Dermatological Conditions

Alexis Lara Rivero : Skin and Cancer Foundation. Sydney NSW
Mark Kelly : Armidale Rural and Referral Hospital, Armidale, NSW
Cassy Workman : Enmore Medical Practice, Sydney, NSW
Margot Whitfeld : Skin and Cancer Foundation, Sydney NSW

Approach to dermatological presentations

Dermatological conditions are common at all stages of human immunodeficiency virus (HIV) infection. Cutaneous manifestations of HIV can present as the initial sign of HIV infection either as part of a seroconversion illness or in association with infectious, inflammatory and neoplastic diseases, or even as a cutaneous drug reaction.   Since the advent of combination antiretroviral therapy (ART), dermatological presentations are increasingly encountered in the setting of immune reconstitution inflammatory syndrome (IRIS).

Although a few skin conditions occur almost exclusively in people with HIV infection, in general, the spectrum of dermatological conditions (Table 1) is similar to that found in the general population. These general dermatological problems may present as classically seen, or be found more frequently, or be atypical in presentation. Depending on the degree of immune suppression involved they are often less responsive to the usual therapies. Dermatological disease is a common presentation of IRIS and may associate with other organ involvement. With the restoration of the immune system the prognosis for resolution of skin disease is generally good.

Table 1          The spectrum of dermatological conditions affecting people with HIV infection

Rash morphology

Differential diagnosis

Follicular

Bacterial,  follicular eczema, eosinophilic folliculitis and Malassezia folliculitis

Eczematous

Psoriasis, dermatitis, Reiter syndrome, drug eruptions

Papular

Molluscum contagiosum, human papillomavirus, scabies cryptococcosis, and Kaposi sarcoma, pruritic and papular eruption of HIV

Macular / maculopapular

Secondary syphilis, parvovirus B19, disseminated candidiasis, widespread scabies and drug reactions
Consider opportunistic infections with skin manifestations, such as cryptococcosis, penicillinosis, histoplasmosis and coccidioidomycosis

Vesicular

Herpes zoster (varicella-zoster virus), herpes simplex virus and drug reactions

Petechial / pustular

Bacterial causes such as disseminated gonococcal infection, pseudomonal or staphylococcal sepsis, infective endocarditis, listeriosis. Also viral causes such as parvovirus B19, cutaneous vasculitis and drug reactions

Nodular

Prurigo nodules from persistent scratching, basal and squamous cell carcinomas, Kaposi sarcoma, mycobacteria,

Bartonella, histoplasmosis

Physical examination and investigation

History taking is essential (Table 2).  Note the distribution, type of rash and any other associated physical findings including: mucosal changes, hair and nail changes as well as musculoskeletal involvement, lymphadenopathy and organomegaly. If the patient is febrile, urine analysis, chest X-ray and blood cultures should be considered.

Table 2          History essentials in the setting of cutaneous presentations

HIV status

Current and nadir CD4 cell count, and viral load assays

History

Medical and surgical history

Medications

Current and recent medical therapy, including complementary therapy and over-the-counter medications

Contacts

ŸWith children and adults experiencing similar symptoms

ŸSexual contacts

ŸWith pets, animals, insects, wildlife

Occupation

Associated exposure

Travel

Recent and past

Swabs should be considered for pustular and vesicular lesions. Punch biopsy may also be useful for histopathology. Appropriate cultures or polymerase chain reaction (PCR) studies may need to be performed to detect opportunistic infections such as bacterial, atypical mycobacterial, viral or fungal infections. Imaging may be helpful in evaluating extracutaneous involvement if it is suspected.

Viral infections

All viral infections are more common and, depending on the degree of immunodeficiency caused by the HIV infection, the clinical presentation may vary from classical to atypical. Atypical presentations include multidermatomal herpes zoster, chronic ulcers due to herpes simplex and recalcitrant or extensive warts. Molluscum contagiosum umbilicated papules may enlarge and extend down hair follicles.

Herpesviridae infections

Cutaneous    disease    resulting    from    herpes    virus    infection includes:

  • Primary varicella zoster virus (VZV) infection
  • Dermatomal herpes zoster (HZ) from endogenous latent VZV reactivation
  • Chronic cutaneous and  mucocutaneous  ulcers  caused  by herpes simplex virus (HSV)
  • Disseminated papules of cytomegalovirus (CMV) infection
  • Oral hairy leukoplakia and Epstein-Barr virus

Varicella zoster virus: primary (varicella or chicken-pox) and secondary (herpes zoster or shingles) infections

Clinical presentation

The cutaneous presentation of primary and secondary VZV infection in patients with HIV commonly follows a typical course with crops of pruritic vesicles that become generalised in primary varicella and remain unidermatomal in HZ. In the setting of more advanced HIV infection, varicella is often more florid with a pronounced systemic prodrome (malaise, headache, fever and myalgia), has a prolonged course, and has a greater incidence of complications such as encephalitis, pneumonitis and hepatitis. Although mortality from varicella infection is somewhat higher in adults with HIV infection, children with HIV infection have a significant mortality rate from primary varicella infection and may also develop severe complications.[1]

HZ generally presents as a vesicular eruption involving one or more dermatomes. Most patients have prodromal pain in the affected dermatome before vesicular eruption.[2] This pain may be initially confused with other aetiologies.[3]

The classical rash of HZ is grouped vesicles or bullae, evolving into pustular and haemorrhagic lesions within a few days. Subsequently, crusting occurs and the resultant scarring may produce hypo or hyperpigmentation. The ulceration is often deeper and more prolonged, and scarring more severe. The diagnosis of HZ in the distribution of the ophthalmic division of the trigeminal nerve is important, as it can cause uveitis and keratitis. Ophthalmological review is indicated to minimise ocular complications.4 Disseminated cutaneous zoster has been defined as more than 20 vesicles outside the area of the primary and adjacent dermatomes, and is rare.[4]

Atypical, disseminated and chronic HZ infections usually occur in the setting of advanced HIV disease or IRIS. Chronic herpes zoster can present as indolent and chronic haemorrhagic, echthymatous or verrucous lesions.

The risk of HZ varies with the CD4 cell count. Increased rates of HZ occur in patients with a CD4 cell count of 50 to 200 cells/μL.[5],[6] Children with HIV infection who develop chickenpox have a higher incidence of developing HZ and are more likely to have recurrent HZ. A lower CD4 cell count increases this risk.7 VZV vaccination is important to consider in those with HIV infection.

