the individual with HIV who has recently started highly active antiretroviral therapy [8,9].

Characteristic fever and rash syndromes in the patient with HIV will be reviewed here. Recognition of these syndromes may allow for earlier detection of HIV infection and the salutary effects of initiating antiretroviral therapy.

The diagnosis and treatment of the individual diseases as well as the epidemiology, etiology, and diagnostic approach to fever and rash in immunocompromised hosts without HIV and in normal hosts are discussed separately. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in the immunocompetent patient".)

BACTERIAL INFECTIONS — Patients with HIV infection have an increased incidence of bacterial infections, which is related to both deficiencies in T-cell function and dysregulation of humoral immunity in advanced disease. Risk factors associated with the development of skin and soft tissue infections in outpatients with HIV include the presence of certain comorbid conditions (eg, diabetes, psoriasis, and lymphedema), as well as an HIV viral load greater than 1000 copies/mL and the presence of an intravenous catheter [10]. However, the incidence of skin and soft tissue infections in persons with HIV appears to be decreasing. In one report that evaluated the rate of skin and soft tissue infections in patients with HIV who were seen in United States-based emergency departments, the incidence decreased by approximately 15 percent between 2009 and 2014 [11].

Staphylococcus aureus — Staphylococcus aureus is a common cause of skin infection and bacteremia in patients with the acquired immunodeficiency syndrome (AIDS). Risk factors for S. aureus bacteremia include nasal colonization with S. aureus, injection drug use (IDU), lymphedema due to Kaposi sarcoma (KS), neutropenia, and indwelling vascular catheters [12].

Colonization with S. aureus is increased in individuals with HIV, and an increasing number of isolates are methicillin-resistant [13-17]. Risk factors for methicillin-resistant S. aureus (MRSA) include the following: history of prior MRSA infection; recent systemic antibiotic use or hospitalization (ie, within last six months); lower CD4 count; recent sexually transmitted infection; and prior incarceration [18-23]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology".)

HIV infection also appears to increase the risk for community-associated MRSA skin and soft tissue infections and subsequent recurrences [24,25]. In one retrospective cohort study, almost one-third of patients with HIV experienced a recurrent episode of skin and soft tissue infections within the following year [26]. HIV infection is also an independent risk factor for recurrence of infection due to S. aureus in patients with a history of S. aureus bacteremia [27].

The varied skin manifestations of S. aureus infection include impetigo, ecthyma, folliculitis, cellulitis, abscesses/furuncles, plaques, ulcerations, or ecthyma gangrenosum (picture 1 and picture 2). Progression of staphylococcal infections can lead to cutaneous botryomycosis, a plaque-like, nodular, or papular lesion that clinically resembles a fungal infection and is characterized by aggregates of bacteria in the skin [28,29] (see "Botryomycosis"). Secondary staphylococcal infections of underlying skin disorders such as herpetic ulcers, abrasions/trauma, eczema, adverse cutaneous drug eruptions, and other dermatoses should also be considered.

Therapy with antibiotics and debridement or drainage, when indicated, is imperative because these sites can serve as portals of entry for disseminated disease. (See "Impetigo" and "Infectious folliculitis" and "Acute cellulitis and erysipelas in adults: Treatment".)

Bacillary angiomatosis — Bacillary angiomatosis, a vascular skin lesion that can mimic several other conditions (eg, KS (picture 3), pyogenic granuloma, cherry angioma, dermatofibroma, hemangioma, and verruga peruana), is usually seen in patients with HIV when the CD4 cell count is less than 100 cells/microL. These cutaneous lesions result from proliferation of small blood vessels. The etiologic agents of this disease, Bartonella henselae and Bartonella quintana, can also cause bloodstream, liver, lymph node, lung, bone, bone marrow, brain, and heart valve infection. Cat exposure has been associated with B. henselae infections and body louse exposure with B. quintana.

