Clinical Skills

Cutaneous manifestations of human immunodeficiency virus infection Asha Rajeev, Claire Fuller

Abstract

Human immunodeficiency virus (HIV) infection continues to be a major challenge to medical science worldwide. Diseases of the skin and mucous membranes were among the first recognised clinical manifestations of acquired immunodeficiency syndrome (AIDS) in the early 1980s.There is no skin condition reported so far that is specific for HIV infection but some, like Kaposi’s sarcoma and eosinophilic folliculitis, are strongly suggestive. Skin diseases which usually are self-limited or tend to run a milder course may become chronic, with frequent relapses and resistance to treatment. Drug resistance has added problems in management with profound effects on health economy. Recognising HIV-related skin diseases may lead to early diagnosis and initiation of antiretroviral therapy and the role of histopathology and microbiology in the diagnostic process should not be underestimated. Relevance of the article As of June 2010, there have been 26,262 people with a diagnosis of AIDS in the United Kingdom and 19,457 people diagnosed with HIV have died (Health Protection Agency Centre for Infections, 2010). Basic knowledge about cutaneous manifestations of HIV is mandatory for health professionals as the skin lesions are more frequently encountered in our dayto-day practice. Diseases such as refractory candidiasis, bacillary angiomatosis, Kaposi’s sarcoma and multi-dermatomal herpes zoster should alert us to look into factors causing immunosuppression, HIV being the first to come to mind. Some skin diseases give a clue with regards to the progression of HIV to AIDS.The most important fact about HIV in terms of diagnosis is that common skin diseases have unusual presentations.This article aims to give an overview of the skin manifestations of HIV/AIDS, including clinical features, investigations and management.

Cutaneous signs of primary HIV infection: Pathophysiology HIV produces cellular immune deficiency characterised by depletion of T-Helper Dr Asha Rajeev is Speciality Doctor, Dermatology, and Dr Claire Fuller is Consultant Dermatologist, Kent and Canterbury Hospital

12

cells (CD4) cells. Most infections and neoplasms of the skin are facilitated by the loss of CD4 cells. Primary HIV infection is usually asymptomatic. Some patients develop a maculopapular rash associated with a flu-like syndrome. Mucosal lesions in the form of erosions have been reported. The symptoms resolve on their own and are often not identified as part of primary HIV infection unless the patient is considered to be at high risk of acquiring HIV. In the early asymptomatic stage of HIV disease, no signs of infection other than lymphadenopathy are present and it can last 10 years or longer. With the onset of immunosuppression, common disorders with atypical clinical features are seen.

Mucocutaneous manifestations of established HIV infections Viral infections: Herpes simplex (HSV) Early in the HIV epidemic, chronic persistent infection with HSV was recognised in patients with advanced HIV disease. Now it is one of the AIDSdefining illnesses as per the Centre for Disease Control (CDC) criteria (Centre for Disease Control, 1992). Herpes simplex infection is usually a self-limiting viral infection affecting the oral or genital mucosa. As HIV infection progresses, HSV becomes persistent

and progressive. Perianal and perioral ulcers could be large and severely painful. In paediatric patients, herpes simplex stomatitis may become chronic and ulcerative. Periungual infection is another characteristic manifestation of HSV-2 infection in an HIV-infected patient; all paronychial lesions should be cultured for HSV (Glickel, 1988). Giemsa stained Tzanck smear from the edge of the ulcer when positive for multinucleated giant cells gives a rapid diagnosis. A biopsy sample with a portion of it sent for viral culture may be needed in some cases for a diagnosis. Oral acyclovir is very effective in most cases and may need intermittent or chronic suppressive therapy. Famciclovir and Valaciclovir are alternatives. Acyclovirresistant strains are treated with Foscarnet. Herpes zoster Herpes zoster is common in HIV patients and may be multi-dermatomal, bullous, necrotic and haemorrhagic. A young patient with recurrent or disseminated zoster and no other contributing factor to suggest immunosuppression will need investigation to rule out HIV. Chronic varicella zoster virus (VZV) infections associated with HIV begin as vesicles and

