Viral Infections

Acute retroviral syndrome occurs approximately 2 to 4 weeks after acute HIV infection. This process is a self-limiting clinical syndrome of varying severity. It presents with “flu-like” symptoms such as fever, fatigue, weight loss, headache, myalgias, pharyngitis, lymphadenopathy, in addition to a morbilliform (measles-like) cutaneous eruption and mucosal ulcerations. Cutaneous immune responses to the HIV virus dissemination are possibly the cause of the maculopapular rash. Because the symptoms of the acute retroviral syndrome are nonspecific and anti-HIV antibodies are usually negative at this stage, the diagnosis is established by detecting plasma viral RNA (usually >5 × 10 ⁴ copies/mL, and as high as 1 × 10 ⁶ copies/mL) and/or p24 antigen. The viremia is accompanied by a drop in the circulating CD4+ T-lymphocyte count and a rise in the CD8+ T-lymphocyte count.

Mucocutaneous infections due to herpes simplex virus (HSV)-1, HSV-2, and the varicella-zoster virus (VZV) are commonly seen in association with HIV infection and AIDS; the typical clinical presentations of these three viruses are reviewed in Chapter 31 . Because herpes zoster (uni- or multidermatomal) can serve as one of the presenting signs of HIV infection ( Fig. 35-1 ), this diagnosis should prompt a discussion of risk factors. In contrast to the self-limiting episodes of herpes zoster or orogenital herpes simplex that occur in immunocompetent hosts, patients with AIDS can have lesions that last for months until appropriate therapy is instituted. More recently, the development of herpes zoster or severe recurrent HSV infection has been described in the setting of immune reconstitution inflammatory syndrome (IRIS) on commencement of HAART. Chronic perianal ulcers due to HSV are sometimes misdiagnosed as decubitus ulcers ( Fig. 35-2 ) and chronic oral ulcers as aphthous stomatitis ( Fig. 35-3 ), until a direct immunofluorescence antibody assay, viral culture, or polymerase chain reaction (PCR) of scrapings from the ulcer edge points to the correct diagnosis. One clue to the diagnosis of HSV as the etiologic agent is scalloping of the border of the ulcer and preceding vesicles ( Fig. 35-4 ). In patients with AIDS, chronic dermatomal and disseminated VZV lesions can become verrucous ( Fig. 35-5 ) and the clinical diagnosis requires a high index of suspicion. For patients who are immunocompromised, including those with AIDS, antiviral therapy should be continued until there is complete clinical resolution. Hospitalization or intravenous therapy may be necessary in some cases.

Herpes zoster involving the palate and lip in an HIV-infected patient.

Chronic perianal ulcerations that represent herpes simplex infection in this HIV-infected man.

Multiple erosions on the hard and soft palate due to herpes simplex virus in an HIV-infected patient.

(Courtesy of Yale Residents’ Slide Collection.)

Multiple vesicles, some of which are hemorrhagic, on the tongue and upper lip of an HIV-infected patient. Note the scalloping of the border of the lesion on the lip that is characteristic of HSV infections.

(Courtesy of Yale Residents’ Slide Collection.)

Verrucous papules of chronic varicella-zoster virus (VZV) in a patient with AIDS.

(Courtesy of Yale Residents’ Slide Collection.)

When lesions of HSV or VZV fail to improve despite appropriate therapy (systemic acyclovir, famciclovir, or valacyclovir), the possibility of an acyclovir-resistant strain needs to be excluded, especially when patients have been receiving chronic suppressive therapy with oral acyclovir. Intravenous foscarnet (which does not require phosphorylation to interact with viral DNA polymerase) is the recommended treatment for acyclovir-resistant strains. However, there are reports of patients developing foscarnet-resistant strains of HSV owing to mutations in the DNA polymerase gene. An alternative treatment is topical (1% gel), intralesional, or intravenous cidofovir.

Administration of the varicella vaccine to prevent primary infection is also an important strategy to protect children and adults who do not have a prior history of varicella. The vaccine can be given to HIV-infected patients who have CD4 T-lymphocyte counts of >200 cells/μL despite the theoretical risk of live-virus vaccination in this population. Some clinicians choose to offer the zoster vaccine to HIV-infected persons who are >50 years of age and have good HIV control and CD4 counts of >200 cells/μL; however, zoster vaccination should be avoided in patients with CD4 counts of <200 cells/μL. (Note that the vaccine used to prevent reactivated VZV disease [Zostavax] contains 14 times the amount of virus as the vaccine to prevent primary infection.) If an HIV-infected adult develops a postvaccination varicella-like cutaneous eruption a prompt evaluation should be made and consideration should be given to starting antiviral therapy.

Infections with two other members of the herpes family, cytomegalovirus (CMV) and Epstein–Barr virus (EBV), are seen in HIV-infected individuals. The most common EBV-induced mucocutaneous disorder is oral hairy leukoplakia, which is characterized by filiform white plaques and papules, primarily on the lateral aspects of the tongue ( Fig. 35-6 ). These lesions may have a somewhat corrugated appearance, and improvement is seen in the setting of HAART therapy.