The skin lesions associated with Bartonella, which may be isolated or multiple, are typically hemangiomatous, small, and papular before becoming larger, nodular, and potentially friable with trauma-associated bleeding. Occasional lesions are subcutaneous in location (with or without overlying erythema) and appear cyst-like or manifest as a small tumor-like mass. Ulcerative lesions have also been described [30]. Intermittent fever is often associated with Bartonella bacteremia and should be considered in patients with AIDS and fever of unknown origin [31]. (See "Bartonella infections in people with HIV".)

Neisseria gonorrhoeae — Patients with HIV have an increased rate of gonococcal infection that is related more to sexual behavior than to immunosuppression. Fever, rash, tenosynovitis, and polyarthralgia are typically part of disseminated gonococcal infection (DGI). The rash typically consists of painless lesions, often between two and ten in number, often located over trunk, extremities, or soles/palms. The lesions are usually pustular or vesiculopustular, although hemorrhagic macules, papules, or nodules rarely occur (picture 4). Pustular or vesicular skin lesions are often transient and, even without treatment, may only last for three to four days. (See "Disseminated gonococcal infection".)

Syphilis — Syphilis is important to recognize because of its important public health implications, including its association with increased HIV acquisition and seroprevalence [32,33]. The skin manifestations of syphilis are often an important diagnostic clue, although persons with HIV who have repeat syphilis infection are more likely to be asymptomatic (or at least less symptomatic) than during initial infection [34,35]. When skin lesions are present, they usually present in a manner similar to individuals without HIV; however, some clinical manifestations may be altered in the setting of HIV infection [36-38].

Primary syphilis — The first, or primary stage of syphilis, presents as a chancre usually two to three weeks after sexual contact with an infected partner. A painless papule forms at the mucosal surface where Treponema pallidum, the causative agent of syphilis, was inoculated (picture 5). The papule can grow to 0.5 to 2 cm in diameter, and ulcerate to form a clean-based, well-demarcated lesion with firm and indurated margins. Associated non-tender regional lymph nodes are often seen. Although chancres are usually solitary, multiple chancres can occur, particularly in the setting of HIV infection [39]. (See "Syphilis in patients with HIV", section on 'Early syphilis' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

Secondary syphilis — Rash is the most characteristic finding in secondary syphilis, occurring in more than 80 percent of patients. Secondary syphilis occurs three to six weeks after the primary stage resolves and is characterized by hematogenous dissemination of treponemes. Additional symptoms and signs include malaise, low grade fever, sore throat, lymphadenopathy, alopecia, arthralgias, and headache.

Skin manifestations of secondary syphilis can present in a variety of forms (ie, "the great imitator") including a nonpruritic macular, maculopapular, papular, papulosquamous, nodular, erythroderma, plaque-like, erythema multiforme-like or pustular rash; vesicular lesions are notably absent. The anogenital region and other moist intertriginous areas may contain condylomata lata, wart-like lesions consisting of flat eroded papules. Mucous patches consisting of slightly raised grayish-white painless ulcerations may be seen on mucous membranes. An uncommon but severe nodular-ulcerative presentation of secondary syphilis known as lues maligna has also been reported in patients with HIV infection [40]. The rash usually begins on the trunk and extremities. When lesions are seen on the palms and soles, secondary syphilis should be strongly considered (picture 6). Hair loss with a patchy "moth-eaten" appearance may also be seen.

In most patients with syphilis, the primary chancre resolves prior to the presentation of secondary syphilis. However, overlap of the primary and secondary stages of syphilis has been reported in patients with HIV (9 of 21 in one report) [41,42]. (See "Syphilis in patients with HIV".)

Tertiary syphilis — Gummatous lesions of late benign syphilis can involve any organ, including the skin. Often solitary, gummas can present as ulcerative, nodular, or papulosquamous lesions, usually located over the trunk, extremities, and face. Patients with HIV are reported to have a shorter interval to the development of destructive localized gummatous lesions than HIV-seronegative patients [39,43]. (See "Syphilis: Treatment and monitoring" and "Syphilis in patients with HIV".)

Pneumococcus — The presence of HIV infection substantially increases the risk of invasive pneumococcal infection, particularly when the CD4 count is less than 200 cells/microL [44-48]. Skin manifestations of disseminated pneumococcal infection can include cellulitis and purpura fulminans (picture 7) [49,50].

