hiv associated pruritus etiology and management.4

HIV-Associated PruritusEtiology and Management

Fiza Singh and Donald RudikoffMount Sinai Medical School of Medicine, New York, New York, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1771. Infections and Infestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1782. Non-Infectious Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

2.1 Atopic-Like Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1802.2 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1812.3 Seborrheic Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822.4 Pruritic Papular Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822.5 Eosinophilic Folliculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1832.6 Prurigo Nodularis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

3. Miscellaneous Causes of Pruritus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853.1 Photodermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853.2 Xerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853.3 Pruritus Associated with Systemic Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Abstract With the advent of highly active antiretroviral therapy (HAART), life-threatening opportunistic infectionhas become less common in patients with HIV infection and longevity has increased dramatically. With in-creased longevity, the problems of living with a chronic disease have become more prominent in this patientpopulation. Disorders such as fat redistribution and metabolic abnormalities can result from antiviral medica-tions and from HIV disease itself. Pruritus is one of the most common symptoms encountered in patients withHIV.

The spectrum of skin diseases in such patients encompasses dermatoses of diverse etiologies; a few arepeculiar to patients with HIV while others are not. Some of these conditions may cause severe and sometimesintractable pruritus that provokes scratching, picking, disfigurement, sleep loss, and significant psychologicalstress. Moreover, the expense of ongoing medical treatments can be daunting. Skin rash can sometimes be theinitial 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 inpatients who are HIV positive, presumably as a result of immune dysregulation, altered drug metabolism, andpolypharmacy. Itching can also result from systemic diseases such as chronic renal failure, liver disease, orsystemic lymphoma.

Workup of pruritus should include a careful examination of the skin, hair, nails, and mucous membranes toestablish a primary dermatologic diagnosis. If no dermatologic cause is found, a systemic cause or medication-related etiology should be sought. Idiopathic HIV pruritus is a diagnosis of exclusion and should only beconsidered when a specific diagnosis cannot be established.

The management of HIV-associated pruritus should be directed at the underlying condition. Phototherapyhas been found to be useful in the treatment of several HIV-associated dermatoses and idiopathic pruritus aswell. Unfortunately, some of the treatments that have been suggested for patients with HIV are anecdotal orbased on small uncontrolled studies. The last decade has seen a surge in the utilization of HAART which, tosome 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, HAARTdoes not need to be stopped.

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The skin is probably the organ most commonly affected inpatients with HIV. With the introduction of highly active anti-retroviral therapy (HAART), many patients are living longer[1]

and display chronic skin conditions that can be challenging to thedermatologist. Among the conditions affecting the integument inthis population, some can cause severe and, at times, intractablepruritus that provokes sleep loss, scratching, and picking thatsometimes leads to disfigurement and major psychologicalstress.[2] The cost of physician visits, medications, and treat-ments, that may or may not be covered by health insurance plans,not to mention time lost from work, causes added financial pres-sures to patients and their families. The range of skin diseases inpatients who are HIV-positive is broad, encompassing both HIVand non-HIV related dermatoses. For example, skin rash can bethe initial presentation of HIV infection, or serve as the harbingerof disease progression. The immune status of the patient, re-flected in the CD4 T-cell count and viral load, is an importantparameter since there is often a strong correlation between theCD4 count and the presence of particular HIV-associated rashes.A number of skin diseases initiate a chronic ‘itch-scratch-itchcycle’ that can result in lichenification, excoriation, prurigonodularis, pigmentary alteration, and secondary infection.

Recent advances in the field of cutaneous neurobiology haveelucidated some mechanisms underlying pruritus but our under-standing of these mechanisms is still in its infancy. It is thoughtthat both central and peripheral neurologic mediators may be in-volved. A number of chemical mediators including histamine,serotonin, prostaglandins, cytokines, proteases, tachykinins (e.g.substance P), and opioid peptides are thought to be involved ona local level.[3]

The causes of pruritus in patients infected with HIV includemany ordinary dermatoses, some of which may be more severeor more common in the setting of HIV infection. They includepapulosquamous disorders, infestations, infections, drug erup-tions and occasionally lymphoproliferative disorders such as cu-taneous T-cell lymphoma (CTCL). A variety of conditions pecu-liar to patients with HIV infection have been described. Atypicalcutaneous lymphoproliferative disorder (ACLD), also calledpseudo-Sezary or CTCL-simulant, presents as a pruritic, wide-spread eruption with pigmentary changes and an atypical lym-phocytic infiltrate. This condition has been reported in patientswith late-stage HIV infection and rarely progresses to frank lym-phoma.[4]

Drug eruptions are more common in patients with HIV in-fection than in their non-HIV-infected counterparts,[5] purportedlyas a result of immune dysregulation, altered drug metabolism,and polypharmacy. They include morbilliform drug eruptions,Stevens-Johnson syndrome, toxic epidermal necrolysis, drug hy-

persensitivity syndrome, and photodermatitis related to sulfon-amides, sulfones, and antiviral treatment. The protease inhibitor,indinavir may cause a pruritic eruption.[6]