Despite the established use of ART, the incidence of HZ has not decreased and patients remain at higher risk of HZ compared with the general population,[7], [8] particularly with CD4 cell counts of 50 to 200 cells/μL.[9] IRIS-related HZ presentations are generally uncomplicated and can be managed with oral antivirals such as acyclovir, valaciclovir or famciclovir.[10] Isolated cases of transverse myelitis, keratitis, iritis and acute retinal necrosis in the setting of IRIS have been reported.[11] It is thought that the use of ART may be protective against complicated zoster.[12]

Diagnosis

The   diagnosis   of   VZV   infection   is   usually   clinical.   If   the cutaneous presentation is atypical, or laboratory confirmation is required, VZV polymerase chain reaction (PCR) is used. In urgent cases, immunofluorescence can be performed within 2 hours, or a Tzanck smear considered. PCR for viral nucleic acid is highly sensitive and can also distinguish between HSV and VZV.[13] PCR is typically performed on vesicular fluid.[14] Antibody testing for VZV immunoglobulin IgM and IgG detects either acute infection or past exposure. Measurement of VZV IgG can determine immunity to varicella, which is useful in determining if patients need zoster immunoglobulin after varicella exposure, or varicella vaccination. VZV IgM is detected in acute chickenpox and in about 70% of people with HZ.[15]

Management, prevention and vaccination

Varicella   vaccine   has   been   demonstrated   to   be   safe   and immunogenic   in   children   with   HIV   infection   with   minimal symptoms and CD4 cell percentages according to their age of 25% or more.[16] A study evaluated the safety and efficacy of varicella vaccine in children with either moderate symptoms and CD4 cell percentages more than 15%, or a history of severe immunosuppression who had achieved immune reconstitution. Regardless of immunological category, 79% of vaccine recipients with HIV infection developed VZV-specific antibody or cell-mediated immunity, or both, 60 days after the immunisation series.[17] The current recommendations from the Advisory Committee on  Immunization  Practices  (ACIP)  of  the  Centers for Disease Control and Prevention states that single-antigen  varicella  vaccine  should  be  administered  to  children with   HIV   infection   with   a   CD4   T   lymphocyte   percentage greater than 15%, whereas the Australian guidelines currently recommend  vaccination  at  greater  than  25%.[18],[19],[20] The ACIP also recommend   that   single-antigen   varicella   vaccine   may   be considered in VZV-seronegative adolescents or adults with HIV infection with a CD4 cell count greater than 200 cells/μL. Two doses should be administered 3 months apart.[21],[22] A recent review reported the use of live-attenuated HZ vaccine in adults with HIV infection with a CD4 cell count over 200 cells/µL with immunogenic response, a good safety profile and no cases of vaccine strain infection.[23]

Zoster immunoglobulin is indicated for patients with HIV infection within 96 hours of significant first VZV exposure (e.g. household or classroom contact), and protection may last for approximately 3 weeks or alternatively a thymidine kinase inhibitor (acyclovir) can be given up to 7 days post exposure.[24]

In terms of prevention of HZ recurrences, one study found that the use of oral acyclovir among patients with HIV infection at a dose of 400 mg twice daily decreases the risk of HZ recurrence by 62%, although this result has not been repeated.[25]

Treatment of primary varicella zoster

Antiviral treatment for chicken pox is administered in neonates, children and adults with HIV infection or other immunocompromise or in those with severe, complicated disease. Treatment should begin within 24–48 hours of onset. Severe disease is treated with intravenous acyclovir.[26] 

Treatment of herpes zoster

Acyclovir, valaciclovir and famciclovir are efficacious in acute HZ and should be used in ophthalmic HZ and can ameliorate postherpetic neuralgia. Ideally antiviral therapy should be commenced within 72 hours of rash onset.[27] The choice of the drug will depend on the patient’s adherence, the doctor’s prescription habits and costs. However, all three drugs are equally effective and with a similar safety profile.[28],[29] Oral acyclovir has been the mainstay of HZ treatment, but it has poor bioavailability and needs to be given frequently. Valaciclovir and famciclovir need less frequent dosing (Table 3). There are no standard recommendations for treating children with HIV infection. However, the World Health Organization (WHO) guidelines suggest that the acyclovir dosage for HZ should be 80 mg/kg/day by mouth (maximum 800 mg per dose) or intravenous acyclovir 30 mg/kg/day in three doses for severe cases.[30] Novel drug therapies against herpes simplex and varicella-zoster viruses are currently in development and under clinical trials.[31]23

Table 3          Oral antiviral medications for herpes zoster

Medication

Dosage

Duration of treatment

Most common side effect

Precaution and contraindication

Acyclovir

800 mg  5 times a day

7-10 days or until lesions heal

Nausea,

gastrointestinal side effects

Dose adjust for renal impairment if creatinine clearance  < 25mL/min

Valaciclovir

1000 mg 3 times a day

7 days or until lesions heal

Nausea

Dose adjust for renal insufficiency, if creatinine clearance < 50mL/min.

Thrombocytopenic purpura and haemolytic uraemic syndrome reported at 8000 mg doses in immunocompromised patients

Famciclovir

500 mg 3 times a day

7 days or until lesions heal

Nausea, headache

Dose adjust for renal insufficiency if creatinine clearance  < 60mL/min

Source : Adapted from Dworkin, R, Johnson RW, Breuer J, Guann JW, Levin MJ, Backonja M, et al. Recommendations for the management of herpes zoster.   Clin Infect Dis 2007:44:S1

Acyclovir-resistant varicella zoster infection

Acyclovir-resistant varicella zoster infection is rare, especially in the post ART era, but when it does occur it is associated with significant mortality and morbidity. These patients usually have advanced disease with CD4 cell counts below 20 cells/μL. The presence of atypical lesions or a failed clinical response should prompt evaluation for acyclovir susceptibility. Foscarnet is recommended for the treatment of acyclovir-resistant zoster infection.[32]

Herpes simplex virus

Clinical presentation

HSV types 1 and 2 are the causative agents of herpes labialis, herpes genitalis, herpes gladiatorum, herpetic whitlow, herpetic keratoconjunctivitis, eczema herpeticum, herpes folliculitis (herpes sycosis), lumbosacral herpes, disseminated herpes, neonatal herpes and herpes encephalitis. They have also been linked to some cases of erythema multiforme.[33]

The onset of clinical illness is usually sudden, with the appearance of multiple characteristic vesicular lesions superimposed upon an inflammatory, erythematous base. Primary infection may also be associated with systemic symptoms such as fever and malaise. In the setting of HIV infection, HSV lesions may be chronic, larger, atypical, more widespread in distribution, and extend into deeper cutaneous layers resulting in necrotising ulcers. The presence of herpes ulcers for 1 month or more in patients with HIV infection is considered an AIDS-defining illness. Recurrent episodes are common in HIV. Mucocutaneous herpes can present as an IRIS- like phenomenon in patients initiated on ART.[34]

