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]. 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 acquired immunodeficiency syndrome (AIDS) [5,6].

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, parasitic, 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 antiretroviral therapy [7,8].

Characteristic fever and rash syndromes in the patient with HIV will be reviewed here. This list is not exhaustive and focuses on syndromes that occur with more frequency in patients with HIV. Additionally, it is important to consider other syndromes that present with fever and rash that can be seen in immunocompetent patients, including those with HIV. (See "Fever and rash in the immunocompetent patient".)

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 are discussed separately. (See "Fever and rash in immunocompromised patients without HIV infection" and "Fever and rash in the immunocompetent patient".)

GENERAL DIAGNOSTIC APPROACH

History and physical — History and physical examination are crucial in the evaluation of a fever and rash, since many dermatologic conditions can be diagnosed based on history and physical examination alone.

Need for urgent evaluation — Certain fever and rash syndromes require immediate attention and evaluation by the evaluating clinician. Most patients presenting with these infections will appear quite ill, although occasionally patients may present in the initial stages of the infection. Fever is almost always present in these patients. These infections are not limited to immunocompromised patients and are discussed in more detail elsewhere. (See "Fever and rash in the immunocompetent patient", section on 'Selected fever and rash emergencies'.)

These syndromes include:

●Toxic shock syndrome (TSS) – generalized macular erythema (picture 1 and picture 2 and picture 3)

●Purpura fulminans – retiform purpura with branched or angular purpuric lesions that can be seen with various infections (eg, invasive streptococcal or meningococcal disease) and disseminated intravascular coagulation (DIC) (picture 4 and picture 5)

●Necrotizing fasciitis and Fournier gangrene – localized erythema (picture 6 and picture 7)

●Rocky Mountain spotted fever (RMSF) – generalized maculopapular and petechial lesions (picture 8 and picture 9 and picture 10)

●Vibrio vulnificus – often bilateral, severe cellulitis with fluid-filled bullae that can become hemorrhagic (picture 11 and picture 12)

●Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) – generalized or localized sloughing of epidermal skin (picture 13 and picture 14 and picture 15 and picture 16 and picture 17 and picture 18)

●Bacterial endocarditis – occasionally present with distal extremity lesions (picture 19 and picture 20 and picture 21)

Characteristics of the rash — A thorough history of the rash should include the following questions [9]:

●Where and when did the rash start?

●What does the rash look like?

●Has the rash progressed in location or changed in appearance?

●What symptoms are associated with the rash (and did any precede the rash)?

●What treatment has been tried and how did it affect the rash?

Details on the evaluation of a rash and how to characterize it is discussed elsewhere. (See "Fever and rash in the immunocompetent patient", section on 'Characteristics of the rash'.)

Epidemiologic exposures/factors — When forming a differential diagnosis, in addition to evaluation and characterization of the rash, we also consider the following:

●Geographic location/travel history – Certain infections are caused by organisms specific to a certain geographic area, such as coccidioidomycosis, histoplasmosis, blastomycosis, leishmaniasis, and talaromycosis (see 'Endemic mycoses' below). Additionally, some infections, such as tuberculosis, are more frequently encountered in certain high prevalence areas versus others. When evaluating a patient with fever, rash, and human immunodeficiency virus (HIV), it is important to ask about country of origin and recent travel history as well as to consider the common infectious organisms that can cause fever and rash in the geographic location of where the patient lives. For example, 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. However, cutaneous and visceral leishmaniasis is often seen in patients with HIV in Brazil, Ethiopia, and the state of Bihar in India [10].

●Recreational activities and exposures – A thorough history of a patient's recreational activities and exposures to animals, certain types of water (eg, freshwater, brackish water, or saltwater), soil, plants, caves, bird droppings, and/or construction/remodeling sites can help gain insight into potential causes of a fever and rash.