Some patients with HIV infection develop systemic diseasesthat can cause pruritus. Among these are end-stage renal diseasefrom HIV nephropathy, chronic liver disease possibly from hep-atitis B or C, or HAART-induced hepatotoxicity, hypothyroid-ism, and systemic lymphoma.[7-11] Evaluation should includehead-to-toe physical examination concentrating on the integu-ment with laboratory testing dictated by the findings on historyand physical exam. In addition, the patient’s immune statusshould be assessed by CD4 T-cell count and viral load. Optimumanti-viral therapy should be instituted since it not only slows theprogression of HIV infection and increases life expectancy, butalso reportedly reverses certain HIV-related skin disorders.[12]

Some conditions such as eosinophilic folliculitis may be tempo-rarily 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-infectedpopulation but the incidence is not uniform in all risk groups.Scabies may be more common in patients who acquired HIV viasexual contact. A recent Japanese study showed a lower incidenceof certain infectious diseases such as molluscum contagiosum,condyloma acuminata, and scabies in hemophiliac patients withHIV, when compared with patients infected with HIV via meth-ods other than blood transfusion.[15]

Several presentations of scabies, both usual and unusual,have been reported in the setting of HIV infection. These includetypical interdigital burrows, nodular scabies, and crusted scabies(see figure 1 and figure 2). Nodular scabies presents as erythem-atous nodules on the scrotum, penis, axillae, groin, and upperback. It is a hypersensitivity reaction to mite proteins so usuallyevident only in patients with intact cell-mediated immunity inearly HIV infection or after HAART treatment. Nodular scabiesmay be confused with arthropod bites or with lymphomatoidpapulosis.

Patients with severe immune suppression may present withoverwhelming scabies mite infestations that may not be very pru-ritic because of absent cell-mediated inflammation. Patients withscabies who are on HAART with attendant immune reconstitu-tion can display significantly greater pruritus than patients withcrusted scabies. Itching may be worse at night.

Crusted scabies presents with localized or widespread hyper-keratotic plaques located on almost any part of the body. It canoccur in typical areas of scabetic involvement such as the web

178 Singh & Rudikoff

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spaces of the hands, the genitals, and periaxillary region but alsoin 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 dirtygrayish-brown scale in what appears to be a typical case of severexerosis, atopic dermatitis, or psoriasis suggests the diagnosis. Itis recommended that microscopic examination of skin scrapingsbe performed to identify mites, eggs, or mite excreta. The pres-ence of itching should be sought in household contacts as a diag-nostic clue.

There are several important considerations in the treatmentof patients with scabies infestations. Since it is highly contagiousand may be spread via fomites, clothing and linens should becarefully laundered in hot water. Another option is to isolate pos-sibly infested garments in a closet for a few days before wearingthem. This is a reasonable course of action because mites can onlylive a few days off the body. Family members should be offeredtreatment to prevent ongoing reinfection in the household. Pa-tients with crusted scabies shed considerable amounts of mite-containing scales, which may contaminate the household envi-ronment. A recent study examining the households of patientswith scabies showed scabies mites in dust samples from 44% ofinfested patients’ homes. Live mites were identified in 64% ofthese homes, most often from bedroom floors or overstuffedchairs and couches.[16]

The usual treatment of scabies infestation in non-pregnant,adult patients includes the use of topical scabicides such as lin-dane lotion or 5% permethrin cream, applied for 8–12 hours fromthe neck down before rinsing off. This is repeated a week later.In patients with crusted scabies, more aggressive therapy is ad-vocated. Topical keratolytics such as urea or lactic acid can be

applied to remove scale crust followed by more frequent use oftopical scabicides. Recurrences resulting from resistance to med-ication are uncommon. Inadequate treatment can result however,because of the sheer number of mites and eggs, from failure toapply sufficient scabicide, neglecting areas like the distal sub-ungual nail beds, reinfection, or forgetting to treat fomites.

Oral ivermectin approved for the treatment of onchocercia-sis, given once weekly at a dose of 200 µg/kg bodyweight for atotal of two doses is an effective treatment for patients withcrusted scabies. Although not approved for the treatment of pa-tients with scabies infestation, it has an excellent safety record.In 19 patients without HIV who were treated for scabies with twodoses of ivermectin a week apart, there was a transient exacerba-tion of pruritus 24–72 hours after the first dose of the study med-ication.[17] One study comparing one or two applications ofivermectin with one overnight application of permethrin in thetreatment of patients with non-crusted scabies, found permethrinto be superior to a single dose of ivermectin and equivalent to twodoses of ivermectin.[18] Although there are no published datacomparing the combination of ivermectin and permethrin witheither agent alone in the treatment of patients with crusted sca-bies, it may be advantageous to use the two agents together insuch patients. Ivermectin therapy should not be prescribed forchildren under 33lb (15kg), and it should be prescribed only withcaution in women who are breast-feeding. Although it appears tohave a good safety profile in pregnancy, we do not treat scabiesin pregnant women with ivermectin.[19]

Antipruritic agents and topical corticosteroids may be help-ful for relief of itching and antibacterials are indicated for thetreatment of secondarily infected lesions. Scabetic nodules re-quire treatment with intralesional corticosteroid injections.

