Abstract
With the advent of highly active antiretroviral therapy (HAART), life-threatening opportunistic infection has become less common in patients with HIV infection and longevity has increased dramatically. With increased longevity, the problems of living with a chronic disease have become more prominent in this patient population. Disorders such as fat redistribution and metabolic abnormalities can result from antiviral medications and from HIV disease itself. Pruritus is one of the most common symptoms encountered in patients with HIV.
The spectrum of skin diseases in such patients encompasses dermatoses of diverse etiologies; a few are peculiar to patients with HIV while others are not. Some of these conditions may cause severe and sometimes intractable pruritus that provokes scratching, picking, disfigurement, sleep loss, and significant psychological stress. Moreover, the expense of ongoing medical treatments can be daunting. Skin rash can sometimes be the initial presentation of HIV infection or serve as a harbinger of disease progression.
Causes of pruritus include skin infections, infestations, papulosquamous disorders, photodermatitis, xerosis, drug reactions, and occasionally lymphoproliferative disorders. Drug eruptions are particularly common in patients who are HIV positive, presumably as a result of immune dysregulation, altered drug metabolism, and polypharmacy. Itching can also result from systemic diseases such as chronic renal failure, liver disease, or systemic lymphoma.
Workup of pruritus should include a careful examination of the skin, hair, nails, and mucous membranes to establish a primary dermatologic diagnosis. If no dermatologic cause is found, a systemic cause or medicationrelated etiology should be sought. Idiopathic HIV pruritus is a diagnosis of exclusion and should only be considered when a specific diagnosis cannot be established.
The management of HIV-associated pruritus should be directed at the underlying condition. Phototherapy has been found to be useful in the treatment of several HIV-associated dermatoses and idiopathic pruritus as well. Unfortunately, some of the treatments that have been suggested for patients with HIV are anecdotal or based on small uncontrolled studies. The last decade has seen a surge in the utilization of HAART which, to some degree, reconstitutes the immune system and ameliorates some dermatologic diseases. On the other hand, some skin diseases flare temporarily when HAART is started. Unless frank drug allergy is suspected, HAART does not need to be stopped.
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The skin is probably the organ most commonly affected in patients with HIV. With the introduction of highly active antiretroviral therapy (HAART), many patients are living longer[1] and display chronic skin conditions that can be challenging to the dermatologist. Among the conditions affecting the integument in this population, some can cause severe and, at times, intractable pruritus that provokes sleep loss, scratching, and picking that sometimes leads to disfigurement and major psychological stress.[2] The cost of physician visits, medications, and treatments, that may or may not be covered by health insurance plans, not to mention time lost from work, causes added financial pressures to patients and their families. The range of skin diseases in patients who are HIV-positive is broad, encompassing both HIV and non-HIV related dermatoses. For example, skin rash can be the initial presentation of HIV infection, or serve as the harbinger of disease progression. The immune status of the patient, reflected in the CD4 T-cell count and viral load, is an important parameter since there is often a strong correlation between the CD4 count and the presence of particular HIV-associated rashes. A number of skin diseases initiate a chronic ‘itch-scratch-itch cycle’ that can result in lichenification, excoriation, prurigo nodularis, pigmentary alteration, and secondary infection.
Recent advances in the field of cutaneous neurobiology have elucidated some mechanisms underlying pruritus but our understanding of these mechanisms is still in its infancy. It is thought that both central and peripheral neurologic mediators may be involved. A number of chemical mediators including histamine, serotonin, prostaglandins, cytokines, proteases, tachykinins (e.g. substance P), and opioid peptides are thought to be involved on a local level.[3]
The causes of pruritus in patients infected with HIV include many ordinary dermatoses, some of which may be more severe or more common in the setting of HIV infection. They include papulosquamous disorders, infestations, infections, drug eruptions and occasionally lymphoproliferative disorders such as cutaneous T-cell lymphoma (CTCL). A variety of conditions peculiar to patients with HIV infection have been described. Atypical cutaneous lymphoproliferative disorder (ACLD), also called pseudo-Sezary or CTCL-simulant, presents as a pruritic, widespread eruption with pigmentary changes and an atypical lymphocytic infiltrate. This condition has been reported in patients with late-stage HIV infection and rarely progresses to frank lymphoma.[4]
Drug eruptions are more common in patients with HIV infection than in their non-HIV-infected counterparts,[5] purportedly as a result of immune dysregulation, altered drug metabolism, and polypharmacy. They include morbilliform drug eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug hypersensitivity syndrome, and photodermatitis related to sulfonamides, sulfones, and antiviral treatment. The protease inhibitor, indinavir may cause a pruritic eruption.[6]