Examples of historical clues that suggest certain etiologies are as follows:

Exposure to animals:

•Cats – consider bacillary angiomatosis

•Birds/bird droppings – consider histoplasmosis and cryptococcosis

Diseases associated with specific animal exposures are discussed in detail elsewhere. (See "Zoonoses: Dogs" and "Zoonoses: Cats" and "Zoonoses: Animals other than dogs and cats".)

Environmental exposures:

•Construction/remodeling sites – consider histoplasmosis, blastomycosis, and coccidioidomycosis, depending on geographic location and travel history

•Caves – consider histoplasmosis

•Wound exposure to water – consider nontuberculous mycobacteria, Pseudomonas aeruginosa, and Vibrio vulnificus

•Wound exposure to soil – consider sporotrichosis and nocardiosis

•Decaying vegetation/wood/compost – consider blastomycosis

Exposure to sick contacts:

•Exposure to homeless shelters/prisons or healthcare settings – consider tuberculosis

•Friends or family members with a similar pruritic rash – consider scabies

•Exposure to daycare centers or to young children – consider varicella or parvovirus B19

●Changes to medications – Patients should be questioned about any changes to their medication, including recent start of any new medications (including antiretroviral therapy [ART] and prophylactic antimicrobials in patients with acquired immunodeficiency syndrome [AIDS]) or any over-the-counter remedies and/or herbal supplements. Dermatologic syndromes presenting with fever and rash due to a medication side effect include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (table 1), drug reaction with eosinophilia and systemic symptoms (DRESS) (table 2), exanthematous drug reactions, and acute generalized exanthematous pustulosis (AGEP) (table 3 and table 4).

Examples of typical drugs and the rash syndromes they cause:

•Trimethoprim-sulfamethoxazole – consider cutaneous drug reaction, DRESS, or SJS/TEN [11]

•Dapsone – consider cutaneous drug reaction or DRESS

•Protease inhibitors – consider acute generalized exanthematous pustulosis

•Raltegravir – consider DRESS

•Nevirapine – consider SJS/TEN

•Abacavir – consider hypersensitivity reaction (maculopapular or urticarial rash and systemic symptoms)

●Sexual activity – Unprotected sexual activity with multiple partners increases the risk of sexually transmitted infections (STIs) that can present with fever and a rash. These syndromes include disseminated gonorrhea, syphilis, acute HIV infection, mpox, and genital herpes virus.

●Vaccination history – Vaccination documentation should be obtained, as certain syndromes, such as measles, rubella, or hepatitis B, can be ruled out if the patient has been vaccinated. Additionally, shingles and disseminated zoster are much less likely in someone who has received vaccination against herpes zoster.

●HIV history – Knowledge of the patient's HIV history is crucial to understanding the patient's current state of immunocompromise and to which conditions they are susceptible. A recent HIV viral load and CD4 cell count and the patient's adherence to ART can also be very helpful in narrowing the differential. For example, a rash in a patient recently diagnosed with acute HIV may be caused by acute retroviral syndrome. In patients with CD4 counts <200, certain AIDS-defining conditions should be considered.

Syndromes that generally tend to occur in patients with CD4 counts <200 cells/microL include the following:

•Bacillary angiomatosis

•Kaposi sarcoma (KS)

•Cryptococcosis

•Talaromycosis

•Emergomycosis

Patients with low CD4 counts but with virologic suppression are less likely to present with opportunistic infections.

Physical examination — Physical exam should include a thorough mucocutaneous examination (including genitalia) to evaluate the extent of the rash and determine if various stages of the rash are present. Skin lesions may be the initial sign of a systemic infection. Presence of non-dermatologic abnormalities, such as hepatosplenomegaly or generalized lymphadenopathy, can suggest a systemic disorder. 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 [12-15]. 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 [16].

Exam should also evaluate for any other abnormalities (eg, oral thrush) that may indicate a low CD4 count and the presence of opportunistic infection(s). This can be especially useful in situations where the immune status is not yet established and presence of certain AIDS-defining conditions (eg, oral candidiasis) may modify the differential diagnosis.