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 12

28/02/2011 14:06

Clinical SKILLS systemically are a feature of this opportunistic infection caused by Bartonella. They appear as redviolaceous papules similar to pyogenic granuloma and tend to bleed profusely. Differential diagnosis includes pyogenic granuloma, angioma, Kaposi’s sarcoma and disseminated cryptococcosis. Systemic involvement is common and can be fatal. Early diagnosis using silver stains is important as the organism is difficult to culture and responds well to erythromycin and doxycycline. Unlike Kaposi’s sarcoma, another vascular lesion seen in AIDS, BA does not respond to radiotherapy.

progress into necrotic, non-healing ulcers (Erdal et al, 2009). Dissemination of VZV in HIV is fortunately uncommon (Cohen, Grossman, 1989). VZV does disseminate more commonly than HSV and hence all disseminated herpetiform eruptions should be considered VZV unless proved otherwise and high-dose acyclovir should be given. Since VZV is less sensitive to acyclovir than HSV, four times higher dosage is needed. Some authors believe intravenous treatment is better than oral (Pahwa et al, 1988), especially when the eye is involved. Molluscum contagiosum (MC) The MC virus is a DNA virus causing small papules with central depression, often self-limiting and common in children. MC occurs in approximately 10-20% of HIV-infected persons (Schwartz, Myskowski, 1992). Often large, disfiguring lesions are seen, which can only be differentiated by histology. They can appear on the face, neck, eyelids and scalp, which is not a common site for molluscum in adults. The lesions can get inflamed and there may be associated dermatitis. Treatment is mainly cosmetic with cryotherapy and curettage and cautery. Human papilloma virus Widespread and treatment-unresponsive warts can be seen on the perianal region, face and oral mucosa. HPV is closely linked to sexually transmitted cancers, the most common being cervical cancer and anorectal carcinoma. There is increased risk of intra-epithelial carcinoma even with HPV types not usually associated with malignancy. Regular screening of patients with HIV helps in early detection. Presence of external warts should prompt an internal examination, including smears and colposcopy in women and anoscopy in men. Management is similar to that in immunocompetent individuals, except that multiple attempts are needed and treatment resistant lesions should be surgically removed and sent for histology. Cytomegalovirus (CMV) CMV, another DNA virus, can cause persistent perineal ulceration. Herpes virus infection might be present concurrently. Diagnosing CMV cutaneous infection is important as it is considered a poor prognostic sign in HIV (Erdal et al, 2009).

Figure 1. Human papilloma virus: genital warts.

Bacterial infections:

Staphylococcus aureus Staphylococcal infections are the most common bacterial infection in HIV patients. Folliculitis, abscesses and furuncles, as well secondary infection of eczema, scabies and ulcers are frequently seen. In patients with bacteraemia, Staph aureus is a common cause.

HPV is closely linked to sexually transmitted cancers, the most common being cervical cancer and anorectal carcinoma. The risk factors include intravenous catheter use, intravenous drug use and trauma. Impetigo and folliculitis may be recurrent and persistent in HIV disease, particularly in children. Folliculitis caused by Staphylococci can be severely pruritic and often mistaken for other itchy skin conditions. Gram stain and culture confirms the diagnosis and appropriate treatment can be given at the earliest. Nasal mupirocin, topical antibacterial washes, hydrogen peroxide/ benzyl peroxide washes/creams all help elimination of bacteria and may prevent relapses. Bacillary angiomatosis (BA) Vascular tumours that can disseminate

Syphilis Syphilis has made a reappearance in the HIV era, as it frequently co-exists with HIV. Syphilitic ulcers are believed to increase HIV transmission. Even though most cases are typical, atypical features include painful chancre, absent or abnormally high antibody titres, necrotising lesions and rapid progression into tertiary or neurosyphilis. For latent syphilis of longer than one year or of unknown duration, CSF examination is recommended for all HIV-infected patients. Penicillin still remains the drug of choice for the treatment of syphilis. Mycobacteria Systemic infections with Mycobacterium tuberculosis and atypical mycobacteria are a frequent problem in HIV disease and AIDS.The skin manifestations of Mycobacterium avium complex are not characteristic and can present as crusted ulcers, inflammatory nodules and scaly plaques. Localised lesions resembling the linear ascending pattern of sporotrichosis is rare. Other mycobacteria which cause skin lesions are M. kansasi and M. haemophilum. Unless special stains for AFB are ordered, misdiagnosis may result. Atypical mycobacteria should be suspected when smears for Acid fast bacilli (AFB) are positive, yet standard AFB cultures are negative.Treatment includes clarithromycin, doxycycline and clofazimine.

