Cryptococcal disease presenting as necrotizing cellulitis in transplant recipients.

Disseminated cryptococcosis uncommonly presents with skin lesions in immunocompromised hosts. Necrotizing fasciitis, necrotizing vasculitis, myositis, or necrotizing soft tissue infection are even more rare presentations. We report 3 cases of cryptococcal necrotizing soft tissue infection, 2 in renal transplant patients, and 1 in a heart transplant patient, and discuss similar cases from the literature. Cryptococcus neoformans should be considered in the differential diagnosis of cellulitis or necrotizing soft tissue infections in immunocompromised patients.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Phase specific analysis of herpes zoster associated pain data: a new statistical approach.

Herpes zoster or shingles is a frequent occurrence in both elderly individuals and immunocompromised hosts. The pain associated with herpes zoster is the most debilitating complication of the disease. It can be described as acute pain and post-herpetic neuralgia or zoster associated pain (ZAP). The latter definition encompasses pain from the onset of disease through its resolution and provides a convenient analytic tool for evaluation of antiviral therapy. A heuristic examination of ZAP historical data suggests the existence of three phases of pain resolution: the acute, subacute and chronic phases. The subacute and chronic phases comprise the post-herpetic neuralgia (PHN) stage. Common analytic methods, such as a Kaplan-Meier survival function or a Cox's model, have been used to assess the pain. However, such approaches do not adequately allow for phase comparison. Notably, in the clinical trial setting the comparison of specific treatment effects on the latter stages of pain are of the greatest medical relevance since this is the most debilitating phase of the illness. In order to incorporate the phase-specific information in the modelling of time to cessation of ZAP, we assumed the hazard function was a stepwise constant. Utilizing the full likelihood function, we obtained the maximum likelihood estimate for the transition times (that is, change-points), and other parameters of medical importance. The standard error of the change-point estimates were obtained through a bootstrapping method. The asymptotic properties of the parameter estimates are also discussed. Hence, the rates of pain resolution across all phases can be examined in order to precisely define the existence of multiple phases. In addition, the covariates effect can be examined across phases and populations, thereby allowing us to translate potential efficacy of a standard therapy to different populations. These results can be utilized in the design of clinical trials or in targeting the outcome for a specific phase while controlling for the effect of other variables.

Recurrence of the acute HIV syndrome after interruption of antiretroviral therapy in a patient with chronic HIV infection: A case report.

BACKGROUND: Clinical and virologic consequences of temporary interruption of HIV therapy are incompletely understood. OBJECTIVE: To describe a febrile illness that was consistent with the acute HIV syndrome and occurred after interruption of antiretroviral therapy. DESIGN: Case report. SETTING: University clinic. PATIENT: HIV-infected man. MEASUREMENTS: Plasma viral load, lymphocyte subsets, diagnostic evaluation (including cultures and serologic tests), and analysis of lymph node tissue. RESULTS: The patient began antiretroviral therapy 3 months after initial HIV exposure and had sustained viral suppression, except during a brief scheduled treatment interruption. One hundred sixty-nine days after resuming therapy, the patient discontinued it again immediately following an influenza vaccination. Eleven days later, he presented with a febrile mononucleosis-like syndrome associated with dramatic shifts in plasma HIV RNA level (<50 to >1 000 000 copies/mL) and CD4 cell count (0.743 x 10(9) cells/L to 0.086 x 10(9) cells/L). Evaluation for alternative causes of fever was unrevealing. Symptoms resolved rapidly with resumption of HIV therapy. CONCLUSION: Therapeutic interruption may be associated with profound viral rebound and recurrence of the acute HIV syndrome.

Human herpesvirus 8 and Kaposi's sarcoma in persons infected with human immunodeficiency virus.