Oral hairy leukoplakia.

Although the disorder most commonly associated with CMV is retinitis, this herpes virus can lead to gastrointestinal (GI) ulcers and, occasionally, orogenital or perianal ulcers as well as morbilliform eruptions. The detection (via specific immunohistochemical stains) of intranuclear CMV inclusions within dermal endothelial cells usually proves to be a more sensitive assay than viral cultures. In mucocutaneous ulcers, CMV often “coexists” with other viruses such as HSV or VZV, and as a result its true pathogenicity has been questioned.

Because condylomata acuminata and mollusca contagiosa (MC)—cutaneous viral infections due to human papilloma viruses (HPV) and poxvirus, respectively—can be sexually transmitted, HIV-infected patients are at increased risk for both. Because of the coexistent immunosuppression, their clinical manifestations frequently become quite exaggerated; for example, the individual lesions of MC often coalesce into broad-based plaques and may become so large as to be referred to as “giant.” As expected, the condylomata involve the anogenital region, but in addition to the genitals, the most common site of involvement for MC is the face ( Fig. 35-7 ). Even banal warts (verruca vulgaris) or flat warts can become widely distributed, as in organ transplant patients ( Fig. 35-8 ), and often persist despite HAART.

Numerous dome-shaped papules of mollusca contagiosa on the forehead of an HIV-infected patient. Note the central dell in several of the lesions.

(Courtesy of Yale Residents’ Slide Collection.)

Diffuse hypopigmented verruca plana in a patient with HIV infection.

In women, infections with certain subtypes of HPV, e.g., 16 and 18, are associated with the development of cervical cancer, and this risk increases in the setting of HIV infection. These same HPV strains also increase the risk of vulvar, penile, and anal carcinoma ( Fig. 35-9 ). HIV-infected men who have sex with men, with high-risk HPV infection, are at greatest risk for anal cancer. Serial anal examinations in combination with anal cytology have been advocated for screening such patients, as has histologic examination of any suspicious lesion.

Perianal erythematous plaque representing squamous cell carcinoma developing within condylomata acuminata.

(Courtesy of Yale Residents’ Slide Collection.)

MC and HPV infections may prove recalcitrant to standard destructive therapies (e.g., cryotherapy, curettage, etc.), but improvement of MC has been observed after the institution of HAART. Both MC and condylomata acuminata may respond to topical imiquimod or cidofovir; occasionally, intralesional or intravenous cidofovir is administered for extensive confluent MC or condyloma. In one study of HIV-positive men who have sex with men and anal intraepithelial neoplasia, imiquimod cream (for perianal disease), and suppositories (for intra-anal disease) led to clinical and histologic clearing in 75% of those who used the medication as directed (three times per week for 16 weeks).

Bacterial Infections

Cutaneous bacterial infections that are seen in association with HIV infection and AIDS can be subdivided into a few major categories: soft tissue infections and folliculitis due primarily to Gram-positive cocci; bacillary angiomatosis; sexually transmitted diseases (STDs) (see below); and mycobacterial and atypical mycobacterial infections. Because HIV is often acquired via sexual contact, patients who are HIV-positive need to be screened for other STDs, and vice versa. In addition, the presence of erosions and ulcerations in the anogenital region due to bacterial diseases, such as syphilis, or viral diseases, such as HSV, can increase the transmission rate of HIV.

Soft tissue bacterial infections in patients with HIV are often due to Staphylococcus aureus or Streptococcus spp., and their clinical presentations range from folliculitis and abscesses to cellulitis and necrotizing fasciitis ( Fig. 35-10 ). When S . aureus is identified as the etiology of a cutaneous infection, the possibility of nasal carriage needs to be considered as well as the possibility of meticillin-resistant S. aureus . The cutaneous manifestations of atypical mycobacterial infections are also protean and can vary from subtle areas of erythema to necrotic ulcers. Several species of atypical mycobacteria have been isolated from skin lesions in patients with HIV/AIDS, which may be isolated or disseminated, including Mycobacterium haemophilum , M . fortuitum , M. malmoense , and M . avium intracellulare . HIV-infected patients are also at risk for developing cutaneous tuberculosis, including disseminated miliary tuberculosis. Multidrug treatment regimens for cutaneous mycobacterial infections are the same as for systemic disease.

Large vascular tumor of bacillary angiomatosis in a child with AIDS, which can mimic a tumor of Kaposi’s sarcoma.