Fig. 1. Crusted scabies in a patient with HIV.

Fig. 2. Typical scabetic burrows in a patient with HIV.

HIV-Associated Pruritus 179


Patients sometimes acquire pediculosis pubis (Phthirus) inhair-bearing areas of the body, with itching as the dominantsymptom. The pubic area should be closely searched for nits, crablice, and maculae ceruleae (blue-gray spots where lice have fed).The blue color is caused by the action of louse saliva on hemo-globin products. Pubic lice may also colonize other hairy areasof the body, including the trunk in individuals with a lot of hair,axillae, eyelashes, and occasionally the scalp. Treatment includesagents such as permethrin, lindane lotion and malathion lotion.

Body louse infestation caused by pediculosis corporis ismuch less common but should be considered in patients who arehomeless. In such cases, excoriations sometimes with secondaryinfection, papular bite reactions, and post-inflammatory pigmen-tary changes are often observed. Lice sometimes can be found onthe body but, more commonly, are lurking in the seams of cloth-ing.

Staphylococcus aureus is a frequent cause of cutaneous andsystemic bacterial infections in patients with HIV. S.aureus fol-liculitis is particularly common. It is characterized by widelydistributed pruritic, follicular pustules, and excoriated papules,most commonly located on the arms and legs. Staphylococcalimpetigo may be seen in the axillae and groin. It presents as tendererythematous erosions sometimes with satellite follicular pus-tules. Staphylococci may also exacerbate HIV-related atopic-likedermatitis. Staphylococcal furuncles, abscesses, ecthyma, andcellulitis are sometimes encountered in patients with HIV (figure3). We have seen some patients with localized staphylococcalinfections presenting as ulcerations in the genital area that clearedcompletely on systemic antibacterials.

A chronic recalcitrant ‘toxic-shock-like’ disorder has beendescribed in patients infected with HIV.[20] These patients usuallypresent with widespread scaly, peeling erythroderma. S. aureuscan also superinfect molluscum contagiosum lesions and causethem to feel itchy.

In some studies, such as that of Raviglione et al.,[21] higherrates of staphylococcal nasal colonization were documented inpatients with HIV, suggesting a causative role in cutaneous staph-ylococcal infections. However, other investigators who exam-ined the relationship between nasal carriage rates and diseasemanifestations did not find a significant correlation.[22] Althoughincreased nasal carriage of staphylococci might be a source offrequent staphylococcal skin infections, it might also reflect ageneralized susceptibility to staphylococcal colonization perhapsas a result of alterations in adhesion molecules.

Treatment of staphylococcal infections includes oral anti-bacterials such as dicloxacillin, cefalexin, clindamycin orciprofloxacin, and topical treatment with antibacterial cleanserssuch as chlorhexidine gluconate and topical antibacterial prepa-

rations like mupirocin. Although, mupirocin ointment appliedintranasally in patients with HIV eradicated S. aureus for severalweeks, the effect waned over time with persistently negative cul-tures in 63, 45 and 29% of patients at 2, 6, and 10 weeks respec-tively.[23]

2. Non-Infectious Skin Diseases

2.1 Atopic-Like Dermatitis

Some patients with HIV infection develop a dermatitis thatstrongly resembles atopic dermatitis and is sometimes referred toas atopic-like dermatitis.[24,25] Although some of these patientshave a personal or family history of atopy such as asthma orseasonal allergic rhinitis, the majority never experienced child-hood eczema. There is often generalized xerosis and areas offlexural or extensor lichenification on the arms, legs, and neck.Extensive excoriation is usual and secondary infection and pru-rigo nodularis lesions are common. According to a recent surveyof individuals with HIV, up to 29% of those interviewed hadatopic manifestations, including chronic pruritic rashes or ec-zema.[26] Many of these patients had a personal or family historyof allergic rhinitis and asthma.

A hyperimmunoglobulinemia E (hyper-IgE)-like syndromehas been described in patients with AIDS with hypereosinophilia,hyper-IgE, chronic dermatitis and recurrent staphylococcal infec-tions.[27] The immunologic mechanisms in this condition seem todiffer from those known in primary hyper-IgE syndrome, becauseCD4+ T helper (Th) 2 type cells, which are currently believed tohave a role in IgE production, are severely depleted in patientswith AIDS.[28]

Fig. 3. Staphylococcal abscesses in a patient with HIV and leukopenia.