Most people with sexually-acquired HIV have HSV-2 co-infection. Recently studies have shown an association between HSV-2 infection and HIV acquisition. HIV-1 is shed from genital ulcers caused by HSV-2.[35] In this setting, ART has little influence on frequency or level of mucosal HSV-2 shedding, with 85% of episodes being subclinical. Frequent subclinical episodes of HSV-2 reactivation are associated with both a higher frequency and a higher amount of HIV-1 in genital secretions. In addition, valaciclovir has activity against HIV replication.[36] In spite of this proven interaction between HSV-2 and HIV, there is no strong evidence that supports the acceleration of the HIV disease progression, either clinically or regarding the decrease of CD4 cells count, with the HSV-2 co-infection.[37],[38] However, acyclovir appears to have both some direct anti-HIV activity as well as some indirect immunologic changes.[39]

Diagnosis

The diagnosis of mucocutaneous HSV is made by clinical observation in uncomplicated cases and in atypical cases HSV PCR of lesion secretions may be required. Viral cultures from swabbed vesicles are required for resistance testing.

Management

Few randomised, controlled trials have been performed in patients with HIV infection. Acyclovir, famciclovir and valaciclovir have all been shown to be safe and effective as both intermittent and continuous therapy for HSV-2 clinical and subclinical infection in HIV-positive men and women.[40]

In the majority of situations, mucocutaneous HSV responds to oral therapy with acyclovir (400 mg three times a day); valaciclovir (1g twice a day); or famciclovir (250 mg three times a day). Primary episodes are treated for 7 to 10 days; recurrent episodes are treated for 5 days.[41] If standard dosing fails, biopsy and culture should be performed to obtain viral sensitivities and to exclude alternative pathology. Higher doses may be useful with acyclovir 800 mg twice a day or valaciclovir 1 g three times a day.[42] Severe cases or clinically-unresponsive confirmed cases may require high doses of oral agents or, rarely, intravenous acyclovir. Treatment of acyclovir-resistant HSV includes non-thymidine kinase dependent therapies such as foscarnet or cidofovir.[43]

Prevention

Chronic antiviral suppressive therapy is suggested for HIV-seropositive people whose herpetic disease is poorly controlled.[44],[45] Valaciclovir 500 mg twice a day or acyclovir 400 mg twice a day is recommended for suppressive therapy.[46] In addition, people with HIV and HSV-2 co-infection who are sexually active should be advised of the association between HSV-2 reactivation and mucosal HIV-1 shedding. Although the topical use of tenofovir to inhibit HIV-1 transmission demonstrated antiherpetic activity, the reduction of risk for HSV-2 transmission was reported to be around 50%.[47] Suppressive acyclovir did not decrease the risk of HSV-2 transmission from persons with HSV-2/HIV-1 infection to susceptible partners.  Therefore, more effective prevention strategies to reduce HSV-2 transmission from persons with HIV-1–infection are required.[48]

Human papilloma virus (warts)

Clinical presentation

HPV infection results in common warts (verruca vulgaris), plantar warts, filiform, condylomata accuminata (CA) and mucocutaneous warts, which can occur in the oral, ocular and anogenital mucosa.[49] CA is the most common clinical form of anogenital warts.[50] Although warts may be larger, multiple, recalcitrant to therapy and disfiguring, with a significant psychological burden, most commonly the warts look like those found in the general population. While most cases are asymptomatic, some patients may experience pruritus, mild burning or bleeding.[51]

In general, HPV infections are considered benign. In the anogenital areas however, it can be more difficult with both common genital warts (usually HPV types 6 and 11) occurring, as well as other lesions due to other wart types.[52]  The well-defined plaques of erythematous lesions of both low-grade and high-grade disease are often due to HPV 16 and 18. Anal squamous carcinoma can arise de novo or from pre-existing areas of dysplasia.[53]

HPV types 16, 18 and several others have oncogenic potential and have been shown to be associated with malignant transformation.[54] Cutaneous squamous cell carcinoma neoplastic transformation can occur   in association HPV infection of the skin, oral mucosa, pharyngeal, cervix, vulva, and anogenital mucosa. Bowen disease can occur. These can be ether in situ or invasive carcinoma.[55]

Diagnosis

The   diagnosis   of   HPV   warts   is   usually   clinical.   It   can   be confirmed by whitening of the mucosa when acetic acid is applied. This can be done with and without magnification, including colposcopy and anoscopy. Cytologic examination is used for mucosal evaluation. 42 Perianal, anal and penile intraepithelial neoplasia classically present as a velvety erythematous plaque or as a hyperpigmented well-defined plaque. A biopsy is helpful in establishing a diagnosis, particularly in verrucal lesions unresponsive to therapy or when warts have unusual features, such as hyperpigmentation, ulceration or excessive bleeding.[56]

Management

Treatment is directed on the alleviation of signs and symptoms with traditional treatment modalities focusing on the destruction of infected tissue.  This includes cryotherapy, imiquimod, podophyllin resin, podophyllotoxin, salicylic acid, trichloroacetic acid, laser and surgical techniques. Despite the fact that patients with HIV infection tend to have larger or more numerous lesions, and might not show good response to therapy, data do not support altered approaches to treatment for persons with HIV infection.[57] 43 Antiretroviral therapy does not seem to reduce the incidence or persistence of genital warts in this population.{/ref}

Immunomodulatory  compounds  with  antiviral  properties have  demonstrated  superior  efficacy   with   clearance   rates up to 77% and low recurrence rates in some recent studies.[58]  Topical imiquimod 5% has however been proven to be safe and effective and is recommended for those with CD4 cell counts of more than 200 cells/μL or who are on ART. Best outcomes have been with application three times a week for 6-10 hours until visible inflammation occurs and the warts disappear. Side effects can be controlled by decreasing the frequency of application.[59] Recently, topical cidofovir has been demonstrated to be effective in treating anogenital warts in patients with HIV infection. However, its cost limits its widespread use. Combining surgical and medical therapies may have a beneficial effect on treatment outcomes.[60]

The management and monitoring of cervical intraepithelial neoplasia and anal intraepithelial neoplasia are described in section Oncological conditions.

Molluscum contagiosum

Molluscum contagiosum (MC) virus is a poxvirus that causes a chronic localised infection most often seen in children, but also occurs in adults and in  immunocompromised patients. The severity of MC is inversely related to the CD4 cell count. MC is spread by direct skin-to-skin contact, occurring anywhere on the body except the palms of the hands and soles of the feet.