Some patients with HIV infection develop systemic diseases that can cause pruritus. Among these are end-stage renal disease from HIV nephropathy, chronic liver disease possibly from hepatitis B or C, or HAART-induced hepatotoxicity, hypothyroidism, and systemic lymphoma.[7–11] Evaluation should include head-to-toe physical examination concentrating on the integument with laboratory testing dictated by the findings on history and physical exam. In addition, the patient’s immune status should be assessed by CD4 T-cell count and viral load. Optimum anti-viral therapy should be instituted since it not only slows the progression of HIV infection and increases life expectancy, but also reportedly reverses certain HIV-related skin disorders.[12] Some conditions such as eosinophilic folliculitis may be temporarily exacerbated on the initiation of HAART.[13,14]
1. Infections and Infestations
Infectious etiologies of pruritus such as scabies, pediculosis, and folliculitis are encountered commonly in the HIV-infected population but the incidence is not uniform in all risk groups. Scabies may be more common in patients who acquired HIV via sexual contact. A recent Japanese study showed a lower incidence of certain infectious diseases such as molluscum contagiosum, condyloma acuminata, and scabies in hemophiliac patients with HIV, when compared with patients infected with HIV via methods other than blood transfusion.[15]
Several presentations of scabies, both usual and unusual, have been reported in the setting of HIV infection. These include typical interdigital burrows, nodular scabies, and crusted scabies (see figure 1 and figure 2). Nodular scabies presents as erythematous nodules on the scrotum, penis, axillae, groin, and upper back. It is a hypersensitivity reaction to mite proteins so usually evident only in patients with intact cell-mediated immunity in early HIV infection or after HAART treatment. Nodular scabies may be confused with arthropod bites or with lymphomatoid papulosis.
Crusted scabies in a patient with HIV.
Typical scabetic burrows in a patient with HIV.
Patients with severe immune suppression may present with overwhelming scabies mite infestations that may not be very pruritic because of absent cell-mediated inflammation. Patients with scabies who are on HAART with attendant immune reconstitution can display significantly greater pruritus than patients with crusted scabies. Itching may be worse at night.
Crusted scabies presents with localized or widespread hyperkeratotic plaques located on almost any part of the body. It can occur in typical areas of scabetic involvement such as the web spaces of the hands, the genitals, and periaxillary region but also in areas not usually involved such as the scalp and beard area. The palms of the hands and soles of the feet may also be involved. It can also present as generalized scaling. The presence of a dirty grayish-brown scale in what appears to be a typical case of severe xerosis, atopic dermatitis, or psoriasis suggests the diagnosis. It is recommended that microscopic examination of skin scrapings be performed to identify mites, eggs, or mite excreta. The presence of itching should be sought in household contacts as a diagnostic clue.
There are several important considerations in the treatment of patients with scabies infestations. Since it is highly contagious and may be spread via fomites, clothing and linens should be carefully laundered in hot water. Another option is to isolate possibly infested garments in a closet for a few days before wearing them. This is a reasonable course of action because mites can only live a few days off the body. Family members should be offered treatment to prevent ongoing reinfection in the household. Patients with crusted scabies shed considerable amounts of mite-containing scales, which may contaminate the household environment. A recent study examining the households of patients with scabies showed scabies mites in dust samples from 44% of infested patients’ homes. Live mites were identified in 64% of these homes, most often from bedroom floors or overstuffed chairs and couches.[16]
The usual treatment of scabies infestation in non-pregnant, adult patients includes the use of topical scabicides such as lindane lotion or 5% permethrin cream, applied for 8–12 hours from the neck down before rinsing off. This is repeated a week later. In patients with crusted scabies, more aggressive therapy is advocated. Topical keratolytics such as urea or lactic acid can be applied to remove scale crust followed by more frequent use of topical scabicides. Recurrences resulting from resistance to medication are uncommon. Inadequate treatment can result however, because of the sheer number of mites and eggs, from failure to apply sufficient scabicide, neglecting areas like the distal subungual nail beds, reinfection, or forgetting to treat fomites.
Oral ivermectin approved for the treatment of onchocerciasis, given once weekly at a dose of 200 μg/kg bodyweight for a total of two doses is an effective treatment for patients with crusted scabies. Although not approved for the treatment of patients with scabies infestation, it has an excellent safety record. In 19 patients without HIV who were treated for scabies with two doses of ivermectin a week apart, there was a transient exacerbation of pruritus 24–72 hours after the first dose of the study medication.[17] One study comparing one or two applications of ivermectin with one overnight application of permethrin in the treatment of patients with non-crusted scabies, found permethrin to be superior to a single dose of ivermectin and equivalent to two doses of ivermectin.[18] Although there are no published data comparing the combination of ivermectin and permethrin with either agent alone in the treatment of patients with crusted scabies, it may be advantageous to use the two agents together in such patients. Ivermectin therapy should not be prescribed for children under 33lb (15kg), and it should be prescribed only with caution in women who are breast-feeding. Although it appears to have a good safety profile in pregnancy, we do not treat scabies in pregnant women with ivermectin.[19]
Antipruritic agents and topical corticosteroids may be helpful for relief of itching and antibacterials are indicated for the treatment of secondarily infected lesions. Scabetic nodules require treatment with intralesional corticosteroid injections.