Human herpesvirus 8 (HHV-8) was detected in 1994 in biopsies of Kaposi's sarcoma (KS) tissues from a patient with AIDS. The evidence that HHV-8 infection is etiologically related to the development of KS is compelling. Essentially all patients with KS of any epidemiological type have serological evidence of HHV-8 infection. About 30%-40% of homosexual men infected with human immunodeficiency virus (HIV) are seropositive for HHV-8; rates are lower (<10%) among HIV-infected women, hemophiliacs, and injection drug users. Among homosexual men, the probability of HHV-8-seropositivity is directly proportional to the numbers of previous male sex partners, which suggets that HHV-8 is a sexually transmitted infection. Although HHV-8 is detectable in saliva and semen, the exact mechanism of transmission is not known. A reduction in KS incidence among patients with AIDS in the 1980s has been attributed to lower rates of HHV-8 transmission that resulted from alterations in sexual behaviors. A further decline in KS incidence has been associated with the use of antiretroviral therapy. Antiretroviral therapy to control HIV replication and to limit the associated immunodeficiency is currently the best approach for preventing KS in persons infected with HHV-8 and HIV.

Therapeutic approaches to the management of herpes zoster.

The past several years have provided exciting advances in the management of herpes zoster in the normal host. In spite of these advances, a significant portion of zoster patients still have persistent complications from this disease. Persistent pain is the most debilitating sequela and it occurs in at least 15% of individuals over 50 years of age. Future research efforts must embrace alternative approaches for pain control.

A mixed model for factors predictive of pain in AIDS patients with herpes zoster.

A unifying model of herpes zoster pain presents considerable analytical challenges due to the requirement for prospective data collection and the varying rates of pain resolution reported by individual patients. Demographic, clinical, and quality-of-life measures were collected on 166 human immunodeficiency virus (HIV)-infected patients enrolled in a randomized, controlled trial of antiviral therapy of herpes zoster comparing acyclovir with sorivudine. A "mixed model" was used to assess factors predictive of pain severity, activity impairment, and sleep interruption. The average rate of change in acute pain was -0.04 unit pain per day for the first month. Chronic pain decreased -0.12 per month for months 1-12. Acute pain severity was positively correlated with number of new skin vesicles, analgesic use, and baseline pain, and negatively related to percentage of lesion healing and crusting. Postherpetic neuralgia was correlated with baseline pain, pain at 1 month, and duration of lesions. Treatment group, gender, race, and CD4 count were not related to change in pain severity. These analyses verify the significance of baseline pain as a significant predictor of pain resolution and average pain severity as a predictor of return to normal daily activities and sleep. The severity of acute pain at presentation and at 1 month are significant predictors of chronic pain.

Herpes zoster: risk categories for persistent pain.

Acute neuritis and persistent pain are the most significant clinical manifestations of herpes zoster and are end points for clinical trials therapy. In an acyclovir and prednisone study, patients were categorized according to pain severity and number of lesions at presentation. Risk categories were defined according to the magnitude of risk ratios (RRs) and a comparison of Kaplan-Meier survival estimates. For acute neuritis and zoster-associated pain, RRs defined rate of resolution. Patients who presented with severe or incapacitating pain and a large number of lesions were less likely to achieve resolution of both acute neuritis and zoster-associated pain (RR, 18.0; 95% confidence interval [CI], 6. 6-48.6, and RR, 5.3; 95% CI, 4.2-17.2, respectively). These analyses identify the subgroups of patients for whom aggressive interventions are most strongly indicated.

Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group.