The incidence of bacteremic pneumococcal disease appears to be decreasing with the use of combination antiretroviral therapy [51,52]. A decrease has also been noted in adults with HIV since the introduction of the pneumococcal conjugate vaccine for children [53]. Since 2012, the use of both pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine are recommended for individuals >19 years of age with HIV. (See "Pneumococcal immunization in adults with HIV".)

Helicobacter cinaedi — Helicobacter cinaedi, a gram-negative spiral-shaped bacillus, can cause (recurrent) cellulitis or erythema nodosum-like lesions, fever, arthritis, and bacteremia in patients with HIV [54-57]. The organism is fastidious and requires special growth conditions. Thus, this infection may be missed if the laboratory is not notified.

MYCOBACTERIAL INFECTIONS — Cutaneous disease may be a clue to underlying disseminated mycobacterial infection. As examples:

●Tuberculosis – The cutaneous manifestations of tuberculous include scrofuloderma (contiguous spread from a deep structure such as lymph node, bone, or joint to overlying skin, leading to a draining, suppurative, nodular process); gummatous lesions (metastatic tuberculous abscesses due to hematogenous spread that progress to draining sinuses and ulcerations); lupus vulgaris (brownish-red papules/plaques involving head, neck, lower extremities, or buttocks, resulting from contiguous infection or hematogenous/lymphatic spread); and pustules [58]. Cutaneous miliary tuberculosis, an unusual manifestation of hematogenous dissemination, has been reported in patients with HIV, particularly when the CD4 count is low [59-62]. Initial lesions are papulopustular, macular, and/or vesicular before becoming ulcerative. Microscopic examination of the skin lesions will demonstrate numerous acid-fast bacilli. (See "Cutaneous manifestations of tuberculosis".)

●Atypical mycobacteria – Atypical mycobacteria, including Mycobacterium avium intracellulare and Mycobacterium kansasii, may also present as isolated cutaneous disease [63-65]. Mycobacterium haemophilum, an uncommon cause of mycobacterial infections, primarily presents as cutaneous or subcutaneous disease in the setting of immunocompromise [66]. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Lesions associated with mycobacterial infections are polymorphous, highlighting the need to isolate the etiologic agent in culture in order to direct therapy [67-69]. Mycobacterial-associated immune reconstitution inflammatory syndrome may also present with cutaneous manifestations [70,71].

VIRAL INFECTIONS — Skin lesions due to viral infections are common in patients with HIV, and include acute HIV infection itself. Since many of these viral infections are vaccine-preventable, a thorough vaccination history should be obtained. (See "Immunizations in persons with HIV".)

Acute HIV infection — Skin rash can be one manifestation of the acute retroviral syndrome, a mononucleosis- or flu-like syndrome that occurs after primary HIV infection in up to 75 percent of cases [72]. Additional signs and symptoms include fever, night sweats, fatigue, malaise, generalized lymphadenopathy, sore throat, arthralgias, myalgias, headache, nausea/vomiting, and diarrhea [73,74]. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Clinical features'.)

A generalized skin eruption typically occurs 48 to 72 hours after the onset of fever and persists for five to eight days. The upper thorax, neck, and face are most often involved though the scalp and extremities, including the palms and soles, may be affected. The lesions are characteristically small (5 to 10 mm), well-circumscribed, oval or round, pink to deeply red colored macules or maculopapules [75]. Vesicular, pustular, and urticarial eruptions have also been reported [74,76] but are not nearly as common as a maculopapular rash. Pruritus is unusual and only mild when present. Oropharyngeal enanthems and ulcerations, as well as anogenital ulcerations can occur [75,77].

Acute HIV infection should be considered in the differential diagnosis of a patient presenting with a mononucleosis-like illness. In a retrospective study of 563 serum samples obtained from patients with suspected mono-like illness with negative heterophile antibody tests, 11 (2 percent) were positive for HIV-1 RNA and four had greater than 100,000 copies/mL of HIV-1 viral RNA, consistent with acute HIV-1 infection [78]. (See "Infectious mononucleosis", section on 'Primary HIV infection'.)