Clinical presentation

The classic lesions of MC consist of dome shaped, flesh-coloured 2-6 mm papules with central umbilication containing either a molluscum body or caseous material. The papules can be pruritic.  Molluscum altered by the immunosuppression of HIV is often larger and more numerous; and persistent lesions may occur. MC tends to appear in patients with HIV infection with advanced disease.[61] Most commonly, MC is on the face, neck, genitals, creases and folds or sites of friction e.g. axilla and groin.

Diagnosis

The diagnosis of MC is usually clinical although a biopsy of the papules may be required if alternate diagnoses are being considered. A lesion smear using Giemsa staining can demonstrate the molluscum bodies. When multiple lesions are present, vulvar syringoma and condyloma acuminatum should be considered. Cutaneous Cryptococcus infection manifesting as a molluscum-like eruption has been reported in patients with acquired immune deficiency syndrome (AIDS).[62]

Management

MC is usually self-limiting and spontaneously resolves after a few months in immunocompetent hosts. In the setting of advanced HIV immunodeficiency, the recalcitrant lesions often improve with immune reconstitution on ART.[63]  Genital lesions should be definitively treated to prevent spread by sexual contact. General advice about the risks of autoinoculation and spreading should be given, such as avoiding waxing or shaving areas with active lesions, instructing patients about not to share clothing or towels, and explaining that condoms may reduce the risk of transmission, but are not absolute.[64] Most common alternatives are curettage, cryotherapy, deroofing the lesions, or laser therapies to remove individual lesions. Topical therapies include: cantharidin (single application that may need to be repeated); tretinoin cream (0.1%) or gel (0.025%) daily; podophyllin; trichloroacetic acid; imiquimod applied under occlusion; silver nitrate or phenol. Topical cidofovir, although expensive, may be useful in recalcitrant disease.[65]

New lesions or inflammation of existing MC lesions may appear in the context of IRIS before disappearing with restored immune function.[66]

Fungal infections

Cutaneous presentations of fungal infections in HIV in Australasia include tinea, Candida, Malassezia, cryptococcosis, penicillinosis and pneumocystis.

Dermatophyte infections

Clinical presentation

Dermatophytosis is most   commonly   due to Trichophytum rubrum, frequently causing tinea cruris, corporis and onychomycosis. Despite ART and fluconazole prophylaxis, superficial dermatophyte infections can be atypical, widespread and refractory in this setting. Dermatophyte infections may also have deep dermal morphologies. These present as multiple fluctuant erythematous ulcerative nodules on the extremities and often are in areas of chronic superficial dermatophytosis. Atypical presentations of T. rubrum also include firm violaceous nodules and papules due to nodular granulomatous perifolliculitis usually with co-existing onychomycosis and tinea pedis. Proximal nail white onychomycosis is also a marker of HIV infection, although some studies have shown that HIV infection is not associated with an increased susceptibility to dermatophytosis.[67], [68], [69] Culture of the fungal skin or nail scraping may be required if the speciation of the fungus is required or microscopic analysis of the samples give negative results.

Management

Superficial disease can be initially treated topically. In children and adults (including pregnant women), localised tinea infections may be treated with topical terbinafine 1% cream/gel (for 2 weeks) or miconazole 2% (for 3 to 4 weeks). However, if this fails or if there is widespread or dermal disease, systemic antifungal therapy is recommended. Duration of treatment depends on the type of therapy and the location of the fungal infection. Treatments of choice include terbinafine, griseofulvin and itraconazole. Onychomycosis can be treated with terbinafine for up to 12 weeks.[70][71]

Candida infections

Clinical presentation

Candidiasis affects the oral, vaginal and gastrointestinal tract mucosae. Oral candidiasis is the most common, usually presenting as white, exudative, mucosal plaques on the tongue, and oral mucosa. It can also   present   as   the   erythematous/atrophic   erythematous   form without white plaques which is often missed. Alternative presentations include angular cheilitis with erythema and white scale, and chronic hyperplastic candidiasis with discrete leukoplakia. In patients with oropharyngeal candidiasis, dysphagia should prompt a presumptive diagnosis of Candida esophagitis, and endoscopy is required for definitive diagnosis.[72]  Recurrent episodes of vulvovaginal candidiasis (VVC) are also common in HIV. Symptoms of VVC are pruritus, dyspareunia and dysuria. The vulval component of the infection presents as a morbiliform rash with papulopustules that may extend to the thighs, and the vaginal infection is associated with white cheesy discharge, and plaques are seen on erythematous vaginal walls.[73]

Diagnosis

The diagnosis of candidiasis is usually made clinically. Samples for microscopic examination and cultures are usually required when fungal resistance is suspected.

Management

Topical therapies like nystatin or clotrimazole are often used initially.[74], [75]  Systemic  antifungal therapy  is  often  required;  fluconazole  is  the  agent  of  choice at a dose of 150 mg single dose given immediately. Itraconazole and voriconazole are alternative agents for disease that is not responsive to fluconazole.  Secondary prophylaxis with fluconazole is not normally recommended but may be used for recurrent disease.[76]

Malassezia infections

Clinical presentation

Malassezia has seven different subspecies that cause or contribute to a spectrum of conditions including pityriasis versicolor,  seborrhoeic dermatitis, atopic dermatitis, infantile acne and malassezia folliculitis, with M. globosa and M. furfur the most common species isolated, particularly from HIV patients .[77], [78] Malassezia   can  present  in  the  setting  of  HIV  as  pruritic pustules,  macules  or  papules  on  the  face,  chest,  back  and shoulders.  Due to its morphology and distribution it may be confused with acne vulgaris. However, malassezia folliculitis does not show comedones on the skin, which helps to distinguish it from  acne vulgaris.[79]

Diagnosis

The diagnosis relies on a KOH preparation test from skin scrapings. Small, round yeast cells and short, hyphal filaments are seen on microscopy.