Fungal infections:

Superficial fungal infections Candida, dermatophytes and tinea versicolor are the usual fungi causing superficial fungal infections. Treatment

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 13

13

28/02/2011 14:06

Clinical Skills et al, 1986). Scabies mites can cause Norwegian (crusted) scabies with immunosuppression and this can be easily confused with psoriasis and severe dermatitis. Unlike ordinary scabies, the host is infested by millions of mites and is highly contagious. Topical treatments by themselves won’t be effective and oral ivermectin is needed.

Regional Dermatology Training Centre, Moshi Tanzania

Demodicosis Demodicosis caused by Demodex folliculorum, a normal hair follicle resident mite, appears as an itchy, papular eruption affecting head, neck, trunk and arms. Permethrin may help get rid of the problem.

Skin tumours in HIV

Figure 2. Kaposi’s sarcoma (KS) was the first reported malignancy associated with HIV infection. resistant candidiasis in the form of thrush, ulcers, erosions, hyperplastic plaques and angular chelitis should raise the suspicion of HIV if no other cause for immunosuppression can be found. Trichophyton rubrum can cause tinea capitis in adults. Nail involvement with dermatophytes results in proximal white onychomycosis, which is the pattern usually seen with HIV. Tinea versicolor can often be resistant and extensive with HIV. Malassezia folliculitis produces multiple follicular centred papules on the face, chest and upper extremities and is often pruritic. Candida and tinea can be diagnosed by potassium hydroxide examination of scales or material from the pustules. Usual topical treatment in the form of nystatin or imidazoles is usually effective. Persistent lesion on the groins should alert to a possible alternative diagnosis of flexural psoriasis/ seborrhoeic dermatitis. Deep mycoses Histoplasma, Cryptococcus, North American blastomycosis and coccidiodomycosis all cause extensive and unusual manifestations when associated with HIV. Mostly deep 14

Scabies in HIV-infected persons usually presents with the typical involvement of skin folds, genitalia and finger webs. mycoses are diagnosed by histology. Granulomas are seen and special stains can identify the organism. Clinical differential diagnosis matters most in selecting special stains. There should be a low threshold to biopsy lesions and send one sample for bacteriology and fungal culture. Cutaneous cryptococcosis can resemble molluscum contagiosum. Amphotericin B and Itraconazole are the usual antifungals used to treat systemic mycoses.

Arthropod infestations:

Scabies Scabies in HIV-infected persons usually presents with the typical involvement of skin folds, genitalia and finger webs. The infestation may become more widespread and refractory to treatment and spares the characteristic areas with advanced immunosuppression (Sadick

Kaposi’s sarcoma Kaposi’s sarcoma (KS) was the first reported malignancy associated with HIV infection and is caused by Human Herpes Virus 8. It is a multifocal, vascular tumour affecting the skin, lymph nodes and viscera. One form of Kaposi’s sarcoma is endemic in the African subcontinent. The type associated with HIV/AIDS can be localised or systemic. Lesions present with red, purple or brown macules, nodules or plaques affecting trunk, legs, face and oral cavity. While taking a biopsy, precautions such as avoiding foot and lower leg lesions, waiting at least 5 minutes after injecting the anaesthetic with adrenaline, and suturing minimises the risk of bleeding (Maurer, Berger, 1998). Therapy aims at controlling the symptoms and includes antiretroviral treatment, radiation, alpha interferon or chemotherapy. Other skin tumours Lymphomas can produce skin nodules. An increase in multiple squamous cell carcinoma, metastatic basal cell carcinoma and aggressive malignant melanoma has been repor ted. Children with AIDS have a higher risk of developing leiomyosarcoma (smooth muscle sarcoma) although the incidence is low. Since the introduction of Highly Active Antiretroviral Therapy (HAART), the incidence of non-AIDS defining cutaneous cancers like basal cell carcinoma among HIV-infected individuals has exceeded that of

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 14

28/02/2011 14:06

Clinical SKILLS

Appeel ad

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 15

15

28/02/2011 14:06

Clinical Skills

Regional Dermatology Training Centre, Moshi Tanzania

secondary to pityrosporum folliculitis, demodicosis, scabies, hypersensitivity to insect bites and prurigo. Xerosis of the skin, which is common in HIV, also contributes to itchy skin. Asteatotic eczema needs topical steroids and emollients for control.