Patients sometimes acquire pediculosis pubis (Phthirus) in hair-bearing areas of the body, with itching as the dominant symptom. The pubic area should be closely searched for nits, crab lice, and maculae ceruleae (blue-gray spots where lice have fed). The blue color is caused by the action of louse saliva on hemoglobin products. Pubic lice may also colonize other hairy areas of the body, including the trunk in individuals with a lot of hair, axillae, eyelashes, and occasionally the scalp. Treatment includes agents such as permethrin, lindane lotion and malathion lotion.
Body louse infestation caused by pediculosis corporis is much less common but should be considered in patients who are homeless. In such cases, excoriations sometimes with secondary infection, papular bite reactions, and post-inflammatory pigmentary changes are often observed. Lice sometimes can be found on the body but, more commonly, are lurking in the seams of clothing.
Staphylococcus aureus is a frequent cause of cutaneous and systemic bacterial infections in patients with HIV. S. aureus folliculitis is particularly common. It is characterized by widely distributed pruritic, follicular pustules, and excoriated papules, most commonly located on the arms and legs. Staphylococcal impetigo may be seen in the axillae and groin. It presents as tender erythematous erosions sometimes with satellite follicular pustules. Staphylococci may also exacerbate HIV-related atopic-like dermatitis. Staphylococcal furuncles, abscesses, ecthyma, and cellulitis are sometimes encountered in patients with HIV (figure 3). We have seen some patients with localized staphylococcal infections presenting as ulcerations in the genital area that cleared completely on systemic antibacterials.
Staphylococcal abscesses in a patient with HIV and leukopenia.
A chronic recalcitrant ‘toxic-shock-like’ disorder has been described in patients infected with HIV.[20] These patients usually present with widespread scaly, peeling erythroderma. S. aureus can also superinfect molluscum contagiosum lesions and cause them to feel itchy.
In some studies, such as that of Raviglione et al.,[21] higher rates of staphylococcal nasal colonization were documented in patients with HIV, suggesting a causative role in cutaneous staphylococcal infections. However, other investigators who examined the relationship between nasal carriage rates and disease manifestations did not find a significant correlation.[22] Although increased nasal carriage of staphylococci might be a source of frequent staphylococcal skin infections, it might also reflect a generalized susceptibility to staphylococcal colonization perhaps as a result of alterations in adhesion molecules.
Treatment of staphylococcal infections includes oral antibacterials such as dicloxacillin, cefalexin, clindamycin or ciprofloxacin, and topical treatment with antibacterial cleansers such as chlorhexidine gluconate and topical antibacterial preparations like mupirocin. Although, mupirocin ointment applied intranasally in patients with HIV eradicated S. aureus for several weeks, the effect waned over time with persistently negative cultures in 63, 45 and 29% of patients at 2, 6, and 10 weeks respectively.[23]
2. Non-Infectious Skin Diseases
2.1 Atopic-Like Dermatitis
Some patients with HIV infection develop a dermatitis that strongly resembles atopic dermatitis and is sometimes referred to as atopic-like dermatitis.[24,25] Although some of these patients have a personal or family history of atopy such as asthma or seasonal allergic rhinitis, the majority never experienced childhood eczema. There is often generalized xerosis and areas of flexural or extensor lichenification on the arms, legs, and neck. Extensive excoriation is usual and secondary infection and prurigo nodularis lesions are common. According to a recent survey of individuals with HIV, up to 29% of those interviewed had atopic manifestations, including chronic pruritic rashes or eczema.[26] Many of these patients had a personal or family history of allergic rhinitis and asthma.