Genital herpes virus — The primary episode of genital herpes simplex virus (HSV) infection usually presents with fever, headache, and malaise, in association with localized symptoms of pain and pruritus in the area of the vesicular lesions. However, most genital HSV infections occurring in patients with HIV reflect reactivation syndromes, and the appearance of lesions is usually not accompanied by fever. Rates of reactivation appear to be inversely correlated with CD4 counts [79]. In addition, immune reconstitution inflammatory syndrome (IRIS)-associated events involving genital herpes virus infection appear to be more common than other manifestations [8]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

The clinical presentation of symptomatic HSV episodes may include extensive mucocutaneous involvement, a variable appearance of genital lesions, and the development of chronic nonhealing and recurrent ulcers. Tumor-like, deep ulcerative, and hypertrophic lesions have also been reported [80]. Recurrences are often more frequent, more extensive, and of longer duration than in immunocompetent patients (picture 8A-C).

Of note, herpes simplex virus type 2 infections may increase the risk of HIV acquisition [81-86]. (See "Screening for sexually transmitted infections" and "Prevention of sexually transmitted infections".)

Varicella-zoster virus — The incidence of herpes zoster (HZ) (including recurrent HZ) is higher in patients with HIV compared with those without concomitant HIV, with recurrent HZ being reported in up to 20 percent of HIV infected patients [87-89]. In general, the risk of HZ increases as CD4 cell counts fall [90,91], while the use of effective combination antiretroviral therapy decreases the risk of HZ [92]. However, an increased frequency of varicella-zoster virus (VZV) reactivation can be seen during immune recovery following initiation of ART [8,70,93,94]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'HIV infection'.)

Like HSV infections, chronic (ie, greater than one month) mucocutaneous infections with VZV are well described in individuals with HIV [95]. Atypical presentations of HZ also include verrucous varicella, which has been mainly reported in the setting of HIV infection [91,96]. This diagnosis should be considered in the patient with multiple, chronic, wart-like lesions [96,97]. Bullous, necrotic, and hemorrhagic lesions have also been described.

Parvovirus — Parvovirus B19 can cause fever, arthralgia and a lacy reticular rash on the trunk and extremities in both immunocompetent and immunocompromised individuals. Cutaneous vasculitis due to human parvovirus B19 has also been reported [98]. However, in the setting of HIV, severe, chronic anemia with reticulocytopenia may persist due to impaired humoral responses in those with advanced immunosuppression [99,100]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Hepatitis B — Because of shared routes of transmission, patients with HIV may also acquire hepatitis B virus through unprotected intercourse with a chronically infected partner or through injection drug use [101]. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)

Acute hepatitis B infection may be heralded by a serum sickness-like syndrome, manifested as fever, skin rash (including urticaria), arthralgia and arthritis, which usually subsides with the onset of jaundice. Chronic hepatitis B virus infection can be associated with the development of polyarteritis nodosa, and skin lesions may include palpable purpura or livedo reticularis. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease'.)

FUNGAL INFECTIONS — Skin lesions may be the initial sign of a systemic fungal infection. Endemic fungi must be considered in any patient with HIV, skin lesions, and systemic disease. Fungi can disseminate when cell-mediated immunity falls, either during the acute stage of infection or as a result of reactivation of prior disease [102-105]. Patients with HIV may harbor more than one fungus responsible for systemic infection and associated cutaneous manifestations, underscoring the importance of histopathologic and microbiologic evaluation of suspicious skin lesions [106].

Cryptococcosis — Cryptococcus neoformans is an encapsulated yeast that is found worldwide. It is a common opportunistic infection in immunosuppressed patients with AIDS, particularly when the CD4 count is <100 cells/microL.

Approximately 10 percent of patients with HIV who develop cryptococcal infection have cutaneous manifestations of disease [107]. Skin lesions secondary to C. neoformans may represent the sentinel clue to underlying disseminated infection.