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

OBJECTIVE: To determine the effect of acyclovir and prednisone treatment of herpes zoster on chronic pain and quality-of-life outcomes. DESIGN: Randomized, double-blind, placebo-controlled study with a 2 x 2 factorial design. SETTING: 15 university hospitals or affilliated clinics. PATIENTS: 208 immunocompetent patients older than 50 years of age who had localized herpes zoster that developed less than 72 hours before study enrollment. INTERVENTION: Acyclovir or a matched placebo was administered orally, 800 mg five times daily, for 21 days. Prednisone or a matched placebo was administered orally at 60 mg/d for the first 7 days, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. The four treatments regimens given were acyclovir plus prednisone; acyclovir plus prednisone placebo; prednisone plus acyclovir placebo; and placebos for both acyclovir and prednisone. MEASUREMENTS: Patients were monitored daily for the first 28 days for lesion healing, resolution of pain, return to usual activity, and return to uninterrupted sleep. Monitoring was then done monthly for 6 months. Patients documented analgesic requirements each day, and adverse events and laboratory abnormalities were recorded at each clinical visit. An intention-to-treat analysis was used. RESULTS: Patients were randomly allocated to receive one of the four regimens. Demographic characteristics were similar for each group. Time to total crusting and healing was accelerated for patients receiving acyclovir plus prednisone compared with patients receiving two placebos; the risk ratios were 2.27 (95% Cl, 1.46 to 3.55) for total crusting and 2.07 (Cl, 1.26 to 3.38) for healing. Similarly, compared with the placebo group, patients receiving acyclovir plus prednisone had accelerated time to cessation of acute neuritis (risk ratio, 3.02 [Cl, 1.42 to 6.41]), time to return to uninterrupted sleep (risk ratio, 2.12 [Cl, 1.25 to 3.58]); time to return to usual daily activity (risk ratio, 3.22 [Cl, 1.92 to 5.40]); and time to cessation of analgesic therapy (risk ratio, 3.15 [Cl, 1.69 to 5.89]). In the acyclovir plus prednisone group, resolution of pain during the 6 months after disease onset did not statistically differ from that in the other groups. No important clinical or laboratory adverse events occurred in any group. CONCLUSIONS: In relatively healthy persons older than 50 years of age who have localized herpes zoster, combined acyclovir and prednisone therapy can improve quality of life.

New antivirals with activity against varicella-zoster virus.

Herpes zoster is a serious medical problem, not only because of the discomfort associated with the acute rash, but also because of the potential for post-herpetic neuralgia. Acyclovir is currently the antiviral drug of choice for the treatment of herpes zoster. Efforts are underway to develop new drugs that have improved activity against varicella-zoster virus as well as more favorable pharmacokinetic properties. The goal of these efforts is to develop an orally administered antiviral drug that will accelerate the events of cutaneous healing as well as reduce the frequency and severity of post-herpetic neuralgia. Investigational drugs currently under evaluation include valaciclovir and famciclovir, the prodrugs of acyclovir and penciclovir, respectively. Two new uracil derivatives, sorivudine and BW882C87, with increased anti-varicella-zoster virus activity in vitro are also being studied.

Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group.

Seventy-three immunocompromised patients with disseminated herpes zoster were evaluated in a double-blind controlled trial of acyclovir (n = 37) versus vidarabine (n = 36) therapy. Acyclovir was administered at 30 mg/kg/day at 8-h intervals and vidarabine was given as a continuous 12-h infusion at 10 mg/kg/day for 7 days (longer if resolution of cutaneous or visceral disease was incomplete). No demographic differences existed between treatment groups. No deaths attributable to varicella-zoster virus infection occurred within 1 month of treatment. Neither rates of cutaneous healing, resolution of acute neuritis, and frequency of postherpetic neuralgia nor adverse clinical and laboratory events differed between treatment groups. Acyclovir recipients were discharged from the hospital more promptly than vidarabine recipients (P = .04, log rank test). These data indicate that disseminated herpes zoster is amenable to therapy with either acyclovir or vidarabine; resultant mortality is low.

Natural history and treatment of varicella-zoster in high-risk populations.

Rigorous clinical trials have established that both acyclovir and vidarabine favourably alter the clinical course of herpes zoster and chicken-pox in immunocompromised patients. In one comparative study, acyclovir was shown to be superior to vidarabine for zoster in bone marrow transplant recipients. These data, plus the fact that acyclovir is easier to administer than vidarabine, and perhaps less toxic, have made intravenous acyclovir the recognized drug of choice for treatment of herpes zoster in immunocompromised patients. Acyclovir sodium sterile powder received Federal Drug Administration (FDA) approval for this indication in 1990 in the United States. Since complications of zoster occur in only a minority of immunocompromised patients, most physicians would prefer to initiate therapy with an orally-administered drug and avoid the cost and inconvenience of hospitalization. Future studies will compare the efficacy and safety of orally administered bromovinyl arabinosyl uracil and acyclovir in treatment of varicella-zoster virus infections.