A hyperimmunoglobulinemia E (hyper-IgE)-like syndrome has been described in patients with AIDS with hypereosinophilia, hyper-IgE, chronic dermatitis and recurrent staphylococcal infections.[27] The immunologic mechanisms in this condition seem to differ from those known in primary hyper-IgE syndrome, because CD4+ T helper (Th) 2 type cells, which are currently believed to have a role in IgE production, are severely depleted in patients with AIDS.[28]
It is currently thought that ordinary atopic dermatitis is initiated, in predisposed individuals, by a Th2-dominant (type-2) cytokine milieu that goes on, in chronic lesions, to express the Th1 cytokine, interferon-γ. There is some evidence that patients with advanced HIV infection may develop a predominance of type-2 cytokines and this is thought by some to predispose to atopic manifestations. It has also been suggested that an allergen specific IgE mechanism may contribute to eczematous reactions in HIV-infected patients.[29]
Treatment of atopic-like dermatitis includes skin hydration, avoidance of irritants, application of emollients, and the use of topical corticosteroid preparations, preferably ointments. Since these patients are frequently infected with staphylococci, oral antibacterials may be indicated. We have also had success using topical tacrolimus ointment to treat several patients and more recently using pimecrolimus cream. The more challenging cases are those with widespread lichenification or eczematous dermatitis. These will sometime require systemic corticosteroids for flares. They should be started on phototherapy as soon as feasible in order to limit systemic adverse effects or theoretical exacerbation of immunosuppression from long-term corticosteroid use.
2.2 Psoriasis
Patients with HIV can present with psoriasis that may sometimes be pruritic (figure 4). It is controversial whether the incidence of psoriasis is greater in patients with HIV but the incidence of psoriatic arthritis is definitely increased.[30] Psoriasis in patients with HIV is frequently more extensive, destructive, and therapy-resistant than its counterpart in immunocompetent patients. There is often a more acral distribution; psoriatic arthritis, and destructive nail changes may be prominent.
Severe psoriasis in a patient with HIV.
In patients with known risk for HIV exposure, new onset psoriasis may sometimes be a marker of HIV infection.[31] Erythroderma may occur in patients with HIV as a result of psoriasis, atopic dermatitis, crusted scabies, and drug eruption. Erythroderma may be a presenting sign of HIV disease, especially in young, Black patients.[32]
In a recent review, researchers studying psoriasis in patients with HIV suggested that HIV-associated immune dysregulation might trigger psoriasis in those carrying the HLA-Cw0602 allele.[33] In this schema, the HLA-Cw0602 allele might be a target for CD8 cytotoxic T-lymphocytes (CTLs) responding to processed peptides presented in the context of major histocompatibility complex-1.
Treatment of patients with HIV-related psoriasis includes HAART treatment, bland emollients, topical agents, phototherapy, and systemic antipsoriatic drugs. Antiviral therapy should be optimized since clinical improvement of the skin often parallels reduction in HIV viral load induced by HAART.[34–37] As in patients without HIV, emollients, salicylic acid preparations, tar, topical corticosteroids, topical tazarotene, and topical calcipotriol are often useful for localized disease.
Phototherapy in the form of broadband ultraviolet (UV) B, combined UVA/UVB or psoralen plus UVA (PUVA) is effective for more extensive disease. Despite in vitro and transgenic mice studies that suggest that UV light might cause progression of HIV disease,[38,39] this has not borne out in clinical studies and UV therapy is considered have a good safety profile by most investigators.[40] Gelfand et al.[40] found no increase in HIV viral load in patients treated with UVB phototherapy. Moreover, pilot studies have not found evidence of increased HIV replication or activity in patients treated with PUVA.[41,42] Akaraphanth and Lim[43] reviewed the published studies on UV-induced immunosuppression in patients with HIV and concluded that phototherapy and photochemotherapy appears to be safe in this patient population.
It has been suggested that PUVA may be preferable to UVB therapy in patients with thick plaques and palmoplantar involvement.[44] Since PUVA has recently been linked to a small increase in the incidence of malignant melanoma in immunocompetent patients, and since patient life span has been extended with the advent of HAART, PUVA therapy should be used with care in this patient population.[45]
Systemic retinoids such as acitretin or etretinate have proven to be particularly useful for treatment of extensive psoriasis in patients infected with HIV;[46] however, etretinate is no longer being manufactured. Early case reports suggested that methotrexate should not be used for HIV-related psoriasis because of leukopenia and death in some patients.[31] In a more recent report there was no clear deterioration associated with methotrexate use for AIDS-associated psoriatic arthritis.[47] Be that as it may, methotrexate should only be used with careful monitoring. Practitioners should be particularly mindful of the fact that combined use of methotrexate and trimethoprim/sulfamethoxazole (cotrimoxazole) can induce pancytopenia since many patients with HIV take the latter drug for Pneumocystis carinii pneumonia prophylaxis.[48,49] Hydroxyurea (hydroxycarbamide) is a chemotherapeutic agent that has recently been looked at for possible antiviral effects in patients with HIV infection. Although this agent has been used for treatment of severe psoriasis in immunocompetent patients, recent reports of hepatotoxicity cast doubt as to whether this agent should be tried in patients with HIV-related psoriasis.[50,51] Etanercept, a recombinant tumor necrosis factor-α receptor-Fc fusion protein can be quite effective for psoriatic arthritis and psoriasis patients with HIV.[52] Some patients have developed polymicrobial infections, so it should be used with caution.