Treatment

Topical ketoconazole and miconazole can be used initially but systemic fluconazole or itraconazole may be used if topical therapy fails.[80], [81]

Cryptococcosis

Cryptococcus neoformans is the most common invasive fungal infection in patients with HIV infection. Cutaneous disease due to dissemination is an AIDS-defining illness.[82]

Clinical presentation

Approximately   10-20%   of   patients   with   HIV   infection   and cryptococcal infection have cutaneous lesions, which usually represent   haematogenous   spread, and it is a marker of disseminated infection.[83], [84]   These   lesions   can   have varying   morphologies   including:   umbilicated   papules   and nodules similar to molluscum, erythematous papules, nodules, pustules, ulcers, herpetiform vesicles and infiltrated plaques or subcutaneous swelling. The differential is broad and therefore the lesions should be biopsied and cultured.[85] 

Diagnosis

The diagnosis of cutaneous cryptococcal infection requires investigation for systemic disease. Biopsies may demonstrate granulomas, which may be absent in the immunocompromised state. Cryptococcal antigen can be measured in blood and body fluids or the organisms demonstrated in cerebrospinal fluid (CSF) by India ink staining.[86] Blood cultures should be taken. Peripheral blood eosinophilia is a common but unspecific marker for disseminated cryptococcal infection.[87] 

Management and prevention

Cutaneous cryptococcosis without evidence of central nervous system invasion can be treated with fluconazole 200-400 mg/day. If extracutaneous disease is found then the recommended treatment is amphotericin B 0.7 mg/kg/day and flucytosine 100 mg/kg/day, for at least 2 weeks, and then followed by fluconazole 400 mg daily for at least 8 weeks. Liposomal forms of amphotericin B have proven to have a better safety profile for amphotericin B-induced kidney injury, and similar or even superior efficacy compared with amphotericin B deoxycholate. However, the cost can be a limiting factor for its use.[88]

Patients newly diagnosed with HIV infection with CD4 counts  below 50 cells/μL, should be tested for cryptococcosis prior to starting ART. If positive, it is recommended to withhold ART for at least 2 weeks after starting antifungal therapy for cryptococcosis.[89],[90] Primary prophylaxis is not recommended, particularly in the absence of a positive serum cryptococcal antigen. However secondary prophylaxis is the standard of care with either fluconazole 200- 400 mg/day or itraconazole 400 mg daily. It can be discontinued with immune reconstitution of CD4 cell counts over 200 cells/μL for 6 months (see section Key opportunistic infections).[91] 

Penicillinosis

Penicillium marneffei is a fungus that can cause a fatal systemic mycosis in patients with HIV infection. It is endemic in tropical Asia where it is the third most common opportunistic infection in patients with AIDS after tuberculosis and cryptococcosis.[92] 

Clinical presentation

Disseminated P.  marneffei infection in HIV presents as fever, anaemia, weight loss, lymphadenopathy, hepatosplenomegaly, respiratory signs and cutaneous lesions. Cutaneous lesions are of particular importance, appearing in 75% of patients who have penicillinosis, and are specific for the disease. The typical cutaneous lesions are umbilicated papules with central necrotic core. Other morphologies include: ecthyma-like lesions, folliculitis, subcutaneous nodules and morbilliform eruptions.[93] The distribution is on the face and neck and less commonly on the limbs and torso. The differential diagnosis of these lesions includes molluscum contagiosum, Histoplasma and Cryptococcus.[94] ) Patients with severe or persistent dyspnoea, ascites, and increased lactate dehydrogenase (LDH) blood levels are considered at high risk to have a fatal outcome.[95], [96] Cutaneous ulcerations due to P. marneffei in the context of ART have been anecdotally reported, with few cases reported as IRIS phenomenon.[97], [98] 

Diagnosis

Microscopic diagnosis by identification of P. marneffei in clinical specimens can be made before cultures are positive, by demonstration of intracellular P. marneffei yeast cells in the infected tissue. Serum galactomannan test can be useful for diagnosing penicilliosis and results are available within hours, prompting for systemic antifungal therapy if results are positive.[99], [100]

Management and prophylaxis

There  is  a  poor  prognosis  with  a  high  mortality  rate  in  the setting of delayed diagnosis and antifungal therapy. Standard primary treatment is 2 weeks of parenteral amphotericin B at a dose of 0.6 mg/kg/day, followed by 400 mg of itraconazole per day orally in two divided doses for 10 weeks.[101] Prolonged secondary suppressive therapy with oral itraconazole (200 mg once daily) is required to prevent relapse.[102]

All patients with HIV infection and with CD4 counts below 100 cells/ μL who reside or stay for a long period in South East Asia, particularly in rural areas, should be administered primary prophylaxis. Oral itraconazole, 200 mg/day is the preferred choice, but an alternative drug is oral fluconazole 400 mg once weekly. Primary prophylaxis is not formally indicated in other geographic areas to date.[103] 

Pneumocystis jirovecii (carinii) 

Clinical presentation

Infrequently skin lesions of Pneumocystis jirovecii have been reported with a variety of morphologies. They may present as friable, reddish papules or nodules in the nares or external auditory meatus or resemble molluscum contagiosum lesions. The skin lesions are due to disseminated disease (see section Pneumocystis jirovecii pneumonia). With the advent of ART, extrapulmonary cases of Pneumocystis are exceedingly rare to date, particularly with skin involvement.[104], [105]

Diagnosis

Lesional   biopsy   with   staining   for   microscopy   stains   with Gomori’s methenamine silver or Steiner stains to show foamy-appearing cells with a teacup and saucer appearance. 72 PCR for diagnosing Pneumocystis has been introduced as an alternative method with quicker results.[106]

Parasitic infections

Scabies

Scabies is caused by Sarcoptes  scabiei  var  humanus   and commonly presents in patients with HIV infection in a similar manner to the immunocompetent population.[107] There are other types of mites that can cause a myriad of dermatologic symptoms but that do not display characteristic features as scabies does. However, some of these mites can be vectors for bacterial and rickettsial diseases, in contrast to Sarcoptes.[108], [109] Scabies transmission occurs by direct skin-to-skin contact with a person who has the infection. The likelihood of transmission is higher when the parasite burden in the affected patient is bigger. Transmission via inanimate objects, such as shared clothing, is rare, but it occurs in immunocompromised individuals.[110]

Crusted scabies has been reported to be extremely frequent in remote communities in the Australian Northern Territory, but not related to HIV infection.[111] 

Clinical presentation

In patients with HIV infection, both the classic form and crusted Norwegian scabies (named because of its initial description in Norwegian patients with leprosy) can occur. The classic  form can occur at  any  CD4  cell  count,  while  Norwegian  scabies is  usually  seen  in  patients  with  a  CD4  cell  count  below 150 cells/μL.([112]  Classic scabies presents as papulovesicular lesions. The distribution varies, favouring the wrists, interdigital web spaces, elbows, axillae, breasts and genitals. Predominantly night-time pruritus is usually seen. Due to the associated pruritus, excoriation of the lesions often occurs. Bacterial superinfection may occur with impetigo, cellulitis and, in some cases, fatal sepsis. In patients with neurological disorders or immunosuppression, the number of mites can increase unchecked due to the impaired immunity, absence of pruritus or the patient’s physical inability to scratch. Clinically, the eruption is suspected when there is marked thickening, often psoriasiform plaques, papules and crusting of the skin. It occurs primarily on the hands, although the entire body including the face and scalp is often involved.[113]

Diagnosis

The diagnosis is usually clinical. Medical practitioners with experience in dermoscopy can increase the accuracy of the clinical diagnosis with this tool.[114], [115]  Definitive diagnosis of scabies is by microscopic examination of the scrapings in potassium hydroxide 10% solution, demonstrating mites, ova or faeces. The skin is scraped with a sterile blade and the skin sample is placed in mineral oil for transport.[116]  A standard skin biopsy may make the diagnosis. 