It is currently thought that ordinary atopic dermatitis is ini-tiated, in predisposed individuals, by a Th2-dominant (type-2)cytokine milieu that goes on, in chronic lesions, to express theTh1 cytokine, interferon-γ. There is some evidence that patientswith advanced HIV infection may develop a predominance oftype-2 cytokines and this is thought by some to predispose toatopic manifestations. It has also been suggested that an allergenspecific IgE mechanism may contribute to eczematous reactionsin HIV-infected patients.[29]

Treatment of atopic-like dermatitis includes skin hydration,avoidance of irritants, application of emollients, and the use oftopical corticosteroid preparations, preferably ointments. Sincethese patients are frequently infected with staphylococci, oralantibacterials may be indicated. We have also had success usingtopical tacrolimus ointment to treat several patients and morerecently using pimecrolimus cream. The more challenging casesare those with widespread lichenification or eczematous derma-titis. These will sometime require systemic corticosteroids forflares. They should be started on phototherapy as soon as feasiblein order to limit systemic adverse effects or theoretical exacerba-tion of immunosuppression from long-term corticosteroid use.

2.2 Psoriasis

Patients with HIV can present with psoriasis that may some-times be pruritic (figure 4). It is controversial whether the inci-dence of psoriasis is greater in patients with HIV but the inci-dence of psoriatic arthritis is definitely increased.[30] Psoriasis inpatients with HIV is frequently more extensive, destructive, andtherapy-resistant than its counterpart in immunocompetent pa-tients. There is often a more acral distribution; psoriatic arthritis,and destructive nail changes may be prominent.

In patients with known risk for HIV exposure, new onsetpsoriasis may sometimes be a marker of HIV infection.[31] Eryth-roderma may occur in patients with HIV as a result of psoriasis,atopic dermatitis, crusted scabies, and drug eruption. Erythro-derma may be a presenting sign of HIV disease, especially inyoung, Black patients.[32]

In a recent review, researchers studying psoriasis in patientswith HIV suggested that HIV-associated immune dysregulationmight trigger psoriasis in those carrying the HLA-Cw0602 al-lele.[33] In this schema, the HLA-Cw0602 allele might be a targetfor CD8 cytotoxic T-lymphocytes (CTLs) responding to pro-cessed peptides presented in the context of major histocompati-bility complex-1.

Treatment of patients with HIV-related psoriasis includesHAART treatment, bland emollients, topical agents, photother-apy, and systemic antipsoriatic drugs. Antiviral therapy should

be optimized since clinical improvement of the skin often paral-lels reduction in HIV viral load induced by HAART.[34-37] As inpatients without HIV, emollients, salicylic acid preparations, tar,topical corticosteroids, topical tazarotene, and topical calci-potriol are often useful for localized disease.

Phototherapy in the form of broadband ultraviolet (UV) B,combined UVA/UVB or psoralen plus UVA (PUVA) is effectivefor more extensive disease. Despite in vitro and transgenic micestudies that suggest that UV light might cause progression of HIVdisease,[38,39] this has not borne out in clinical studies and UVtherapy is considered have a good safety profile by most investi-gators.[40] Gelfand et al.[40] found no increase in HIV viral loadin patients treated with UVB phototherapy. Moreover, pilot stud-ies have not found evidence of increased HIV replication or ac-tivity in patients treated with PUVA.[41,42] Akaraphanth andLim[43] reviewed the published studies on UV-induced immuno-suppression in patients with HIV and concluded that photother-apy and photochemotherapy appears to be safe in this patientpopulation.

It has been suggested that PUVA may be preferable to UVBtherapy in patients with thick plaques and palmoplantar involve-ment.[44] Since PUVA has recently been linked to a small increasein the incidence of malignant melanoma in immunocompetentpatients, and since patient life span has been extended with theadvent of HAART, PUVA therapy should be used with care inthis patient population.[45]

Systemic retinoids such as acitretin or etretinate have provento be particularly useful for treatment of extensive psoriasis inpatients infected with HIV;[46] however, etretinate is no longerbeing manufactured. Early case reports suggested that methotrex-

Fig. 4. Severe psoriasis in a patient with HIV.



ate should not be used for HIV-related psoriasis because of leu-kopenia and death in some patients.[31] In a more recent reportthere was no clear deterioration associated with methotrexate usefor AIDS-associated psoriatic arthritis.[47] Be that as it may,methotrexate should only be used with careful monitoring. Prac-titioners should be particularly mindful of the fact that combineduse of methotrexate and trimethoprim/sulfamethoxazole (cotri-moxazole) can induce pancytopenia since many patients withHIV take the latter drug for Pneumocystis carinii pneumonia pro-phylaxis.[48,49] Hydroxyurea (hydroxycarbamide) is a chemother-apeutic agent that has recently been looked at for possible anti-viral effects in patients with HIV infection. Although this agenthas been used for treatment of severe psoriasis in immunocom-petent patients, recent reports of hepatotoxicity cast doubt as towhether this agent should be tried in patients with HIV-relatedpsoriasis.[50,51] Etanercept, a recombinant tumor necrosis factor-α receptor-Fc fusion protein can be quite effective for psoriaticarthritis and psoriasis patients with HIV.[52] Some patients havedeveloped polymicrobial infections, so it should be used withcaution.