2.3 Seborrheic Dermatitis
Seborrheic dermatitis is a common dermatologic manifestation of HIV infection.[53] There is usually erythema, as well as greasy scaling involving the nasolabial area, eyebrows, external ears, postauricular areas and scalp. It can be more widespread and recalcitrant to treatment in HIV-infected patients, however, with involvement of most of the face including the forehead and malar areas as well as other areas of the body such as the mid-chest, axillae, groin, and back.
Seborrheic dermatitis often occurs early on in HIV-infection (CD4 counts >500), or may reflect disease progression.[54–56] In a recent longitudinal study of women with HIV, CD4 T-cell depletion and increased viral load were correlated with seborrheic dermatitis and other skin abnormalities.[57] Although possible overgrowth of the yeast Pityrosporum ovale has been suggested as a cause for seborrheic dermatitis in patients with HIV, studies have not borne this out.[58,59] The possible role of Pityrosporum has recently been reviewed.[60] Occasionally, tinea faciei may be confused with seborrheic dermatitis in patients with HIV.[61]
Patients with seborrheic dermatitis are usually treated with low potency topical corticosteroids alone or in combination with topical azole antifungals. Topical agents such as ketoconazole and bifonazole are thought to have mild anti-inflammatory activity and are used to reduce the amount of corticosteroid needed. Adjunctive therapy includes coal tar, selenium sulfide, and pyrithione zinc and for severe disease narrow-band UVB phototherapy has been reported to be effective.[62] We have recently found both tacrolimus ointment and pimecrolimus cream to be efficacious in the treatment of patients with seborrheic dermatitis (unpublished observation).
2.4 Pruritic Papular Eruptions
From early on in the HIV pandemic, patients with itchy papular eruptions have been described by a number of authors under the moniker of papular eruption or pruritic papular eruption.[63] James et al.[64] described a chronic waxing and waning, variably pruritic eruption of ‘noncoalescing, skin-colored papules of the head, neck, and upper trunk’ measuring 2–5mm in seven patients infected with HIV. A chronic perivascular mononuclear cell infiltrate was characteristic and eosinophils were sometimes present. One patient had ‘granuloma formation’.
Colebunders et al.[65] described a symmetrically distributed papular eruption in African patients with AIDS that involved the extensor surfaces of the arm, dorsa of the hands, lower legs, ankles, and dorsa of the feet. The lesions started as itchy papules that released a clear fluid when scratched. On healing, they left hyperpigmented macules.
Liautaud et al.[66] described a pruritic macular, papular, and nodular eruption that started on the arms and later extended to the legs, face (primarily the forehead) and trunk in a group of Haitian patients. A mixed perivascular or perifollicular polymorphonuclear leukocyte infiltrate displayed a predominance of eosinophils. Of particular interest is that this eruption was not seen in Haitian patients with AIDS who were living in New York City, but was common in such patients in Miami, Florida, and Haiti as well as in cases of patients reported from Zaire, Africa. The authors also stated categorically that the eruption was distinct from eosinophilic pustular folliculitis and suggested it might represent a reaction to insect saliva similar to papular urticaria.[67]
Hevia et al.[68] also described the histopathologic features of pruritic papular eruption. A superficial and mid-dermal perivascular and perifollicular mononuclear cell infiltrate was associated with numerous eosinophils and varying follicular damage. Eosinophilic folliculitis was found in 25% of patients. The authors considered that eosinophilic folliculitis as described in HIV infection was part of the spectrum of pruritic papular eruption and they also differentiated pruritic papular eruption from the eruption described by James and colleagues.[64]
Eosinophilic folliculitis with histology reminiscent of Ofuji’s disease has also been described in patients with HIV in a number of reports.[69–72] It was predominantly localized on the face, neck, upper chest, and back and upper arms. McCalmont et al.[73] reviewed the histology of eosinophilic folliculitis and considered it to be distinct from other papular eruptions. In a review of the subject, Bason et al.[63] concluded that it is likely that pruritic papular eruption represents a spectrum of diseases, including eosinophilic folliculitis. This interpretation agrees with the experience of the authors. Eosinophilic folliculitis, involving the face, scalp, neck, upper chest and back and proximal arms appears distinct from pruritic papular eruptions occurring predominantly on the arms, legs and trunk although it is sometimes more widespread.
