Case 4: Discussion
Primary varicella infection (chicken pox) occurs infrequently in HIV-infected adults, as more than 90% of adults in the United States possess antibodies to the virus as a result of childhood varicella infection. Given the widespread prevalence of varicella-zoster virus (VZV) infection in adults, most HIV-infected adults are at risk of developing VZV reactivation and herpes zoster. The incidence of zoster among HIV-infected adults is more than 15-fold higher than age-matched VZV-infected immunocompetent persons, with nearly 30 cases per year observed for every 1,000 HIV-infected adults. The diagnosis of herpes zoster should prompt the clinician to consider HIV testing, particularly in persons with known HIV risk factors, those younger than 50 years of age, or those who develop multi-dermatomal herpes zoster. Although herpes zoster can occur in patients at any stage of their HIV disease, the risk of disease is the highest in patients who have a CD4 count less than 200 cells/mm3[4,5]. In addition, the incidence of zoster increases within the first 4 months after initiating highly active antiretroviral therapy (mean 5 weeks), probably related to immune reconstitution.
Pathogenesis of Herpes Zoster
As with all human herpesviruses, primary infection with VZV is followed by a period of viral latency, or "hibernation." Latent VZV resides in dorsal spinal ganglia, until a cycle of "lytic" or active viral replication is initiated. The factors governing the maintenance of latency or the progression to viral replication remain poorly understood, but the increased incidence of zoster among immunocompromised persons suggests that cell-mediated immunity probably plays a critical role. Replication of VZV in the ganglia leads to inflammation and cell death, followed by transport of the virus down the neuronal axons to the skin, with the migrating virus subsequently causing vesicles to emerge along the path of sensory nerves in a dermatomal distribution.
Primary varicella infection ("chickenpox") in HIV-infected patients manifests as a generalized outbreak of vesicular lesions that follow a 1 to 2 day prodrome of malaise and fever (Figure 1 and Figure 2). New skin lesions typically continue to emerge for 3 to 4 days. Patients with herpes zoster often present with dysesthesias of the skin several days prior to the onset of cutaneous lesions. Some patients develop dysesthesias of the skin without developing skin lesions in a condition referred to as "zoster sine herpete." The cutaneous lesions of zoster initially appear as clusters of vesicles surrounded by an erythematous base (Figure 3), with the individual lesions ranging in size from several millimeters to a centimeter. In some instances, the lesions may coalesce to form larger hemorrhagic bullae (Figure 4). Although herpes zoster can occur anywhere on the body, the skin of the thorax is the most frequently involved region. The vesicles characteristically progress to form crusted lesions (Figure 5) during the subsequent one to three weeks. Although other infections, such as herpes simplex virus and smallpox, may cause similar appearing vesicular lesions, the characteristic dermatomal distribution of herpes zoster helps to distinguish herpes zoster from these other disorders.
Complications of Localized Zoster
Significant scarring may result from cutaneous herpes zoster and this is most problematic with facial involvement. Reactivation of herpes zoster in the trigeminal ganglia may lead to the development of herpes zoster ophthalmicus, a condition that includes a number of inflammatory manifestations in the eye, such as conjunctivitis, episcleritis, keratitis, and iritis. Post-herpetic neuralgia (defined as pain that persists longer than 30 days after the onset of the rash) is a significant problem associated with herpes zoster infection, but, after adjusting for age, the risk of post-herpetic neuralgia does not differ significantly among HIV-infected persons compared with immunocompetent persons. Post-herpetic neuralgia manifests as chronic (more than 30 days after the onset of lesions) severe skin pain along the distribution of the initial zoster outbreak. Patients with this condition may suffer severe and prolonged pain that is often difficult to manage. Bacterial superinfection of vesicles can also complicate cutaneous herpes zoster (Figure 6).
Persons infected with HIV have a greater risk of developing disseminated infection, including development of widespread cutaneous lesions, ocular infection, visceral organ inflammation, and central nervous system disease[9,10]. With dissemination and ocular involvement, patients may develop acute retinal necrosis or progressive outer retinal necrosis ("PORN"), conditions that represent necrotizing retinopathy. Severely immunocompromised patients (CD4 counts less than 50 cells/ mm3) have a greater risk of suffering bilateral involvement, retinal detachment, and blindness, unless they receive prompt antiviral therapy specific for VZV. In the absence of antiviral therapy for VZV, dissemination may extend to the central nervous system. Aseptic meningitis commonly occurs in both immunocompetent and HIV-infected patients, and may be characterized by headache, cerebrospinal fluid (CSF) pleocytosis and the presence of VZV DNA in the CSF. Encephalitis, presenting as delirium, may either precede or follow the cutaneous manifestations of VZV in the severely immunocompromised patient, and can lead to white matter demyelination, vasculitis, and stroke. Direct spread from the dorsal root ganglion to the spinal cord may result in transverse myelitis and manifest as flaccid paraplegia.