2.3 Seborrheic Dermatitis

Seborrheic dermatitis is a common dermatologic manifesta-tion of HIV infection.[53] There is usually erythema, as well asgreasy scaling involving the nasolabial area, eyebrows, externalears, postauricular areas and scalp. It can be more widespread andrecalcitrant to treatment in HIV-infected patients, however, withinvolvement of most of the face including the forehead and malarareas 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] Ina recent longitudinal study of women with HIV, CD4 T-cell de-pletion and increased viral load were correlated with seborrheicdermatitis and other skin abnormalities.[57] Although possibleovergrowth of the yeast Pityrosporum ovale has been suggestedas a cause for seborrheic dermatitis in patients with HIV, studieshave not borne this out.[58,59] The possible role of Pityrosporumhas recently been reviewed.[60] Occasionally, tinea faciei may beconfused with seborrheic dermatitis in patients with HIV.[61]

Patients with seborrheic dermatitis are usually treated withlow potency topical corticosteroids alone or in combination withtopical azole antifungals. Topical agents such as ketoconazoleand bifonazole are thought to have mild anti-inflammatory activ-ity and are used to reduce the amount of corticosteroid needed.Adjunctive therapy includes coal tar, selenium sulfide, andpyrithione zinc and for severe disease narrow-band UVB photo-

therapy has been reported to be effective.[62] We have recentlyfound both tacrolimus ointment and pimecrolimus cream to beefficacious 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 pap-ular eruptions have been described by a number of authors underthe moniker of papular eruption or pruritic papular eruption.[63]

James et al.[64] described a chronic waxing and waning, variablypruritic eruption of ‘noncoalescing, skin-colored papules of thehead, neck, and upper trunk’ measuring 2-5mm in seven patientsinfected with HIV. A chronic perivascular mononuclear cell in-filtrate was characteristic and eosinophils were sometimes pres-ent. One patient had ‘granuloma formation’.

Colebunders et al.[65] described a symmetrically distributedpapular eruption in African patients with AIDS that involved theextensor surfaces of the arm, dorsa of the hands, lower legs, an-kles, and dorsa of the feet. The lesions started as itchy papulesthat released a clear fluid when scratched. On healing, they lefthyperpigmented macules.

Liautaud et al.[66] described a pruritic macular, papular, andnodular eruption that started on the arms and later extended to thelegs, face (primarily the forehead) and trunk in a group of Haitianpatients. A mixed perivascular or perifollicular polymorphonu-clear leukocyte infiltrate displayed a predominance of eosino-phils. Of particular interest is that this eruption was not seen inHaitian patients with AIDS who were living in New York City,but was common in such patients in Miami, Florida, and Haiti aswell as in cases of patients reported from Zaire, Africa. The au-thors also stated categorically that the eruption was distinct fromeosinophilic pustular folliculitis and suggested it might representa reaction to insect saliva similar to papular urticaria.[67]

Hevia et al.[68] also described the histopathologic features ofpruritic papular eruption. A superficial and mid-dermal peri-vascular and perifollicular mononuclear cell infiltrate was asso-ciated with numerous eosinophils and varying follicular damage.Eosinophilic folliculitis was found in 25% of patients. The au-thors considered that eosinophilic folliculitis as described in HIVinfection was part of the spectrum of pruritic papular eruptionand they also differentiated pruritic papular eruption from theeruption described by James and colleagues.[64]

Eosinophilic folliculitis with histology reminiscent ofOfuji’s disease has also been described in patients with HIV in anumber of reports.[69-72] It was predominantly localized on theface, neck, upper chest, and back and upper arms. McCalmont etal.[73] reviewed the histology of eosinophilic folliculitis and con-



sidered it to be distinct from other papular eruptions. In a reviewof the subject, Bason et al.[63] concluded that it is likely that pru-ritic papular eruption represents a spectrum of diseases, includingeosinophilic folliculitis. This interpretation agrees with the expe-rience of the authors. Eosinophilic folliculitis, involving the face,scalp, neck, upper chest and back and proximal arms appearsdistinct from pruritic papular eruptions occurring predominantlyon the arms, legs and trunk although it is sometimes more wide-spread.