Whether these eruptions are one pathologic entity or distinct will influence our interpretation of studies looking at histopathology and etiology. Ramos,[74] describing pruritic papular eruption occurring predominantly on the extremities, noted a superficial and deep perivascular lymphohistiocytic infiltrate with a variable number of eosinophils. The density of dermal CD8+ lymphocytes was increased while that of CD4+ lymphocytes was markedly reduced. Rosatelli et al.,[75] not differentiating between pruritic papular eruption and eosinophilic folliculitis, described the cutaneous infiltrate of pruritic papular eruption in a recent series. They also found a predominance of CD8+ cells as well as a predominance of lymphocytes followed by mast cells and eosinophils in lesional skin but did not describe the histologic localization of the infiltrate (i.e. perivascular, folliculocentric, or both). They concluded that the eruption was better described as pruritic papular eruption than as eosinophilic folliculitis. This same group also identified immediate cutaneous hypersensitivity to insect antigens in patients with pruritic papular eruption.[76]
Most of our patients with pruritic papular eruption who do not have typical eosinophilic folliculitis usually display histopathology somewhat reminiscent of papular urticaria that is not folliculocentric (Phelps R, personal communication). If follicular involvement is present, it is usually not the primary pathology as seen in patients with eosinophilic folliculitis. It has been our opinion that this eruption is the result of a disordered immune response most likely to arthropod antigens or less likely to some as yet not identified antigen. The process appears to be akin to papular urticaria. We consider eosinophilic folliculitis more likely to be a reaction to some antigen in the pilosebaceous apparatus.
Other itchy papular eruptions occurring in patients with HIV, besides eosinophilic (pustular) folliculitis and pruritic papular eruption include prurigo nodularis, papular mucinosis and possibly some drug eruptions. The morphology and distribution of these eruptions can be helpful in differentiating them. Lesions may be pustular, urticarial, papular or polymorphic and folliculocentric or non-folliculocentric.
Whether there is actually a distinct clinical entity pruritic papular eruption or whether it possibly represents a variant of papular urticaria remains an open question in our opinion. As mentioned previously in this section, we and others[63] regard it as distinct from HIV-related eosinophilic folliculitis. We usually reserve the diagnosis of pruritic papular eruption for eruptions localized to the trunk and extremities that do not conform to more well-defined entities such as eosinophilic folliculitis, arthropod bites, scabies, and prurigo nodularis or drug reaction. Lesions are usually excoriated and typically found on the extremities and trunk with sparing of the palms, soles, and digital web spaces. Pruritic papular eruption follows a chronic waxing and waning course and may have an associated peripheral eosinophilia and elevated levels of IgE.
Pruritic papular eruption is usually associated with advanced HIV infection and severe immunosuppression. In one study, 81.25% and 75% of patients with pruritic papular eruption had CD4 counts <100/mm3 and <50/mm3, respectively.[77] In a Haitian study, pruritic papular eruption was seen in 46% of patients with AIDS and was the presenting manifestation in 79% of patients, often appearing months before the diagnosis of an AIDS defining condition.[66] We have seen pruritic papular eruption as the presenting sign of HIV infection but these patients usually had very low CD4 counts to begin with.
Recent studies have looked at serum cytokine levels and plasma kallikrein activity in pruritic papular eruption.[78,79] Changes in serum interleukin-2 and interferon-γ and undetectable plasma kallikrein activity were noted in patients with pruritic papular eruption.
Pruritic papular eruption should be considered a marker for severe immunosuppression. It may be difficult to treat with minimal response to antihistamines, topical antipruritic preparations, and topical corticosteroids. UVB phototherapy is generally effective and is our treatment of choice. Ultra-potent topical corticosteroid ointments may provide some relief.
2.5 Eosinophilic Folliculitis
HIV-associated eosinophilic folliculitis was described in 1986.[69] At that time there was some confusion as to whether it represented the same clinical entity as Ofuji’s disease because of the similar pathology; however, there were significant differences in presentation.[72] In Ofuji’s disease there are pruritic circinate studded with follicular papules and sterile pustules on the face, trunk, and arms.[80] The palms of the hands and soles of the feet may occasionally be involved. Peripheral leukocytosis, eosinophilia, and elevated IgE levels are noted. Histologic exam shows follicular spongiosis and folliculocentric mixed inflammatory infiltrate of eosinophils, lymphocytes, histiocytes, mast cells, and neutrophils around the outer root sheaths of hair follicles.
In the variety of eosinophilic folliculitis associated with HIV, patients present with discrete erythematous papules, or papules surmounted by a tiny pustule, that involve the face, neck, upper chest, upper back, and outer, proximal aspect of the arms (figure 5). There may be eyelid involvement, post-auricular involvement and scalp lesions. In some patients, the eruption may be more extensive involving the arms, legs and much of the torso.