Laboratory testing and further evaluation — Occasionally, a diagnosis can be reached simply by history and physical examination, especially if the rash is pathognomonic for a certain condition (eg, scabies, shingles) or the history is straightforward (eg, acute HIV). In other cases, laboratory testing may be helpful in both establishing a diagnosis or in modifying the likelihood of certain conditions (table 5). We consider obtaining the following as initial laboratory testing:

●CD4 cell count and HIV viral load

●Complete blood cell count (CBC) with differential to evaluate for leukocytosis, eosinophilia, and thrombocytopenia

●Comprehensive metabolic panel to evaluate renal and liver function

We determine the need for additional and/or further testing (specific serology or antigen testing, skin sampling for microscopy, cultures, and histopathology) based on our level of suspicion for each condition (table 5). For example, patients with recent sexual activity should receive testing for common STIs, including syphilis, herpes simplex virus, gonorrhea, and chlamydia. Patients who have recently started or restarted ART and/or other medications should be evaluated for immune reconstitution inflammatory syndrome (IRIS) as well as for various drug reactions.

ETIOLOGIES — Fever and rash syndromes are caused by a diverse array of pathology in individuals with human immunodeficiency virus (HIV) (table 5). Conditions listed below are divided by the frequency by which they are seen in clinical practice.

Common conditions

Bacterial skin and soft tissue 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 [17]. 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 [18].

Staphylococcus aureus is a common cause of skin and soft tissue infections. The varied skin manifestations of S. aureus infection include impetigo, ecthyma, folliculitis, purulent cellulitis, abscesses/furuncles, plaques, ulcerations, or ecthyma gangrenosum (picture 22 and picture 23). 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 [19,20] (see "Botryomycosis") or staphylococcal scalded skin syndrome, characterized by diffuse and painful erythema followed by superficial blistering and desquamation (picture 24 and picture 25) (see "Staphylococcal scalded skin syndrome"). Secondary staphylococcal infections of underlying skin disorders such as herpetic ulcers, abrasions/trauma, eczema, adverse cutaneous drug eruptions, and other dermatoses are also common.

HIV infection also appears to increase the risk for community-associated methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections and subsequent recurrences [21,22]. 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 [23]. 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 [24].

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 "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Acute cellulitis and erysipelas in adults: Treatment".)

Syphilis — Syphilis is important to recognize because of its important public health implications, including its association with increased HIV acquisition and increasing seroprevalence [25-27]. The United States Centers for Disease Control and Prevention (CDC) sexually transmitted disease surveillance reports have detailed a dramatic increase in syphilis cases in the United States recently, with a 79 percent increase in reported cases from 2018 to 2022 [28]. 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 [29,30]. 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 [31-33]. (See "Syphilis in patients with HIV".)

●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 26). 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 [34].

●Secondary syphilis – Rash (especially if present on palms and soles) 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. When lesions are seen on the palms and soles, secondary syphilis should be strongly considered (picture 27). 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 [35]. The rash usually begins on the trunk and extremities. 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) [36,37].

●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 in patients without HIV [34,38].

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 a classic combination that accounts for approximately 20 percent of disseminated gonococcal infections (DGI) [39]. The rash typically consists of painless lesions, often between two and ten in number, typically located over trunk, extremities, or soles/palms. The lesions are usually pustular or vesiculopustular, although hemorrhagic macules, papules, or nodules rarely occur (picture 28). Pustular or vesicular skin lesions are often transient and, even without treatment, may only last for three to four days. (See "Disseminated gonococcal infection".)

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 [40]. Additional signs and symptoms include fever, night sweats, fatigue, malaise, generalized lymphadenopathy, sore throat, arthralgias, myalgias, headache, nausea/vomiting, and diarrhea [41,42]. (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, face, 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 [43]. Vesicular, pustular, and urticarial eruptions have also been reported [42,44] 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 [43,45].