Whether these eruptions are one pathologic entity or distinctwill influence our interpretation of studies looking at histopathol-ogy and etiology. Ramos,[74] describing pruritic papular eruptionoccurring predominantly on the extremities, noted a superficialand deep perivascular lymphohistiocytic infiltrate with a variablenumber of eosinophils. The density of dermal CD8+ lymphocyteswas increased while that of CD4+ lymphocytes was markedlyreduced. Rosatelli et al.,[75] not differentiating between pruriticpapular eruption and eosinophilic folliculitis, described the cuta-neous infiltrate of pruritic papular eruption in a recent series.They also found a predominance of CD8+ cells as well as a pre-dominance of lymphocytes followed by mast cells and eosino-phils in lesional skin but did not describe the histologic localiza-tion of the infiltrate (i.e. perivascular, folliculocentric, or both).They concluded that the eruption was better described as pruriticpapular eruption than as eosinophilic folliculitis. This same groupalso identified immediate cutaneous hypersensitivity to insectantigens in patients with pruritic papular eruption.[76]

Most of our patients with pruritic papular eruption who donot have typical eosinophilic folliculitis usually display histopa-thology somewhat reminiscent of papular urticaria that is notfolliculocentric (Phelps R, personal communication). If follicularinvolvement is present, it is usually not the primary pathology asseen in patients with eosinophilic folliculitis. It has been our opin-ion that this eruption is the result of a disordered immune re-sponse most likely to arthropod antigens or less likely to some asyet not identified antigen. The process appears to be akin to pap-ular urticaria. We consider eosinophilic folliculitis more likely tobe a reaction to some antigen in the pilosebaceous apparatus.

Other itchy papular eruptions occurring in patients with HIV,besides eosinophilic (pustular) folliculitis and pruritic papulareruption include prurigo nodularis, papular mucinosis and possi-bly some drug eruptions. The morphology and distribution ofthese eruptions can be helpful in differentiating them. Lesionsmay be pustular, urticarial, papular or polymorphic and follicu-locentric or non-folliculocentric.

Whether there is actually a distinct clinical entity pruriticpapular eruption or whether it possibly represents a variant ofpapular urticaria remains an open question in our opinion. As

mentioned previously in this section, we and others[63] regard itas distinct from HIV-related eosinophilic folliculitis. We usuallyreserve the diagnosis of pruritic papular eruption for eruptionslocalized to the trunk and extremities that do not conform to morewell-defined entities such as eosinophilic folliculitis, arthropodbites, scabies, and prurigo nodularis or drug reaction. Lesions areusually excoriated and typically found on the extremities andtrunk with sparing of the palms, soles, and digital web spaces.Pruritic papular eruption follows a chronic waxing and waningcourse and may have an associated peripheral eosinophilia andelevated levels of IgE.

Pruritic papular eruption is usually associated with advancedHIV infection and severe immunosuppression. In one study,81.25% and 75% of patients with pruritic papular eruption hadCD4 counts <100/mm3 and <50/mm3, respectively.[77] In a Hai-tian study, pruritic papular eruption was seen in 46% of patientswith AIDS and was the presenting manifestation in 79% of pa-tients, often appearing months before the diagnosis of an AIDSdefining condition.[66] We have seen pruritic papular eruption asthe presenting sign of HIV infection but these patients usuallyhad very low CD4 counts to begin with.

Recent studies have looked at serum cytokine levels andplasma kallikrein activity in pruritic papular eruption.[78,79]

Changes in serum interleukin-2 and interferon-γ and undetectableplasma kallikrein activity were noted in patients with pruriticpapular eruption.

Pruritic papular eruption should be considered a marker forsevere immunosuppression. It may be difficult to treat with min-imal response to antihistamines, topical antipruritic preparations,and topical corticosteroids. UVB phototherapy is generally effec-tive and is our treatment of choice. Ultra-potent topical cortico-steroid ointments may provide some relief.

2.5 Eosinophilic Folliculitis

HIV-associated eosinophilic folliculitis was described in1986.[69] At that time there was some confusion as to whether itrepresented the same clinical entity as Ofuji’s disease because ofthe similar pathology; however, there were significant differ-ences in presentation.[72] In Ofuji’s disease there are pruritic cir-cinate studded with follicular papules and sterile pustules on theface, trunk, and arms.[80] The palms of the hands and soles of thefeet may occasionally be involved. Peripheral leukocytosis, eo-sinophilia, and elevated IgE levels are noted. Histologic examshows follicular spongiosis and folliculocentric mixed inflamma-tory infiltrate of eosinophils, lymphocytes, histiocytes, mastcells, and neutrophils around the outer root sheaths of hair folli-cles.



In the variety of eosinophilic folliculitis associated withHIV, patients present with discrete erythematous papules, orpapules 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 in-volvement and scalp lesions. In some patients, the eruption maybe more extensive involving the arms, legs and much of the torso.