Eosinophilic folliculitis in a patient with HIV.
Eosinophilic folliculitis is usually seen at CD4 T-cell counts below 300/mm3.[72] Elevated IgE levels and peripheral eosinophilia have suggested that a type 2 cytokine response to an unknown antigen may cause eosinophilic folliculitis. Not only has a type 2 cytokine response been described in late stage HIV infection but also recently investigators have shown increased expression of the type 2 cytokines, interleukin-4 and interleukin-5 and the chemokines RANTES and eotaxin in lesional skin of patients with HIV-associated eosinophilic folliculitis. It has been suggested that the disorder might be a result of immune dysregulation to a variety of agents such as Pityrosporum ovale, or the follicular mite Demodex folliculorum, an autoimmune reaction to the sebocyte, or a component of sebum.[81]
In a recent paper, Magro et al.[82] described a new entity called necrotizing eosinophilic folliculitis, a novel manifestation of the atopic diathesis. They described a small series of patients with HIV who were atopic and developed an unconventional form of eosinophilic folliculitis, characterized by ulceration, nodules, and dermal and follicular necrosis. They proposed that the mechanism of this disease was an unrepressed Th2 type response to epicutaneous stimuli in atopic individuals.
The typical clinical presentation of eosinophilic folliculitis suggests the diagnosis, which is confirmed by biopsy or by the demonstration of eosinophils on a Wright’s stained smear from an intact pustule. A recent study suggests that horizontal sectioning may be useful in diagnosing eosinophilic folliculitis.[83] Some investigators have noted a decrease in eosinophilic folliculitis prevalence with the advent of aggressive antiretroviral treatment, although the immune reconstitution attendant with such treatment can sometimes cause a flare up of eosinophilic folliculitis.[13,14]
Treatment options include phototherapy (UVB), oral metronidazole, itraconazole, and oral 13-cis-retinoic acid along with antipruritic agents for symptomatic relief.[71,84–87]
2.6 Prurigo Nodularis
Prurigo nodularis (picker’s nodule) is a disorder characterized by hyperpigmented, excoriated, papules, nodules, and plaques in patients with severe itching from a variety of causes. In patients with HIV, it typically involves the arms, thighs, and legs but it may be more extensive, sparing only areas that the patient cannot reach. Pigmentary changes, more common in darker skinned individuals include hyperpigmentation or central hypopigmentation surrounded by hyperpigmentation. Ulceration can be seen from uncontrolled picking (figure 6).
Ulcerated prurigo nodules in a patient with AIDS.
Causes of prurigo include itching from HIV-related dermatoses such as pruritic papular eruption, eosinophilic folliculitis and papular urticaria, chronic renal failure, atopic dermatitis, and cocaine addiction. Sometimes, the original cause of itching may no longer be apparent.
The pathophysiology of prurigo nodularis is unclear. A striking feature of this disorder is the incessant, irrepressible scratching and picking seen in these patients. Whether primary immunologic or neurological mechanisms are paramount is not clear. In patients infected with HIV, prurigo can follow papular urticaria induced by arthropod bites. Arthropod bites, in this population, are thought to cause an exaggerated, localized immune response, intractable pruritus and subsequent formation of nodules. Penneys et al.[67] identified antibodies to mosquito salivary gland antigens in patients with papular eruptions. They suggested that in patients infected with HIV, non-specific B-cell activation causes the formation of antibodies that react with these antigens in the skin in a recall reaction.
It has also been suggested, based on polymerase chain reaction detection of mycobacterial DNA in lesional skin, that mycobacterial infection may be responsible for prurigo nodularis. It is more likely that mycobacteria are implanted in these lesions by chronic picking and scratching.[88]
There is evidence that neurologic or neuro-immune mechanisms are of importance. An increased number of histamine-containing mast cells and increased number of nerve growth factor receptor (NGFr)-immunoreactive nerve fibers are found in the upper dermis of prurigo nodularis lesional skin.[89] Mast cells are seen in close vicinity to NGFr-positive nerves and sometimes appeared to contact single nerve fibers.
The neuromediator, substance P, has also been implicated in the pathophysiology of prurigo nodularis and topical capsaicin has been used to treat this condition.[90,91]
Prurigo nodularis is typically resistant to treatment and a frustrating challenge for practitioners. Topical super-potent corticosteroids under occlusion, intralesional corticosteroid injections, and phototherapy are the mainstays of treatment. Systemic therapy with thalidomide appears to be a promising, effective treatment for prurigo nodularis.[92] Thalidomide has both immunomodulatory and neurologic effects. Its mechanism of action in prurigo remains to be determined.