Regional Dermatology Training Centre, Moshi Tanzania

Figure 3. Fixed drug eruption: drug reactions are common when starting new medication.

Figure 4. Toxic epidermal necrolysis, a severe drug reaction, can occur in HIV patients. AIDS-defining cancers like KS (Erdal et al, 2009).

Papulosquamous disorders Seborrhoeic dermatitis as an early skin manifestation of HIV is seen in 83% of patients and is the commonest dermatosis associated with HIV. Lesions may be widespread, atypical, inflammatory and hyperkeratotic. Some cases may progress to erythroderma (Erdal et al, 2009). Treatment includes topical antifungals combined with topical corticosteroid and regular emollients. Phototherapy and oral antifungals may be needed for resistant cases. 16

Psoriasis could manifest for the first time with HIV or the pre-existing psoriasis could flare up and can turn erythrodermic/pustular. Reiter’s disease can present with its classical triad of urethritis, conjunctivitis and arthritis and often could be an early manifestation. The incidence is approximately 250 fold higher in HIV positive patients when compared with the normal population (Penneys, 1995).

Pruritus in HIV Pruritus is a common complaint in patients with advanced HIV disease. It can occur as primary pruritus or

Eosinophilic folliculitis EF is a non-infectious eosinophilic infiltration of hair follicles. The three variants include classic eosinophilic pustular folliculitis, immunosuppressionassociated EF (mostly HIV related) and infancy associated EF (Nervi et al, 2006). The male-to-female ratio is 5:1. Eosinophilic folliculitis, which is considered a distinct marker of advanced HIV, manifests as severely itchy follicular and non-follicular urticarial papules and sterile pustules involving the face, upper trunk and proximal extremities. Treatments including isotretinoin (Annam et al, 2010), phototherapy, dapsone and topical steroids are used in the management of this condition, but with limited efficacy. Drug reactions Early drug reactions also should be thought of when eliciting the history from a patient with HIV and pruritus. Drug reactions are common within 7-12 days of starting a new medication but can occur months later as the patient’s immune status improves. The most common pattern is a maculopapular rash and the usual culprit is sulphonamides. Severe drug reactions include Stevens Johnson’s syndrome, toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP), which can be lifethreatening due to fluid and electrolyte imbalance and secondary infection. Treatment includes stopping the medication and supportive care. Intravenous immunoglobulin may be beneficial in severe cases when started early in the course of the reaction. Pruritic papular eruption Pruritic papular eruption (PPE) of HIV presents as symmetrical, diffuse, multiple discrete scratched red bumps affecting mostly the extremities and

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 16

28/02/2011 14:06

Clinical SKILLS trunk. The mucous membranes, palms and web spaces are spared. The cause is unknown and, according to Boonchai et al (1999), 81.25% of patients with PPE have immunosuppression. Some authors consider it as an exaggerated insect bite reaction. It is three times more common when the CD 4 lymphocyte count is less than 200×109/L.Treatment includes topical steroids, emollients, topical tacrolimus, oral antihistamines and phototherapy. Recurrence is common.

Oral lesions in HIV Oral lesions are seen in almost the whole course of HIV, starting from primary stage into advanced HIV/AIDS. Some lesions such as oropharyngeal candidiasis, especially treatment-resistant ones and frequently relapsing ones, should raise the suspicion of HIV if no other predisposing factors are present. Oesophageal involvement is often seen and presents as painful swallowing. Systemic antifungal treatment is needed. Oral hairy leucoplakia is a distinctive lesion seen as asymptomatic, ribbed plaques along the lateral borders of the tongue and is caused by Epstein Barr Virus. Oral hairy leucoplakia has no malignant potential, but may be the initial sign of progressive immunosuppression. Oral acyclovir 800mg five times daily until lesions clear, followed by minimal suppressive dose, may be considered (Rico et al, 1997). White plaques are often confused with candidiasis and lichen planus. Aphthous ulcers in HIV tend to be larger and more extensive, involving the pharynx, tongue and lips, causing dysphagia and rapid weight loss.

Hair disorders in HIV Diffuse alopecia or alopecia areata can be associated with HIV and it could be inflammatory and permanent. Indinavir, a protease inhibitor used to treat HIV, can cause generalised alopecia. Elongation of eye lashes and straightening and softening of scalp hair may be observed.