Diagnosis of VZV
In most circumstances, the diagnosis of cutaneous herpes zoster is made on clinical grounds. For patients who have an atypical clinical presentation or a questionable diagnosis, confirmatory VZV-specific tests should be performed. The direct fluorescent antibody (FA) assessment of a cellular rich sample from the base of the lesion offers the most sensitive, specific, and rapid diagnosis for herpes zoster. For a high yield on cutaneous vesicular lesions, it is critical to unroof the vesicle and vigorously scrape the base of the lesion. Use of Tzanck smears is not recommended, mainly because of low sensitivity and very poor specificity. Culture of these lesions often fail to yield VZV and may take longer than 7 days before final results are available. Evidence of VZV DNA may be detected in other body fluids, including cerebrospinal fluid, vitreous humor, or bronchoalveolar lavage fluid, but there is little clinical utility in looking for VZV in the serum.
Therapy for Varicella and Zoster Infections
The following treatment recommended for varicella and zoster are based on the 2009 document Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adolescents and Adults. All patients with an acute episode of varicella or zoster should promptly receive antiviral treatment.
Therapy for Varicella
In general, HIV-infected patients with uncomplicated varicella infection can be treated with oral antiviral therapy. In contrast, HIV-infected persons with complicated primary varicella infection, including involvement of visceral organs, retina, or the central nervous system, should receive treatment with intravenous acyclovir and undergo hospitalization for observation (Figure 7). Ideally, consultation should be obtained with a medical provider who has experience and expertise in managing serious VZV infections. In these cases of complicated varicella, if the patient responds well to intravenous acyclovir, they can typically switch to oral antiviral therapy to finish their treatment course.
Therapy for Zoster
initiation of VZV-specific antiviral therapy for localized zoster may prevent serious morbidity among HIV-infected patients. The recommended antiviral treatment options (Figure 8) for localized dermatomal zoster in HIV-infected persons consist of valacyclovir (Valtrex), famciclovir (Famvir), or acyclovir (Zovirax). Note these antiviral medications are administered at doses higher than those commonly used for the treatment of uncomplicated herpes simplex virus infections. In most antiviral studies, therapy was initiated within 3 days of the onset of rash, but one study in immunocompromised patients suggested substantial benefit from administering antiviral drugs even after 72 hours had elapsed. Many experts would consider using intravenous acyclovir for zoster ophthalmicus. In immunocompetent persons, the use of corticosteroids in conjunction with acyclovir reduces the duration of active lesions and pain during an initial outbreak, but has not been well evaluated in HIV-infected persons. Accordingly, the use of corticosteroids as part of the treatment for herpes zoster in HIV-infected persons is not recommended. Treating acute zoster-associated neuropathic pain or post-herpetic neuralgia is an important component of the management of patients with VZV infection. Opioids, tricyclic antidepressants, gabapentin (Neurontin), and topical lidocaine or capsacin (Zostrix) have all been shown to be effective in reducing pain associated with these conditions.
Therapy for Acyclovir-Resistant VZV
Although cases of acyclovir-resistant VZV have been reported in HIV-infected persons, they appear to occur only rarely. In general, resistance should be suspected in patients who have lesions that do not improve with 10 days after starting antiviral therapy. One report described 18 HIV-infected patients with advanced immunosuppression and acyclovir-resistant VZV-related skin lesions that failed to heal despite treatment with acyclovir; most of these patients had an excellent respond to treatment with foscarnet (Foscavir). Based on this report, as well as in vitro data, foscarnet is the recommended drug of choice for acyclovir-resistant VZV.
Therapy for Retinal Necrosis
Management of patients with progressive outer retinal necrosis or acute retinal necrosis requires a multi-pronged approach (Figure 9), including intravenous and intravitreal therapy, and should include an ophthalmologist who has experience managing these types of infections. The duration of therapy, frequency of intravitreal injections, and number of intravitreal injections will depend on the patient's clinical course and should be determined by the ophthalmology expert.
Prevention of Varicella and Prevention of Zoster
The recommendations regarding the use of the varicella vaccine (Varivax) and zoster vaccine (Zostavax) are discussed in the in Case 4 (Appropriate Vaccinations) in the section Initial Evaluation. In the rare instance when an HIV-infected person who is non-immune to VZV has significant exposure to a patient with active varicella or zoster, varicella zoster immune globulin (VZIG) should be administered within 96 hours of exposure (preferably within 48 hours). Unfortunately, the production of VZIG was halted in October 2004. In February 2006, Gangene Corporation, the Canadian manufacturer of an investigation VZIG product (VariZIG), made this product available under an investigational drug application expanded access protocol. Investigational VariZIG is available in 125-U vials and the recommended dose is 125 units/10 kg body weight (maximum 625 units). For more information regarding obtaining VariZIG, contact FFF Enterprises at 1-800-843-7477 or see the company's VariZIG IND Protocol. Given the expense of VZIG and the importance of administering it quickly, clinicians should consider ordering an anti-varicella IgG antibody test at baseline in those patients who do not give a history of prior chicken pox or shingles, since most will show serologic evidence of immunity and would not require VZIG in the event of an exposure. In the situation where a VZV susceptible patient could not receive VZIG within 96 hours of the exposure, it would be reasonable to use valacyclovir (1,000 mg tid x 21 days) for postexposure prophylaxis. Although no data exist that prove efficacy of antiviral agents for varicella prophylaxis in HIV-infected persons, case series from adults and children with immunosuppression in the setting of cancer therapy have documented successful use of valacyclovir for the prevention of varicella.
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