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 ribonucleic acid (RNA) and four had greater than 100,000 copies/mL of HIV-1 viral RNA, consistent with acute HIV-1 infection [46]. (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 [47]. In addition, immune reconstitution inflammatory syndrome (IRIS)-associated events involving genital herpes virus infection appear to be more common than other manifestations [7]. (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 [48]. Recurrences are often more frequent, more extensive, and of longer duration than in immunocompetent patients (picture 29A-C).

Of note, HSV type 2 infections may increase the risk of HIV acquisition [49-54]. (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 9 percent of patients with HIV [55-58]. In general, the risk of HZ increases as CD4 cell counts fall [59,60], while the use of effective combination antiretroviral therapy decreases the risk of HZ [61]. However, an increased frequency of varicella-zoster virus (VZV) reactivation can be seen during immune recovery following initiation of antiretroviral therapy (ART) [7,62-64]. (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 [65]. Atypical presentations of HZ also include verrucous varicella, which has been mainly reported in the setting of HIV infection [60,66]. This diagnosis should be considered in the patient with multiple, chronic, wart-like lesions [66,67]. Bullous, necrotic, and hemorrhagic lesions have also been described.

Drug reactions — Drug reactions, particularly cutaneous manifestations, are common in patients with HIV and appear to be directly related to the degree of immunocompromise and subsequent associated polypharmacy [3,68-71]. A morbilliform rash (74 percent) has been most frequently described (particularly with the use of nonnucleoside reverse transcriptase inhibitors or sulfa drugs), followed by urticarial eruptions (17 percent) [3]. Fever may be a prominent part of the clinical presentation.

●Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) – Severe cutaneous reactions such as SJS and TEN are described more frequently in patients with HIV compared to patients without HIV and are commonly associated with sulfa-based drugs [72,73]. The rash presents as a painful, exanthematous rash that evolves into dusky erythema, purpuric spots, and flaccid bullae, and then eventually to skin sloughing. Generalized malaise, fever, myalgias, and mucosal involvement typically accompany the rash. This syndrome must be evaluated and treated urgently. (See 'Need for urgent evaluation' above and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Sulfonamide allergy in HIV-uninfected patients".)

●ART drug reactions – Amprenavir, atazanavir, abacavir, efavirenz, and in particular nevirapine are antiretroviral agents that are most commonly associated with hypersensitivity reactions [74-76]. 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 [77]. Other antiviral 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 [69,78,79]. 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 [80,81]. Resolution of symptoms typically occurs within three days of discontinuation of the agent [82]. Resuming abacavir therapy after the development of this drug hypersensitivity syndrome is not recommended, regardless of HLA-B(*)5701 status. (See "Abacavir hypersensitivity reaction".)

●Other antimicrobial drug reactions – Many drugs can elicit a cutaneous drug reaction, especially some that are widely used for prophylaxis in patients with HIV. 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]. In addition, risk for adverse cutaneous drug reactions secondary to antituberculous therapy is increased in the setting of HIV infection [83,84]. Morbilliform and urticarial rashes are most common. Severe drug-related rashes besides SJS/TEN include drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). (See "Drug eruptions".)

Less common conditions

Immune reconstitution inflammatory syndrome — IRIS is reported in up to 25 percent of patients who begin ART [7,8]. Cutaneous manifestations are common and can be secondary to nearly all of the viral, fungal, mycobacterial, and parasitic infections described in this article. (See "Overview of immune reconstitution inflammatory syndromes", section on 'Clinical manifestations'.)