Management

People  with  a  CD4  cell  count  over  200  cells/μL  usually respond  to  a single total body application of  topical  permethrin  (5%)  left on for 8 to 14 hours, and repeated after  1 week. If permethrin is not available, benzyl benzoate 25% emulsion for 24-36 hours. The lotion is usually applied once daily at night on 2 or 3 consecutive days. Sulphur 5-10% in cream or paraffin for 3 consecutive days and repeated in 1 week, may be another alternative option, particularly for neonates.[117], [118]  Treatment also involves hot water washing and drying of clothing and linen harbouring the mite. The mite cannot survive longer than 4 days without epidermal contact. Skin lesions and pruritus usually resolve within 6 weeks, the time-frame given before treatment failure is diagnosed.[119]  After that time, re-evaluation of causes of persistent itch should be explored. They include cutaneous irritation secondary to over-treatment (this responds to topical steroids), contact dermatitis from scabicide, treatment failure from low compliance, resistance or relapse (possibly secondary to poor scalp treatment) or delusions.

Treatment failure may also be related to degree of immunosuppression and high mite burden. Repeated applications may be required, especially for patients with crusted scabies. Often, topical treatment does not penetrate the lesions of crusted scabies sufficiently for eradication. Therefore, keratolytic treatment with topical salicylic acid 5-10% or urea 40% can be given concomitantly.[120], [121] In adults, systemic therapy of oral ivermectin 200 μg/kg in two doses 2 weeks apart can be given. However, topical permethrin has a faster onset of action in terms of itch control and reducing lesions count.[122]   Prophylactic treatment should be given for all household members and sexual contacts.[123]

Crusted scabies is highly contagious due to the massive number of mites released in the patient’s flakes to the surrounding environment, and the transmission via fomites is common for this type of scabies.[124] 

Non-infectious disease

Seborrhoeic dermatitis

Seborrhoeic   dermatitis   is   a   very   common   non-infectious cutaneous presentation of HIV and is observed in 85% of patients with AIDS.[125]  In some instances it may be the initial cutaneous manifestation of HIV disease. Although it can present at any CD4 cell count, increased severity and extent of involvement with poorer response to treatment occurs with worsening immunosuppression. Malassezia  may have a role in the pathogenesis of this disease.[126]  However, fungal overgrowth or a rise in the levels of IgG titers against the yeast in HIV-1-seropositive patients has not been demonstrated.[127]  

Clinical presentation

Patients have erythema and yellow-white greasy scaling of the sebaceous areas of the scalp, nasolabial folds, chest, back and intertriginous zone. The eruption is characterised by widespread hyperkeratotic, greasy, inflammatory lesions and may progress to erythroderma.[128]  This entity, similar to that in the immunocompetent population can have a clinical overlap with psoriasis. Examination of the patient for co-existing psoriasis should also occur.

Diagnosis

The   diagnosis   is   made   clinically.   Histological   assessment may reveal marked hyperkeratosis, confluent parakeratosis, follicular plugging, acanthosis, spongiosis with lymphocyte, and neutrophil exocytosis with keratinocyte necrosis and dyskeratosis.[129]  It has been proposed that histopathologic features and tissue molecular profile of HIV-associated seborrhoeic dermatitis are different from those found in immunocompetent patients, but they are not still considered pathognomonic.[130], [131]

Management

Initial therapy includes anti-dandruff shampoo for mild disease with addition of ketoconazole shampoo and cream (two to three times per week for 4 weeks, with a maintenance treatment once per week as needed), topical steroids, selenium sulfide, ciclopirox, salicylic acid and tars for advanced disease. Ultraviolet B (UVB) light therapy is another modality in addition to topical therapies.[132], [133], [134] 83,84,86 Severe seborrhoeic dermatitis and seborrhoeic dermatitis unresponsive to first-line therapy should be treated with a combination therapy of topical antifungals (e.g. ketoconazole 2%) and topical corticosteroids.[135] Pilot studies have demonstrated the benefit of topical pimecrolimus cream 1% twice daily in adults with facial seborrhoeic dermatitis who had not responded satisfactorily to conventional topical corticosteroids and antifungals.[136] Systemic therapy with oral antifungals, prednisone or isotretinoin is not routinely indicated.[137], [138]  

Xerosis

The underlying cause of xerosis in HIV is unknown; it may in part be linked to poor nutritional status, chronic illness and immunosuppression. It is cited as affecting approximately 30% of patients with HIV infection.[139]  Xerosis and ichthyosiform changes of the skin have been considered by several authors as a marker for disease progression as it also correlates with CD4+ T lymphocyte count decline.[140]. [141] 

Clinical presentation

There are varying degrees of xerosis, but it is generally characterised by diffuse dryness of the skin with hyperpigmented scales and focal crusting.  If secondary fissuring occurs, superinfection from breaches in the protective skin barrier can complicate the clinical picture.

Diagnosis

Diagnosis is based on the clinical presentation.

Management and prevention

Adequate nutrition is important.  Dry skin care regimens are effective in the management of this condition, with emollients, including those with urea, lactic acid or salicylic acid.[142]

Psoriasis

Psoriasis affects 2-5% of the population with HIV infection compared to a prevalence of 1-2% in the general population.[143], [144]  Patients often present with more severe disease. It has been suggested that the immunodysregulation from HIV infection can trigger psoriasis in those genetically predisposed to it.[145]  The presence of the haplotype Cw*0602 seems to be more prevalent among the population with HIV infection with psoriasis.[146]  The Th17 pathway recently discovered to be involved in psoriasis is subject of active research for potential therapeutic targets. [147])

Clinical presentation

Psoriasis may present for the first time at progression to AIDS. There  are reports  of improvement of  psoriasis in the setting of immune reconstitution with ART, after initial flares.[148]  HIV infection may alter the course of psoriasis in individual patients with some patients having co-existing patterns of psoriasis such as both guttate psoriasis and psoriasis vulgaris.[149]  More extensive lesions with Increased presence of acral lesions and inverse psoriasis are more frequent.1  Severe  exfoliative  erythroderma  may also occur.[151] Patients with HIV infection are more likely to have arthritis associated with psoriasis.[152]  

Diagnosis

The diagnosis of psoriasis is clinical and can be confirmed on a biopsy.