The skin lesions of cryptococcosis may be quite diverse, but ulcers, nodules, papules, pustules, or molluscum contagiosum-like centrally umbilicated vesicular lesions are commonly described (picture 9). Presentations can also mimic cellulitis or cutaneous malignancies such as basal cell or squamous cell carcinoma(s). Lesions are frequently located on the head and neck [108]. Since cryptococcal skin infection can mimic molluscum contagiosum, a helpful diagnostic clue for cryptococcosis is the finding of a small hemorrhagic center in the lesion and a rapid onset of development of the papules (picture 10) [109]. Cryptococcal-associated immune reconstitution inflammatory syndrome (IRIS) has been reported and commonly includes lymphadenitis [110].

Histoplasmosis — Histoplasmosis is a dimorphic fungus concentrated in the Ohio and Mississippi River valleys in the United States. It is also found in the Caribbean, Central America, South America, Cuba, Southeast Asia, and Africa.

Patients with HIV can acquire primary histoplasmosis infection when visiting areas of endemicity, or can develop reactivation disease many years later, particularly in the setting of advanced immunosuppression [111]. Skin lesions appear to be more common in patients with disseminated histoplasmosis who have acquired immunodeficiency syndrome when compared to those not coinfected with human immunodeficiency virus [112].

Approximately 10 percent of patients with HIV and disseminated histoplasmosis have mucocutaneous manifestations including oropharyngeal ulcerations, macules, papules, pustules, plaques (can be verrucous), nodules, necrosis, or vesicles [113,114]  (picture 11A-B). Cutaneous histoplasmosis can mimic erythema-multiforme, molluscum contagiosum, pyoderma gangrenosum, vasculitic, exfoliative dermatitis, herpetic, acneiform, and psoriatic-like lesions (picture 12A-B) [113-116]. Lesions are commonly located over the face, chest, and extremities. A Histoplasma-associated IRIS involving the skin has also been reported [117,118]. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis".)

Blastomycosis — Blastomyces dermatitidis is a dimorphic fungus seen in the south-central and Midwestern United States, northern New York, the southeastern provinces of Canada, and Africa. Blastomycosis can present with severe disseminated disease (including central nervous system involvement), usually in the setting of advanced immunosuppression [119,120]. (See "Clinical manifestations and diagnosis of blastomycosis", section on 'Extrapulmonary blastomycosis'.)

The skin is the most common site of extrapulmonary involvement, and possible dermatologic manifestations of blastomycosis include papules, pustules, ulcers, subcutaneous nodules, cold abscesses, or verrucoid lesions (picture 13A-B) [119,120]. A retrospective survey of 15 patients with HIV and blastomycosis included eight patients with disseminated disease [119]. All of these individuals had CD4 counts below 200 cells/microL, and three had evidence of cutaneous disease.

Coccidioidomycosis — The dimorphic fungus Coccidioides immitis is endemic in the southwestern United States, including California, Arizona, New Mexico, Utah, Nevada, and Texas, and also in Mexico and Central and South America (particularly Argentina). A prospective study of patients with HIV in a highly endemic area in Arizona reported the development of active coccidioidal infection in approximately 25 percent of this cohort during 3.5 years of follow-up [121]. In another analysis, one percent of AIDS patients residing in counties of the United States endemic for this fungus had coccidioidomycosis [122]. Subsequent data after the introduction of combination ART described a decrease in the severity and incidence of symptomatic coccidioidal infections in a coccidioidomycosis-endemic area [123]. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis".)

Hematogenous dissemination of this organism can manifest cutaneously. Skin lesions in this disease may take many forms, including pustules, nodules, ulcers, verrucous plaques, and erythematous papules; though nonspecific, these lesions are usually hemorrhagic [124]  (picture 14). A thorough travel history should be obtained, since presentations of fungal disease may be due to reactivation of prior infection. Of note in one report of persons with AIDS and disseminated coccidioidomycosis, only about one-half of all cases resided in C. immitis-endemic countries [122]. Disseminated coccidioidomycosis with cutaneous lesions as a manifestation of IRIS has also been reported [125].