Nontuberculous mycobacteria — Cutaneous disease may be a clue to underlying disseminated mycobacterial infection. Atypical mycobacteria, including Mycobacterium avium intracellulare and Mycobacterium kansasii, may also present as isolated cutaneous disease [85-87]. Mycobacterium haemophilum, an uncommon cause of mycobacterial infections, primarily presents as cutaneous or subcutaneous disease in the setting of immunocompromise [88]. Lesions associated with mycobacterial infections are polymorphous, highlighting the need to isolate the etiologic agent in culture in order to direct therapy [89-91]. Mycobacterial-associated IRIS may also present with cutaneous manifestations [62,92]. (See "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV" and "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Tuberculosis (TB) — Cutaneous manifestations of TB are uncommon, accounting for between 1.5 to 3 percent of cases of non-pulmonary tuberculosis [93]. The cutaneous manifestations of tuberculous include:

●Scrofuloderma (continuous 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)

●Pustules [94]

Cutaneous miliary tuberculosis, an unusual manifestation of hematogenous dissemination, has been reported in patients with HIV, particularly when the CD4 count is low [95-98]. Initial lesions are papulopustular, macular, and/or vesicular before becoming ulcerative.

For most tuberculous skin manifestations, microscopic examination of the skin lesions will demonstrate numerous acid-fast bacilli. Lesions associated with mycobacterial infections are polymorphous, highlighting the need to isolate the etiologic agent in culture in order to direct therapy [89-91]. Mycobacterial-associated IRIS may also present with cutaneous manifestations [62,92]. (See "Cutaneous manifestations of tuberculosis".)

Bacillary angiomatosis — Bacillary angiomatosis is a vascular skin lesion (picture 30) that can mimic several other conditions (eg, Kaposi sarcoma [KS], pyogenic granuloma, cherry angioma, dermatofibroma, hemangioma, and verruga peruana) and 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 infections.

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 [99]. Intermittent fever is often associated with Bartonella bacteremia and should be considered in patients with acquired immunodeficiency syndrome (AIDS) and fever of unknown origin [100]. (See "Bartonella infections in people with HIV".)

Leishmaniasis — In patients with AIDS, leishmaniasis has been reported to be the second most common tissue-associated protozoan opportunistic infection [101,102]. 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 (picture 31), or visceral leishmaniasis. Maps for endemicity of cutaneous and visceral leishmaniasis are found here (figure 1 and figure 2). Although some Leishmania species are primarily dermatotropic and 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, particularly in patients with HIV [103]. This was illustrated in a report of 32 patients with HIV and visceral leishmaniasis, six of whom had cutaneous lesions [104].

The cutaneous findings of leishmaniasis include macular, papular, nodular, and plaque-like lesions that can later ulcerate (picture 32 and picture 33). 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 [102]. Leishmaniasis as a manifestation of IRIS has also been reported in patients with AIDS [105]. 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".)

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) [106]. Lesions typically involve the extremities, and, less commonly, the ears, face, scalp, back, buttocks, and nailfold areas [107]. Psoriatic-like lesions with significant hyperkeratosis, a maculopapular dermatitis, an erythroderma, and red papules have also been described [108]. (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 [109]. They can become secondarily infected with bacteria, leading to fever, cellulitis, and bacteremia.

Mpox — Mpox traditionally causes a characteristic vesicular eruption (similar to varicella and smallpox) accompanied by fevers, chills, and myalgias. However, during the 2022 mpox outbreak that disproportionately affected patients with HIV (up to 50 percent of affected patients had HIV), many patients presented with genital, anal, and/or oral lesions without the classic systemic symptoms. Additionally, the lesions tended to be more severe, necrotizing, and disfiguring in patients with low CD4 counts [110,111]. The rash progresses through various stages (figure 3). The rash typically starts with 2 to 5mm in diameter macules and then evolves into umbilicated papules, vesicles, and then pseudo-pustules. Eventually the lesions crust over, generally 7 to 14 days after rash onset. The rash is often painful and then becomes pruritic during the crusting phase (see "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Rash').

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 [112]. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection".)