3. Miscellaneous Causes of Pruritus
3.1 Photodermatitis
Patients with HIV infection may develop photosensitivity reactions from several causes including photosensitizing drugs, porphyria cutanea tarda, or possibly an idiopathic photosensitivity brought on by advanced HIV disease. Berger and Dhar[93] described pruritic, lichenoid photoeruptions in patients with HIV and severe immunosuppression. The lichenoid lesions involved the dorsa of the hands, forearms, face, and neck. The eruption was most common in African-American patients and pigmentary alterations both hyper- and hypopigmentation were seen (figure 7).
Lichenoid photodermatitis in a patient with HIV.
Photosensitivity in individuals infected with HIV appears to be a manifestation of advanced disease. In one study, most patients were sensitive to UVB and more severely affected individuals were sensitive to both UVB and UVA, and sometimes visible light.[94] Over one half of the patients had significant Native American ancestry, an interesting finding since a polymorphous light eruption of the American Indian has been described. In addition, subclinical photosensitivity was detected in patients with eosinophilic folliculitis.
Treatment of photosensitivity eruptions includes avoidance of sun exposure, use of topical sunblocks that block UVA and UVB, and occasionally photochemotherapy (psoralen plus UVA or PUVA) or oral retinoids. Thalidomide has also been reported to be useful.[92]
3.2 Xerosis
Xerosis or dryness of the skin is one of the most common findings in patients with HIV infection. Severe xerosis is seen in about 20% of patients with HIV.[95] Xerosis is often prominent on the extremities and worse in the winter months. It is frequently accompanied by pruritus, excoriation, breaks in the skin, and secondary infection.
Why patients with HIV develop xerosis is unclear, but some have speculated that possible causes might include cutaneous microcirculatory changes, changes in nutrient supply to the skin, alteration of sweat or sebaceous gland activity, and changes in mast cell population of the skin, all of which might effect the epidermal barrier.[96] A search of Medline failed to reveal any studies of epidermal lipids or natural moisturizing factor in HIV-associated xerosis. Rowe et al.[96] recently reported decreased calcitonin gene related peptide (CGRP) and substance P levels in the skin of patients with HIV-related xerosis. The authors postulated that decreased levels of CGRP and substance P may be responsible for altered nutrition and blood supply in the epidermis leading to xerosis.
Treatment of xerosis includes skin hydration followed by measures to maintain skin moisture. Soaking in a tub in tepid to lukewarm water achieves hydration but unless an emollient is applied soon after, evaporation will result in further drying and chapping of the skin. Products such as petrolatum, Aquaphor®Footnote 1, Eucerin® cream, and lactic acid products such as Lactinol E® cream, Lachydrin® cream or Amlactin®, among many others, should be applied to damp skin within 3 minutes after the patient’s shower or bath. Ointments such as petrolatum are preferable to creams or lotions but may not be tolerated by some patients. Soap application should be limited to intertriginous areas. Mild, oilated soaps or soap substitutes are preferred. Cotton clothing is preferable to wool, which can induce itching. Since detergents can be irritating, it is helpful to add an extra rinse cycle when washing clothing.
3.3 Pruritus Associated with Systemic Illness
Pruritus in patients with HIV is usually caused by skin disease but less commonly, certain systemic diseases are identified as the cause of itching. Chronic renal failure as a result of HIV nephropathy, hepatic failure in patients with hepatitis (B or C), or systemic lymphoma are sometimes implicated. Idiopathic HIV pruritus, analogous to the pruritus of Hodgkin’s disease, is probably not very common and is diagnosed by exclusion of other causes. Most patients will turn out to have mild xerosis or some other identifiable cause of itching. Workup should include a complete history and physical exam, complete blood count with differential, liver and kidney function tests, hepatitis serologies, and chest X-ray. Dermatographism occasionally causes pruritus in HIV-infected patients. Medication induced pruritus should also be considered.
4. Conclusion
Pruritus is an important cause of discomfort and morbidity in patients infected with HIV. Diagnosis involves a careful skin examination to rule out a primary dermatologic etiology before attributing itching to idiopathic HIV pruritus. The spectrum of disease in the patient with HIV includes common dermatoses and skin diseases peculiar to the immunosuppression and immune dysregulation associated with HIV. An etiologic delineation of HIV-associated pruritic diseases has been attempted in light of recent advances in this field. If no dermatologic cause is found, a systemic cause or medication-related etiology should be sought.
Notes
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Singh, F., Rudikoff, D. HIV-Associated Pruritus. Am J Clin Dermatol 4, 177–188 (2003). https://doi.org/10.2165/00128071-200304030-00004
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DOI: https://doi.org/10.2165/00128071-200304030-00004