Bacillary angiomatosis is a bacterial infection whose diagnosis warrants the exclusion of an underlying HIV infection or immunosuppression. Only occasionally is it seen in normal hosts. The microorganisms responsible for the appearance of discrete proliferations of cutaneous blood vessels are Bartonella henselae and B . quintana ; the former is also the etiologic agent of cat scratch disease. The characteristic skin lesion is a red to violet papule that resembles a “hemangioma,” pyogenic granuloma, or a lesion of Kaposi’s sarcoma ( Fig. 35-11 ). Additional sites of involvement include the subcutis, with the formation of nodules, the liver (peliosis hepatitis), lymph nodes, bones, and heart (endocarditis). The diagnosis is established by identifying the bacteria in Warthin–Starry-stained histologic sections or by PCR-based analysis of biopsy specimens. Treatment consists primarily of first- and second-generation macrolides.

Red dome-shaped nodules of bacillary angiomatosis in an HIV-positive patient. The lesions have an appearance similar to pyogenic granulomas.

(Courtesy of NYU Slide Collection.)

Fungal Infections

Certain fungal infections, such as oral candidiasis (thrush), can serve as presenting signs of HIV infection ( Fig. 35-12 ), whereas others, such as cryptococcosis, are seen late in the course of the disease. HIV-infected patients are at increased risk for the development of superficial mucocutaneous fungal infections due to Candida spp. and dermatophytes, as well as systemic infections due to Cryptococcus neoformans , Candida spp., and dimorphic fungi (e.g., Histoplasma capsulatum , Coccidioides immitis , Penicillium marneffei ). The cutaneous lesions of cryptococcosis and dimorphic fungal infections are often a mixture of indurated papules, plaques, and ulcerated lesions, and they sometimes resemble the dome-shaped papules of MC ( Fig. 35-13 ). Examination of a potassium hydroxide preparation of dermal scrapings or a periodic acid–Schiff- or silver-stained histologic section allows a presumptive diagnosis, and a simultaneous tissue fungal culture provides a definitive diagnosis. Cryoptococcal cutaneous infections are often a sign of disseminated disease, and should prompt thorough multisystem evaluation including a lumbar puncture.

White friable plaques of oral candidiasis in a patient with AIDS.

(Courtesy of Yale Residents’ Slide Collection.)

Cutaneous cryptococcosis in a patient with AIDS manifesting as multiple dome-shaped papules, some with central umbilication reminiscent of mollusca contagiosa.

Infections with tinea (dermatophytoses) affect three keratin-containing structures, the skin, hair, and nails. HIV-infected patients are not only prone to the more common forms of tinea, e.g., tinea pedis, tinea manuum (hand), tinea unguium (nails), and tinea corporis ( Fig. 35-14 ), but they often have more severe or widespread lesions. These patients also develop an unusual form of tinea unguium known as proximal subungual onychomycosis. In the more common form of tinea unguium (distal subungual onychomycosis), the most pronounced dystrophic changes, e.g., thickening and yellow discoloration, are seen in the distal portions of the fingernails or toenails, whereas in the proximal form there is a white discoloration that first appears in the proximal portion of the nail. This proximal subungual form has also been observed in other immunocompromised patients, such as those who have received organ transplants.

Annular erythematous scaly plaques of tinea corporis in an immunocompromised patient.

DNA analyses have led to a reclassification of Pneumocystis jiroveci ( carinii ) as a fungal species. Pneumonia is the most common clinical presentation of P . jiroveci infection, but rarely cutaneous lesions do develop, especially in the external auditory canal and nares.

Parasitic/Ectoparasitic Infections

One of the more common ectoparasitic infections in patients who have AIDS is scabies, in particular a form characterized by thick scale-crusts and numerous mites of Sarcoptes scabiei var. hominis ; this is sometimes referred to as crusted or Norwegian scabies. Unlike the form of scabies seen in immunocompetent hosts, in which each person is infested with a few dozen mites, these patients have hundreds to thousands of mites and are therefore highly contagious. The thick scale is one of the explanations for the difficulty in eradicating crusted scabies with topical scabicides, such as 5% permethrin cream. One of the off-label uses of oral ivermectin is the treatment of such patients, who often require combination regimens with prolonged and repeat treatments.

HIV-infected patients frequently develop folliculitis, and its etiology can vary from S . aureus and herpes simplex to Malassezia spp., dimorphic fungi, and the Demodex mite. Although the latter ectoparasite is part of the normal inhabitants of the hair follicle, its presumed pathogenetic role is based upon the numerous Demodex mites found in the expressed follicular contents from AIDS patients with folliculitis in whom there was no other explanation for the folliculitis.

Patients with AIDS can also present with cutaneous lesions due to systemic infections with parasites such as Toxoplasma gondii (primarily the central nervous system [CNS]), Acanthamoeba spp. (primarily CNS and sinuses), Strongyloides stercoralis (primarily GI tract and lung), Leishmania spp. (primarily bone marrow), and microsporidia (primarily GI tract). Although these secondary cutaneous lesions are rather unusual and do not have unique clinical presentations, the diagnosis can be made fairly easily by identification of the responsible organisms in biopsy specimens.