●Serum sickness-like syndrome in acute HBV – Acute hepatitis B infection may be heralded by a serum sickness-like syndrome (SSLR), manifested as fever, skin rash (including urticaria), arthralgia and arthritis, which usually subsides with the onset of jaundice. (See "Serum sickness and serum sickness-like reactions".)

●Polyarteritis nodosa in chronic HBV – Chronic hepatitis B virus infection can be associated with the development of polyarteritis nodosa, and skin lesions may include palpable purpura or livedo reticularis (picture 34 and picture 35 and picture 36). (See "Hepatitis B virus: Clinical manifestations and natural history" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease'.)

Parvovirus B19 — 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 [113]. However, in the setting of HIV, severe, chronic anemia with reticulocytopenia may persist due to impaired humoral responses in those with advanced immunosuppression [114,115]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

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 [116]. 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 37). 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 [117]. 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 38) [118]. Cryptococcal-associated IRIS has been reported and commonly includes lymphadenitis [119]. (See "Cryptococcus neoformans infection outside the central nervous system", section on 'Clinical manifestations'.)

Endemic mycoses — Many dimorphic endemic mycoses can present with dermatologic findings. Suspicion for each fungal infection depends on patient's geographic location and travel history. Of note, the geographic regions of endemicity for these pathogens have expanded over time due to the presumed impacts of climate change and human migration [120].

●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 [121]. Skin lesions appear to be more common in patients with disseminated histoplasmosis who have acquired immunodeficiency syndrome, particularly in Central and South America, when compared to those not coinfected with HIV [122,123].

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 [124,125] (picture 39A-B). Cutaneous histoplasmosis can mimic erythema-multiforme, molluscum contagiosum, pyoderma gangrenosum, vasculitic, exfoliative dermatitis, herpetic, acneiform, and psoriatic-like lesions (picture 40A-B) [124-127]. Lesions are commonly located over the face, chest, and extremities. A Histoplasma-associated IRIS involving the skin has also been reported [128,129]. (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 [CNS] involvement), usually in the setting of advanced immunosuppression [130,131].

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 41A-B and picture 42 and picture 43 and picture 44 and picture 45) [130,131]. A retrospective survey of 15 patients with HIV and blastomycosis included eight patients with disseminated disease [130]. All of these individuals had CD4 counts below 200 cells/microL, and three had evidence of cutaneous disease. (See "Clinical manifestations and diagnosis of blastomycosis".)

●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).

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 [132] (picture 46). A thorough travel history should be obtained, since presentations of fungal disease may be due to reactivation of prior infection. In one report of persons with AIDS and disseminated coccidioidomycosis in the United States, only about one-half of all cases resided in C. immitis-endemic counties [133]. Disseminated coccidioidomycosis with cutaneous lesions as a manifestation of IRIS has also been reported [134,135].

Prevalence of coccidioidomycosis among individuals with HIV has been decreasing [133,136,137]. Data collected after the introduction of combination ART describes a decrease in the severity and incidence of symptomatic coccidioidal infections in endemic areas [137]. (See "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis".)

●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. In patients with AIDS, sporotrichosis more commonly presents with extensive cutaneous involvement (ulcerated and crusted nodules) consistent with underlying disseminated disease (picture 47) [138-142]. These atypical ulcerations are often described as "punched-out" [143]. Following dissemination, bone or joint infection can occur. Disseminated sporotrichosis with skin lesions as a manifestation of IRIS has been reported [144]. (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 [145-147]. 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 [148-150]. (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 48). Genital and oral ulcerations have also been reported [151,152]. Disseminated T. marneffei infection with skin involvement can be seen as a manifestation of IRIS [153,154].

In one series of 80 patients with HIV in Thailand with disseminated T. marneffei infection, 71 percent had skin lesions [155]. In another series of 46 patients in India, skin lesions were reported in 81 percent of cases [156]. A series of 127 patients from northern Vietnam reported skin lesions in 83 percent of cases [157].

●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) [158,159]. Clinical findings typically include fever, weight loss, anemia, elevated liver function tests, and chest radiographic findings that mimic Mycobacterium tuberculosis.