Sporotrichosis — Sporothrix schenckii is a dimorphic fungus that is ubiquitous in warmer areas of the world. Cutaneous manifestations of infection may occur from direct inoculation through the skin as a localized, lymphocutaneous infection, classically following trauma involving a rose thorn or soil. Less commonly, sporotrichosis presents with extensive cutaneous involvement (ulcerated and crusted nodules) in patients with advanced AIDS consistent with underlying disseminated disease (picture 15) [126-128]. These atypical ulcerations are often described as "punched-out" [129]. Following dissemination, bone or joint infection can occur. Disseminated sporotrichosis with skin lesions as a manifestation of IRIS has been reported [130]. (See "Clinical features and diagnosis of sporotrichosis".)

Talaromyces (formerly Penicillium) marneffei — Talaromyces (formerly Penicillium) marneffei is an endemic dimorphic fungal pathogen in Southeast Asia, northeastern India, and southern China [131-133]. The clinical presentation often includes weight loss, fever, skin lesions, respiratory symptoms, peripheral lymphadenopathy, transaminitis, and anemia. Disseminated disease usually occurs when the CD4 cell count is less than 50 to 100 cells/microL and most commonly involves the skin, blood, bone marrow, lymph nodes, liver, and lungs [134,135]. (See "Epidemiology and clinical manifestations of Talaromyces (Penicillium) marneffei infection".)

Papular skin lesions, often with central umbilication, are typically located on the trunk and face and may resemble molluscum contagiosum (picture 16). Genital and oral ulcerations have also been reported [136,137]. Disseminated T. marneffei infection with skin involvement can be seen as a manifestation of IRIS [138,139].

In one series of 80 patients with HIV in Thailand with disseminated T. marneffei infection, 71 percent had skin lesions [140]. In another series of 46 patients in India, skin lesions were reported in 81 percent of cases [141]. A series of 127 patients from northern Vietnam reported skin lesions in 83 percent of cases [142].

Emergomyces (formerly Emmonsia) species — Emergomyces (formerly Emmonsia) species are dimorphic fungi that can cause human disease. In South Africa, Emergomyces africanus is the most common endemic mycosis and has been reported to cause disseminated infection in patients with HIV and low CD4 counts (usually <100 cells/microL) [143,144]. Clinical findings typically include fever, weight loss, anemia, elevated liver function tests, and chest radiographic findings that mimic Mycobacterium tuberculosis.

Dermatologic manifestations, seen in most patients with disseminated infection, include papules, plaques, and ulcers, similar to those lesions seen in other disseminated fungal infections, such as sporotrichosis and histoplasmosis. In other cases, lesions have been originally misdiagnosed as Kaposi sarcoma, drug reactions, or varicella [145]. IRIS-associated cutaneous manifestations of disseminated E. africanus infection have also been reported [146,147].

Pneumocystis — Pneumocystis jirovecii (formerly Pneumocystis carinii) most commonly causes pneumonia in immunocompromised patients including those with AIDS, but extrapulmonary disease including cutaneous manifestations has been reported [148]. Skin findings include macular, papular, polypoid, nodular, and molluscum contagiosum-like lesions [149-151].

PARASITIC INFECTIONS — In the United States, parasitic infections with cutaneous manifestations are not common in patients with HIV, with the exception of scabies, which has a worldwide distribution. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

Cutaneous manifestations may also be present in the setting of leishmaniasis. High Leishmania-HIV coinfection rates have been reported in Brazil, Ethiopia, and the state of Bihar in India [152]. (See "Cutaneous leishmaniasis: Epidemiology and control" and "Visceral leishmaniasis: Epidemiology and control".)

Scabies — In patients with HIV, scabies can be widespread as a result of hyperinfestation, presenting as a diffuse, intensely pruritic, erythematous, papulosquamous or papulovesicular eruption (ie, crusted scabies) [153]. Lesions typically involve the extremities, and, less commonly, the ears, face, scalp, back, buttocks, and nailfold areas [154]. Psoriatic-like lesions with significant hyperkeratosis, a maculopapular dermatitis, an erythroderma, and red papules have also been described [155]. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

These highly infectious lesions contain thousands to millions of organisms and are a source for nosocomial infection [156]. They can become secondarily infected with bacteria, leading to fever, cellulitis, and bacteremia.