Eosinophilic folliculitis is usually seen at CD4 T-cell countsbelow 300/mm3.[72] Elevated IgE levels and peripheral eosino-philia have suggested that a type 2 cytokine response to an un-known antigen may cause eosinophilic folliculitis. Not only hasa type 2 cytokine response been described in late stage HIV in-fection but also recently investigators have shown increased ex-pression of the type 2 cytokines, interleukin-4 and interleukin-5and the chemokines RANTES and eotaxin in lesional skin ofpatients with HIV-associated eosinophilic folliculitis. It has beensuggested that the disorder might be a result of immune dys-regulation to a variety of agents such as Pityrosporum ovale, orthe follicular mite Demodex folliculorum, an autoimmune reac-tion to the sebocyte, or a component of sebum.[81]

In a recent paper, Magro et al.[82] described a new entitycalled necrotizing eosinophilic folliculitis, a novel manifestationof the atopic diathesis. They described a small series of patientswith HIV who were atopic and developed an unconventionalform of eosinophilic folliculitis, characterized by ulceration, nod-ules, and dermal and follicular necrosis. They proposed that themechanism of this disease was an unrepressed Th2 type responseto epicutaneous stimuli in atopic individuals.

The typical clinical presentation of eosinophilic folliculitissuggests the diagnosis, which is confirmed by biopsy or by thedemonstration of eosinophils on a Wright’s stained smear froman intact pustule. A recent study suggests that horizontal section-ing may be useful in diagnosing eosinophilic folliculitis.[83] Someinvestigators have noted a decrease in eosinophilic folliculitisprevalence with the advent of aggressive antiretroviral treatment,although the immune reconstitution attendant with such treatmentcan sometimes cause a flare up of eosinophilic folliculitis.[13,14]

Treatment options include phototherapy (UVB), oral metro-nidazole, itraconazole, and oral 13-cis-retinoic acid along withantipruritic agents for symptomatic relief.[71,84-87]

2.6 Prurigo Nodularis

Prurigo nodularis (picker’s nodule) is a disorder charac-terized by hyperpigmented, excoriated, papules, nodules, andplaques in patients with severe itching from a variety of causes.In patients with HIV, it typically involves the arms, thighs, andlegs but it may be more extensive, sparing only areas that thepatient cannot reach. Pigmentary changes, more common indarker skinned individuals include hyperpigmentation or centralhypopigmentation surrounded by hyperpigmentation. Ulcerationcan be seen from uncontrolled picking (figure 6).

Causes of prurigo include itching from HIV-related derma-toses such as pruritic papular eruption, eosinophilic folliculitisand papular urticaria, chronic renal failure, atopic dermatitis, andcocaine addiction. Sometimes, the original cause of itching mayno longer be apparent.

The pathophysiology of prurigo nodularis is unclear. A strik-ing feature of this disorder is the incessant, irrepressible scratch-ing and picking seen in these patients. Whether primary immu-nologic or neurological mechanisms are paramount is not clear.In patients infected with HIV, prurigo can follow papular urti-caria induced by arthropod bites. Arthropod bites, in this popu-lation, are thought to cause an exaggerated, localized immuneresponse, intractable pruritus and subsequent formation of nod-ules. Penneys et al.[67] identified antibodies to mosquito salivarygland antigens in patients with papular eruptions. They suggestedthat in patients infected with HIV, non-specific B-cell activationFig. 5. Eosinophilic folliculitis in a patient with HIV.



causes the formation of antibodies that react with these antigensin the skin in a recall reaction.

It has also been suggested, based on polymerase chain reac-tion detection of mycobacterial DNA in lesional skin, that myco-bacterial infection may be responsible for prurigo nodularis. It ismore likely that mycobacteria are implanted in these lesions bychronic picking and scratching.[88]

There is evidence that neurologic or neuro-immune mecha-nisms are of importance. An increased number of histamine-containing mast cells and increased number of nerve growth fac-tor receptor (NGFr)-immunoreactive nerve fibers are found in theupper dermis of prurigo nodularis lesional skin.[89] Mast cells areseen in close vicinity to NGFr-positive nerves and sometimesappeared to contact single nerve fibers.

The neuromediator, substance P, has also been implicated inthe pathophysiology of prurigo nodularis and topical capsaicinhas been used to treat this condition.[90,91]

Prurigo nodularis is typically resistant to treatment and afrustrating challenge for practitioners. Topical super-potent cor-ticosteroids under occlusion, intralesional corticosteroid injec-tions, and phototherapy are the mainstays of treatment. Systemictherapy with thalidomide appears to be a promising, effectivetreatment for prurigo nodularis.[92] Thalidomide has both im-munomodulatory and neurologic effects. Its mechanism of actionin prurigo remains to be determined.