In one study from South Africa detailing emergomycosis in patients with AIDS, 96 percent of patients with disseminated disease had cutaneous lesions [160]. Dermatologic manifestations, seen in most patients with disseminated infection, include umbilicated papules, nodules, plaques, verrucous lesions, 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 KS, drug reactions, or varicella [161]. IRIS-associated cutaneous manifestations of disseminated E. africanus infection have also been reported [162,163].

Kaposi sarcoma (KS) — KS is a vascular tumor associated with infection by human herpesvirus 8 (HHV-8) that is uncommonly associated with fever [164]. 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 or as a consequence of IRIS have been well recognized [165-168]. (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 [169].

Cutaneous lesions occur most commonly on the trunk (picture 49), 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 50), 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 ART, and it is projected that the incidence rate will continue to decline [170]. In fact, KS is no longer the most common HIV-associated tumor [171]. 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 [172,173]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●General – Patients with human immunodeficiency virus (HIV) infection have a defect in cell-mediated immunity that predisposes them to certain bacterial, fungal, parasitic, 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.)

●Diagnostic approach – The diagnostic approach to a patient with HIV who presents with fever and rash includes evaluating for syndromes that require immediate attention (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], meningococcemia), determining the characteristics of the rash, and obtaining medical, sexual, travel, vaccination, and recreational activity/exposure history (table 5). We also consider obtaining HIV viral load and CD4 count if recent results are not available and a complete blood count (CBC) with differential and comprehensive metabolic panel in those who appear to have systemic symptoms.

We determine the need for additional and/or further testing (eg, specific serology or antigen testing, skin sampling for microscopy, cultures, and histopathology) based on our level of suspicion for each condition (table 5). (See 'General diagnostic approach' above.)

●Etiologies – Common causes of fever and rash in this patient population include bacterial skin and soft tissue infections (SSTIs), sexual transmitted infections (STIs) such as syphilis, gonorrhea, acute HIV, and herpes simplex virus (HSV), varicella-zoster infection, and various drug reactions. Less common etiologies include immune reconstitution inflammatory syndrome (IRIS), bacillary angiomatosis, parasitic infections such as scabies or leishmaniasis, mpox, and KS, among others. Certain clues in the patient's history or physical exam that may increase suspicion for a specific cause are outlined in the table (table 5).

•Staphylococcal skin and soft tissue infection – One of the most common infections is Staphylococcus aureus, which can present as impetigo, folliculitis, cellulitis, abscesses, ulcerations, or ecthyma gangrenosum (picture 22 and picture 23). (See 'Bacterial skin and soft tissue infections' above.)

•Secondary syphilis – A diffuse rash is the most characteristic finding, occurring in more than 80 percent of patients. It also often involves the palms and soles (picture 27). (See 'Syphilis' above.)

•Neisseria gonorrhoeae – Fever, rash (picture 28), tenosynovitis, and polyarthralgia are a classic combination that accounts for approximately 20 percent of disseminated gonococcal infections (DGI). (See "Disseminated gonococcal infection".)

•Acute HIV infection – Acute retroviral syndrome is a mononucleosis- or flu-like syndrome that occurs after primary HIV infection in up to 75 percent of cases. A generalized maculopapular skin eruption typically occurs 48 to 72 hours after the onset of fever and persists for five to eight days.

•Herpes viruses – Rash related to herpes viruses (eg, HSV or varicella-zoster virus [VZV]) usually represents reactivation disease. For patients with HIV, 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 (picture 29A-C). Chronic (ie, greater than one month) mucocutaneous infections can also be seen in VZV infections. (See 'Genital herpes virus' above and 'Varicella-zoster virus' above.)

•Drug reactions – Drug reactions, particularly cutaneous manifestations, are common in patients with HIV and appear to be directly related to the degree of immunocompromise. Fever and 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.