Leishmaniasis — In patients with AIDS, leishmaniasis has been reported to be the second most common tissue-associated protozoan opportunistic infection [157,158]. Leishmaniasis can be classified geographically into New World versus Old World disease, and infections by the various species can be divided into cutaneous, diffuse cutaneous, mucocutaneous, or visceral leishmaniasis. Although some Leishmania species are primarily dermatotropic, while others are mainly viscerotropic, it has become increasingly clear that some species frequently associated with visceral leishmaniasis can produce skin lesions, and conversely, species usually found in the skin can disseminate viscerally. This was illustrated in a report of 32 patients with HIV and visceral leishmaniasis, six of whom had cutaneous lesions [159].

The cutaneous findings of leishmaniasis include macular, papular, nodular, and plaque-like lesions that can later ulcerate. Patients with HIV are at increased risk for Leishmania infection, and may present with more severe and atypical disease. They also have a decreased likelihood of responding to therapy, and an increased likelihood of relapse [158]. Leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome has also been reported in patients with AIDS [160]. More detailed discussions of the dermatologic presentations associated with the various forms of leishmaniasis are presented elsewhere. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis" and "Cutaneous leishmaniasis: Clinical manifestations and diagnosis".)

KAPOSI SARCOMA — Kaposi sarcoma (KS) is a vascular tumor associated with infection by human herpesvirus 8 [161], but it is rarely associated with fever. KS is described most frequently among individuals with HIV and advanced immunosuppression. However, KS can present at any CD4 count, and cases presenting soon after initiation of ART have been well recognized [162,163]. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis".)

KS lesions do not blanch and initially appear as papular or patch-like, but later develop into plaques or nodules that can coalesce or ulcerate. The color of these lesions changes with time from light brown or pink to a darker violet, which can be confused with cutaneous Bartonella (see 'Bacillary angiomatosis' above). Other cutaneous variants are described as patch-like, exophytic, keloidal, telangiectatic, infiltrative, lymphangioma-like, cystic-like, bullous, lymphadenopathic, or ecchymotic [164].

Cutaneous lesions occur most commonly on the trunk (picture 17), the extremities, and the face, and are often asymptomatic. Oral lesions associated with KS are classically found on the hard palate, although the tonsils, gingiva (picture 18), soft palate, tongue, or lips may be involved. In addition to mucocutaneous involvement, KS can involve lymph nodes, the lungs, the gastrointestinal tract, and other visceral organs. (See "AIDS-related Kaposi sarcoma: Staging and treatment".)

In the United States, the incidence, mortality, and morbidity of KS has declined significantly since the introduction of effective combination antiretroviral therapy (ART), and it is projected that the incidence rate will continue to decline [165]. In fact, KS is no longer the most common HIV-associated tumor [166]. In the era of combination ART, the most common cutaneous cancers in patients with HIV infection are non-AIDS-defining cancers, such as basal cell and squamous cell carcinomas [167,168].

DRUG REACTIONS — Drug reactions, particularly cutaneous manifestations, are common in patients with HIV and appear to be directly related to the degree of immunocompromise [3,169-172]. A morbilliform rash (74 percent) has been most frequently described (particularly with the use of nonnucleoside reverse transcriptase inhibitors), followed by urticarial eruptions (17 percent) [3]. Fever may be a prominent part of the clinical presentation.

In one review of 684 patients with HIV infection, trimethoprim-sulfamethoxazole, sulfadiazine, trimethoprim-dapsone, and amino penicillins were associated with the highest incidence of adverse cutaneous drug reactions [3]. Amprenavir, atazanavir, abacavir, efavirenz, and nevirapine are antiretroviral agents that are most commonly associated with hypersensitivity reactions [173-175]. Enfuvirtide, a fusion inhibitor, almost always results in a local injection site reaction, which includes pain/discomfort, induration, erythema, nodules/cysts, pruritus, and/or ecchymosis [176]. Other anti-HIV agents, including integrase strand transfer inhibitors (eg, bictegravir, dolutegravir, elvitegravir, raltegravir), rilpivirine, tipranavir, darunavir, etravirine, and maraviroc, have also been associated with adverse cutaneous reactions of various types [170,177,178]. A more detailed discussion of the individual agents is presented elsewhere. (See "Overview of antiretroviral agents used to treat HIV".)