3. Miscellaneous Causes of Pruritus

3.1 Photodermatitis

Patients with HIV infection may develop photosensitivityreactions from several causes including photosensitizing drugs,

porphyria cutanea tarda, or possibly an idiopathic photosensitiv-ity brought on by advanced HIV disease. Berger and Dhar[93]

described pruritic, lichenoid photoeruptions in patients with HIVand severe immunosuppression. The lichenoid lesions involvedthe dorsa of the hands, forearms, face, and neck. The eruptionwas most common in African-American patients and pigmentaryalterations both hyper- and hypopigmentation were seen (figure 7).

Photosensitivity in individuals infected with HIV appears tobe a manifestation of advanced disease. In one study, most pa-tients were sensitive to UVB and more severely affected individ-uals were sensitive to both UVB and UVA, and sometimes visiblelight.[94] Over one half of the patients had significant NativeAmerican ancestry, an interesting finding since a polymorphouslight eruption of the American Indian has been described. In ad-dition, subclinical photosensitivity was detected in patients witheosinophilic folliculitis.

Treatment of photosensitivity eruptions includes avoidanceof sun exposure, use of topical sunblocks that block UVA andUVB, and occasionally photochemotherapy (psoralen plus UVAor PUVA) or oral retinoids. Thalidomide has also been reportedto be useful.[92]

3.2 Xerosis

Xerosis or dryness of the skin is one of the most commonfindings in patients with HIV infection. Severe xerosis is seen inabout 20% of patients with HIV.[95] Xerosis is often prominenton the extremities and worse in the winter months. It is frequentlyaccompanied by pruritus, excoriation, breaks in the skin, and sec-ondary infection.

Fig. 6. Ulcerated prurigo nodules in a patient with AIDS.

Fig. 7. Lichenoid photodermatitis in a patient with HIV.



Why patients with HIV develop xerosis is unclear, but somehave speculated that possible causes might include cutaneousmicrocirculatory changes, changes in nutrient supply to the skin,alteration of sweat or sebaceous gland activity, and changes inmast cell population of the skin, all of which might effect theepidermal barrier.[96] A search of Medline failed to reveal anystudies of epidermal lipids or natural moisturizing factor in HIV-associated xerosis. Rowe et al.[96] recently reported decreasedcalcitonin gene related peptide (CGRP) and substance P levels inthe skin of patients with HIV-related xerosis. The authors postu-lated that decreased levels of CGRP and substance P may beresponsible for altered nutrition and blood supply in the epider-mis leading to xerosis.

Treatment of xerosis includes skin hydration followed bymeasures to maintain skin moisture. Soaking in a tub in tepid tolukewarm water achieves hydration but unless an emollient isapplied soon after, evaporation will result in further drying andchapping of the skin. Products such as petrolatum, Aquaphor®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 pa-tient’s shower or bath. Ointments such as petrolatum are prefer-able to creams or lotions but may not be tolerated by some pa-tients. Soap application should be limited to intertriginous areas.Mild, oilated soaps or soap substitutes are preferred. Cottonclothing is preferable to wool, which can induce itching. Sincedetergents can be irritating, it is helpful to add an extra rinse cyclewhen washing clothing.

3.3 Pruritus Associated with Systemic Illness

Pruritus in patients with HIV is usually caused by skin dis-ease but less commonly, certain systemic diseases are identifiedas the cause of itching. Chronic renal failure as a result of HIVnephropathy, hepatic failure in patients with hepatitis (B or C),or systemic lymphoma are sometimes implicated. Idiopathic HIVpruritus, analogous to the pruritus of Hodgkin’s disease, is prob-ably not very common and is diagnosed by exclusion of othercauses. Most patients will turn out to have mild xerosis or someother identifiable cause of itching. Workup should include a com-plete history and physical exam, complete blood count with dif-ferential, liver and kidney function tests, hepatitis serologies, andchest X-ray. Dermatographism occasionally causes pruritus inHIV-infected patients. Medication induced pruritus should alsobe considered.

4. Conclusion

Pruritus is an important cause of discomfort and morbidityin patients infected with HIV. Diagnosis involves a careful skinexamination to rule out a primary dermatologic etiology beforeattributing itching to idiopathic HIV pruritus. The spectrum ofdisease in the patient with HIV includes common dermatoses andskin diseases peculiar to the immunosuppression and immunedysregulation associated with HIV. An etiologic delineation ofHIV-associated pruritic diseases has been attempted in light ofrecent advances in this field. If no dermatologic cause is found,a systemic cause or medication-related etiology should be sought.

Acknowledgements

This manuscript was prepared by the authors with no outside funding.Neither author has any conflict of interest relevant to the contents of thismanuscript.

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Correspondence and offprints: Dr Donald Rudikoff, Department of Derma-tology, Mount Sinai Medical Center, 1 Gustave L. Levy Place, PO Box 1048,New York, NY 10029, USA.E-mail: [email protected]



hiv associated pruritus etiology and management.4

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