Nail disorders in HIV Beau’s lines and pallor of the nail beds could be a manifestation of any long standing illness. Zidovudine causes longitudinal, transverse or diffuse hyper pigmentation of the nails. HIV infection

in itself without treatment can also cause pigmentation of the nails. Nail involvement with dermatophytes results in proximal white onychomycosis which is the pattern usually seen with HIV (Erdal et al, 2009).

Indian J Dermatol Venereol Leprol 76(3): 259-62

The value of biopsy in diagnosis

Cohen PR, Grossman ME (1989) Clinical features of human immunodeficiency virus-associated disseminated herpes zoster — a review of the literature. Clin Exp Dermatol 14(4): 273-276

As already mentioned, the average HIV-infected individual has at least two synchronous skin conditions; several biopsies may be needed to avoid oversight (Osbourne et al, 2003). There should be a low threshold for biopsy including histopathology and microbiology. More importantly,

Dermatologists play a major role in diagnosing and managing drug reactions, enabling the patient to have life-long, effective viral suppression. knowledge about the conditions matters most, as differential diagnosis given by the clinician helps the pathologist to do special stains and arrive at an appropriate diagnosis.

Conclusion HIV-infected persons commonly have cutaneous abnormalities. Most of the conditions are the usual ones we see in our day-to-day practice, but a bit or grossly different in the clinical presentation. Progression from HIV to AIDS takes an average of 10 years and being aware of the skin manifestations helps to monitor the progression of HIV. Dermatologists play a major role in diagnosing and managing drug reactions, enabling the patient to have life-long, effective viral suppression.

Acknowledgements The photographs are used by kind permission of RDTC Moshi Tanzania and Professor Ben Naafs, Consultant Dermatologist. DN

References Annam V, Yelikar BR, Inamadar AC, Palit A, Arathi P (2010) Clinicopathological study of itchy folliculitis in HIV-infected patients.

Boonchai W, Laohasrisakul R, Manonukul J, Kulthanan K (1999) Pruritic papular eruption in HIV seropositive patients: a cutaneous marker for immunosuppression. Int J Dermatol 38(5): 348-50

Erdal E, Zalewska A, Schwartz RA (2009) Cutaneous manifestations of HIV disease. eMedicine, Dermatology. Updated 12/8/09 Osbourne GEN, C Taylor, LC Fuller (2003) The management of HIV-related skin disease, Part 1: Infections. Int J STD AIDS 14(2): 78-88 Glickel SZ (1988) Hand infections in patients with acquired immunodeficiency syndrome. J Hand Surg 13(A): 770-775 Health Protection Agency Centre for Infections, Health Protection Scotland and UCL Institute of Child Health (2010) Unpublished HIV/AIDS Surveillance Tables, No. 1:2010 Maurer TA, Berger TG (1998) Dermatologic manifestations of HIV. HIV InSite Knowledge Base Chapter http://hivinsite.ucsf.edu/ InSite?page=kb-04-01-01 Nervi SJ, Schwartz RA, Dmochowski M (2006) Eosinophilic pustular folliculitis: a 40 year retrospect. J Am Acad Dermatol 55(2): 285-9 Pahwa S, Biron K, Lim W, et al (1988) Continuous varicella-zoster infection associated with acyclovir resistance in a child with AIDS. JAMA 260(19): 28792882 Penneys NS (1995) Skin manifestations of AIDS (2nd ed). London: Martin Dunitz Centre for Disease Control (CDC) (1992) 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. MMWR, Recommendations and Reports. Dec 18, 1992/41(RR-17) Rico MJ, Myers SA, Sanchez MR (1997) Guidelines of care for dermatologic conditions in patients infected with HIV. J Am Acad Dermatol 37: 450-72 Sadick N, Kaplan MH, Pahwa SG, et al (1986) Unusual features of scabies complicating human T-lymphotropic virus type III infection. J Am Acad Dermatol 15(3): 482-486 Schwartz JJ, Myskowski PL (1992) Molluscum contagiosum in patients with human immunodeficiency virus infection: a review of twenty-seven patients. J Am Acad Dermatol 27(4): 583-588

Dermatological Nursing, 2011, Vol 10, No 1

12-17_HIV-AIDS_jhpC.indd 17

17

28/02/2011 14:06