Abacavir, a nucleoside reverse transcriptase inhibitor, causes a well-described hypersensitivity reaction in approximately 5 percent of patients within six weeks of beginning this antiretroviral nucleoside reverse transcriptase inhibitor. This hypersensitivity reaction consists of rash (typically maculopapular or urticarial in appearance), fever, constitutional symptoms, respiratory symptoms, and GI complaints. Patients at risk for developing this reaction can be identified by pharmacogenetic screening for the human leukocyte antigen (HLA) HLA-B(*)5701 allele [179,180]. Resolution of symptoms typically occurs within three days of discontinuation of the agent [181]. Resuming abacavir therapy after the development of this drug hypersensitivity syndrome is not recommended, regardless of HLA-B(*)5701 status. (See "Abacavir hypersensitivity reaction".)

Severe cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are described more frequently in patients with HIV compared to HIV-seronegative patients and are commonly associated with sulfa-based drugs [182,183]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Sulfonamide allergy in HIV-uninfected patients".)

In addition, risk for adverse cutaneous drug reactions secondary to antituberculous therapy is increased in the setting of HIV infection [184,185].

The immune reconstitution syndrome is reported in up to 25 percent of patients who begin ART [8,9]. Cutaneous manifestations are common and can be secondary to viral, fungal, mycobacterial and parasitic infections.

SUMMARY AND RECOMMENDATIONS

●Patients with chronic HIV infection have a defect in cell-mediated immunity that predisposes them to certain bacterial, fungal, mycobacterial, and viral infections, many of which have cutaneous findings. Rash can also occur secondary to a drug reaction, underlying Kaposi sarcoma (KS), or as a manifestation of acute HIV infection itself. (See 'Introduction' above.)

●Patients with HIV infection have an increased incidence of bacterial infections that is related to both deficiencies in T cell function and dysregulation of humoral immunity in advanced disease. One of the most common infections is Staphylococcus aureus, which can present as impetigo, folliculitis, cellulitis, abscesses, ulcerations, or ecthyma gangrenosum. Bartonella infection occurs in patients with advanced immunosuppression and usually presents with cutaneous lesions that are violaceous in appearance due to the vascular nature. Rash is the most characteristic finding in secondary syphilis, occurring in more than 80 percent of patients. (See 'Bacterial infections' above.)

●Rash related to herpes viruses (eg, herpes simplex virus or varicella-zoster virus) usually represents reactivation disease. Parvovirus B19 can cause fever, arthralgia, and a lacy reticular rash on the trunk and extremities in both immunocompetent and immunocompromised individuals, although patients with HIV and advanced immunosuppression are at risk for chronic anemia. (See 'Viral infections' above.)

●Endemic fungi must be considered in any patient with HIV, skin lesions, and systemic disease. Fungi can disseminate when cell-mediated immunity falls, either during the acute stage of infection or as a result of reactivation of prior disease. One of the most common fungal infections in patients with HIV includes cryptococcosis, which can present with a variety of cutaneous lesions including ulcers, nodules/papules, pustules, or molluscum contagiosum-like centrally umbilicated vesicular lesions. (See 'Fungal infections' above.)

●In the United States, parasitic infections with cutaneous manifestations are not common in patients with HIV, with the exception of scabies, which has a worldwide distribution. Among patients with HIV, scabies can be widespread, presenting as a diffuse erythematous papulosquamous eruption. Cutaneous manifestations can also be seen in the setting of leishmaniasis. (See 'Parasitic infections' above.)

●KS may present with oral or cutaneous involvement. Papular or patch-like KS lesions later develop into plaques or nodules. The color of these lesions changes with time from light brown or pink to a darker violet. KS is a manifestation of human herpes virus-8, but is rarely associated with fever. (See 'Kaposi sarcoma' above.)

●Drug reactions, particularly cutaneous manifestations, are common in patients with HIV and appear to be directly related to the degree of immunocompromise. Fever and a diffuse morbilliform or urticarial rashes have been reported along with fever. (See 'Drug reactions' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.