Management and prevention

Spontaneous remission to complete unresponsiveness to all therapy has been described for HIV-related psoriasis. Topical therapy includes tar products, emollients, salicylic acid, corticosteroids and retinoids. Traditional systemic therapies such as acitretin (0.5-1 mg/kg) are also used. Methotrexate, although commonly used in the non-HIV psoriatic population, is not commonly used because of its immune modulating effects and increased toxicity in the folate metabolic pathway with diminished renal excretion in many HIV patients also taking trimethoprim/sulfamethoxazole. Cyclosporine can be prescribed at 2·5 mg/kg per day, but careful monitoring of the drug trough concentration is recommended. Cyclosporine is recommended for short intermittent courses of up to 12 weeks. It can also be used when rapid remission is needed in potentially lethal psoriasis variants such as erythroderma or generalised pustular psoriasis.[153]  The use of UV light therapy is debated.[154]  Biologics are being increasingly used for psoriasis and, although there are limited reports, antitumour necrosis factor therapy has been used with success in patients with HIV infection with progressive psoriatic arthritis.[155]  the safety profile of the biologic therapies has yet to be determined in the context of HIV infection.

Eosinophilic folliculitis, pruritic papular eruption and other inflammatory folliculitides

Eosinophilic folliculitis (EF) is a common intensely pruritic condition often occurring in advanced disease or the situation of IRIS, commonly 3 to 6 months post commencement of ART.[156]  There is significant associated morbidity and disfigurement.[157]  The role of usually non-pathogenic commensals of the skin including Malassezia  yeasts , Demodex mites, Corynebacterium and Staphylococcus is debated.[158]  Clinicians should be aware that patients who are about to initiate ART, regardless of regimen, may develop EF during the first 3- to 6-month period after commencing therapy.[159]  Pruritic papular eruption (PPE) or HIV prurigo is an incompletely understood entity in HIV with symmetrical papular eruptions on the trunk and limbs in the absence of other definable causes of itching.[160]  

Although some believe that eosinophilic folliculitis and pruritic papular eruption are part of the same disease spectrum, the distribution of both diseases are different.[161]   PPE occurs more in acral areas and photoexposed areas, and hypersensitivity to arthropod bites or a form of chronic recall reaction to arthropod antigens in the setting of HIV-associated immune dysregulation has been suggested.[162]  

Clinical presentation

Eosinophilic folliculitis presents as intensely pruritic 2-3 mm erythematous oedematous urticarial papules centred on follicles and may have pustules. The distribution is over the forehead, neck, shoulders, trunk and upper arms. Occasionally it can become generalised. Due to the associated pruritus, secondary change with time is common. This includes excoriations with secondary staphylococcal infection, prurigo nodularis, lichen simplex chronicus and postinflammatory pigmentary changes.[163], [164]  

PPE appears as multiple papules, typically symmetric, on the trunk and extensor surfaces of the extremities, as well as on the face, with sparing of the palms and soles. Because of the chronic nature of PPE, the papules are often excoriated and develop inflammation, hyperpigmentation and scarring. Over time, severe inflammation causes the papules to become nodular in appearance.[165] 

Diagnosis

The differential diagnosis is difficult and includes the common causes found in patients without HIV infection such as insect bite reactions, scabies, dermatitis herpetiformis, drug reactions, atopic dermatitis and bacterial folliculitis. Differential diagnoses and their management are listed in Table 4.

Skin biopsies from EF lesions display a folliculocentric predominance of eosinophils and lymphocytes, with frequently associated lysis of the sebaceous gland. In contrast, PPE lesions show a wedge-shaped mild-to-moderate perivascular and interstitial infiltrate of lymphocytes and eosinophils, similar to the microscopic findings of arthropod bites or stings. This, together with eosinophilia and elevated IgE levels, has led to the suggestion that PPE can be the result of an exaggerated immunological reaction to arthropod bites or stings.[166], [167]  

Management

Depending on the cause, management varies, particularly if an infective cause such as scabies is found. The difficulty arises in the diagnosis of eosinophilic folliculitis and pruritic papular eruption, which are usually exclusion diagnoses (Table 4). Eosinophilic folliculitis and pruritic papular eruption can be difficult to manage with the pruritus often unresponsive to traditional therapies. Treatment options for eosinophilic folliculitis and pruritic papular eruption are similar with potent topical corticosteroids, oral antihistamines, oral antibiotics, emollients, antifungals, antiscabies and phototherapy treatments all being recommended.[168], [169] 

WHO guidelines emphasise that In children, adolescents, pregnant women and adults with HIV infection with PPE or EF, ART should be considered as the primary treatment. If PPE or EF appears after the introduction of ART, it should not be discontinued. If there is no response or a failure in response, other causes of papular eruptions of HIV must be considered.[170] 

Table 4.    Differential diagnosis of pruritic papular eruptions

 

Pruritic papular

Eruption

Eosinophilic folliculitis

Demodex

folliculorum

Scabies

Folliculitis: Bacterial (B)

Pityrosporum (P)

Clinical findings

Skin-coloured papules

Excoriations

Pustules rare Postinflammatory hyperpigmentation Prurigo-like nodules Scarring

Oedematous  papules Pustules not predominant Postinflammatory hyperpigmentation Prurigo-like nodules Scarring

Rosacea-like erythematous papules with background erythema

Papules/ plaques with crust or excoriations Burrows Vesicles Nodules Eczematous changes especially

in crusted Norwegian scabies

Pustules predominate Follicular pattern Perifollicular papules

Distribution

Symmetrical Extremities, face, trunk

Rare on palms, soles, digital web spaces

Forehead, eyelids, cheeks, neck, postauricular, upper arms and trunk

Head, neck

Hands, wrists, interdigital, ankles, ears face, scalp

B: head, neck. upper trunk, axillae, groin, buttocks

P: back, chest, shoulders

Histopathology

Dermal perivascular and interstitial lymphocytes, eosinophils Epidermal hyperplasia Follicular damage?

Follicular spongiosis Folliculocentric infiltrate rich in eosinophils

Flames figures Eosinophilic abscesses

Spongiotic, infundibular folliculitis

Scabies mite faeces or eggs in epidermis Eosinophils in reticular dermis

B:  Staphylococcus aureus: suppurative folliculitis, gram stain P: yeast forms

Investigations

Increase IgE Eosinophilia CD4  <100/μL

Increase CD8 T cells increase IgG ? Antibodies to bullous  pemphigoid antigen?

increase IgE Eosinophilia CD4  <300/μL

Skin scraping

Skin scraping PCR from scale

Skin swab

P: KOH yeast forms

Treatment

Potent topical steroids 

Emollients Antipruritic lotions Antifungal creams

Antiscabies therapy Antihistamines

Oral antibiotics Pentoxifylline Antiretrovirals

UVB phototherapy

Potent topical steroids Antihistamines Prednisone Metronidazole Itraconazole Permethrin/ ivermectin Isotretinoin Dapsone

UVB

1% tacrolimus ointment

Permethrin Oral/topical metronidazole Ivermectin

Permethrin Malathion Sulphur ointment Ivermectin

B: intranasal mupirocin ointment

Topical benzoyl peroxide

Topical or oral antibiotics

Antibacterial washes P: topical antifungals Selenium sulphide shampoo

50% propylene glycol in water

Fluconazole Itraconazole

KOH = potassium hydroxide; PCR =  polymerase chain reaction; Ig = immunoglobulin, UBV = ultraviolet B light.

Source Eisman S.  Pruritic Papular Eruption in HIV. Dermatol Clin  2006;24(4):449-57.

Serious adverse drug eruptions including Stevens- Johnson syndrome and toxic epidermal necrolysis

Cutaneous  drug  eruptions  are  reported  more  frequently  in people with HIV infection.[171]) The majority of adverse cutaneous reactions to medications have a low morbidity and mortality and are self-limited. Of note, sulfonamide-induced drug reactions occur in as many as 29-65% of patients with HIV compared with 2-4% of other patients. Often patients with HIV have morbilliform (maculopapular), nonpruritic, nonblistering rashes, as can patients without HIV.[172] 

Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) belong to a spectrum of serious disorders with Stevens-Johnson syndrome at one end and TEN at the other. Both disorders are rare, and virtually always represent an idiosyncratic, adverse drug reaction. The incidence is higher in patients with HIV infection than in the general population, probably due to the decrease in CD25+ regulatory T cells (T-regs) and CD4 cells in the skin, which subsequently leads to an upregulation of cytotoxic CD8 T cells.[173]  There have been well documented case reports of Stevens- Johnson syndrome and TEN in the setting of HIV treatment with protease inhibitors and, most commonly, nevirapine.[174]  Stevens-Johnson syndrome and TEN are also seen in the context of HIV treatment with sulfonamides, and are thought to be attributable to reactive metabolites.[175] 

Clinical presentation

Patients may present with a prodrome of fever, stinging eyes, painful swallowing, followed by the development of dusky erythematous macules that progress to flaccid blisters. Two or more mucous membranes are usually involved, with erythema and erosions of the buccal, genital and ocular mucosa. Severe ophthalmic involvement may lead to permanent scarring and blindness. Epidermal detachment is common, which may lead to massive fluid loss and electrolyte imbalance.

Although several classification systems for Stevens-Johnson syndrome and TEN exist, the most widely accepted divides the spectrum into five categories (Table 5).[176] 

Table 5.    Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme

1. Bullous erythema multiforme:  epidermal detachment involving < 10% of the body surface, couple with localised typical target or raised atypical targets

2. Stevens-Johnson  syndrome  (SJS):  epidermal  detachment  of  < 10%  of  the  body  surface  in  association  with  widespread erythematous or purpuric macules or flat atypical targets, haemorrhagic erosions of the lips

3. SJS  and  toxic  epidermal  necrolysis  (TEN)  overlap:  epidermal  detachment  of  10-30%  of  the  body  surface  plus  widespread purpuric macules or flat atypical targets

4. TEN with spots: epidermal detachment of > 30% of the body surface coupled with widespread purpuric macules or flat atypical targets

5. TEN without spots: large sheets of epidermal detachment involving > 10% of the body surface without purpuric macules or target lesions

Diagnosis

The patient history and clinical presentation usually make the diagnosis of Stevens-Johnson syndrome  and TEN obvious. However, a skin biopsy is used for a definitive diagnosis.

Management

Stevens-Johnson syndrome has an attributable mortality of 5% and TEN an overall mortality of 30%.  Comorbid infections such as bacterial systemic infections or tuberculosis are associated with a higher risk of mortality.[177] Discontinuation of the offending drug is essential. Drugs initiated in the last 1 to 3 weeks before illness should be considered as potential causes including all drugs the patient is receiving, including over-the-counter and non-prescription as well as herbal and traditional medicine. There is no reliable laboratory test to determine the offending drug; diagnosis is based on the patient’s history and the temporal relationship of suspected drugs. Provocation tests are not indicated since re-exposure is likely to elicit a new episode of increased severity.[178]  Stevens-Johnson syndrome and TEN should be managed by an experienced physician. Supportive measures include identification and removal of the offending medication, admission to a burn unit if necessary,  intravenous fluid administration, maintenance of electrolyte and temperature homeostasis, and ophthalmological assessment in case of ocular involvement. Skin care consists of proper wound dressings, oral hygiene (i.e. chlorhexidine rinses), antihistamine and topical corticosteroid therapy for pruritus, and antimicrobial therapy in cases of superinfection due to skin-barrier breakdown. Some Units use high doses of immunoglobulin intravenously as mainstay therapy for TEN; however, more evidence of its effectiveness is needed. 106 The use of systemic corticosteroids, or prophylactic antibiotics for sepsis prevention, is not recommended.[179] 

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Diagnosis

If microbiological confirmation is also required, then a skin scraping or a nail clipping with application of potassium hydroxide (KOH) preparation can be done. Nail clippings that are processed and stained with periodic acid–Schiff (PAS) stain for fungal elements have the highest yield in diagnosing onychomycosis. Results are available within a few days.{ref}Johnson RA. Dermatophyte infections in human immune deficiency virus (HIV) disease. J Am Acad Dermatol. 2000;43(5 Suppl):S135-42. 

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Garman ME, Tyring SK. The cutaneous manifestations of HIV infection.... ↓" data-go-to-footnote-element="dermatological-conditions-150" >[150] aurent F, Gomez-Flores M, Mendez N, et al. New insights into HIV-1-primary skin disorders. J Inte AIDS Soc 2011;14:5.
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