Recurrent Varicella-zoster Virus Infections Research Articles

Eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: report in a woman with chronic lymphocytic leukemia and review of the literature

Eosinophilic dermatosis of hematologic malignancy is a rare papulovesicular eruption that presents in patients with hematoproliferative disorders, particularly chronic lymphocytic leukemia. A 59-year-old woman with chronic lymphocytic leukemia who developed eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection is described. PubMed database was searched with the key words: chronic, dermatosis, eosinophilic, hematologic, infection, leukemia, lymphocytic, malignancy, varicella, zoster. The papers generated by the search and their references were reviewed. The patient presented, on more than 20 occasions, with a dermatomal vesicular eruption. Her oncologist, based on the clinical presentation, treated each episode as recurrent varicella zoster virus infection. A complete workup of the patient not only demonstrated negative viral studies but also revealed pathologic changes consistent with eosinophilic dermatosis of hematologic malignancy on lesional skin biopsy. The recurrence of the patient’s dermatosis was less frequent when her malignancy was under better control. Eosinophilic dermatosis of hematologic malignancy may mimic other reactive dermatoses. The morphology of our patient’s recurrent dermatosis resembled varicella zoster virus infection. Disseminated zoster virus infection with dermatomal and non-dermatomal distribution should be added to the clinical differential diagnosis of eosinophilic dermatosis of hematologic malignancy.

Herpes Simplex Vaccines: Prospects of Live-attenuated HSV Vaccines to Combat Genital and Ocular infections.

Herpes simplex virus type-1 (HSV-1) and its closely related type-2 (HSV-2) viruses cause important clinical manifestations in humans including acute ocular disease and genital infections. These viruses establish latency in the trigeminal ganglionic and dorsal root neurons, respectively. Both viruses are widespread among humans and can frequently reactivate from latency causing disease. Currently, there are no vaccines available against herpes simplex viral infections. However, a number of promising vaccine approaches are being explored in pre-clinical investigations with few progressing to early phase clinical trials. Consensus research findings suggest that robust humoral and cellular immune responses may partially control the frequency of reactivation episodes and reduce clinical symptoms. Live-attenuated viral vaccines have long been considered as a viable option for generating robust and protective immune responses against viral pathogens. Varicella zoster virus (VZV) belongs to the same alphaherpesvirus subfamily with herpes simplex viruses. A live-attenuated VZV vaccine has been extensively used in a prophylactic and therapeutic approach to combat primary and recurrent VZV infection indicating that a similar vaccine approach may be feasible for HSVs. In this review, we summarize pre-clinical approaches to HSV vaccine development and current efforts to test certain vaccine approaches in human clinical trials. Also, we discuss the potential advantages of using a safe, live-attenuated HSV-1 vaccine strain to protect against both HSV-1 and HSV-2 infections.

Herpes and Zoster infections update

AbstractHerpes Simplex Virus (HSV) and Varicella‐zoster Virus (VZV) are the two leading causes of infectious acquired amblyopia. After a phase a latent infection in the trigeminal ganglia, they may reactivate to eventually infect the cornea. There are several common features of keratitis due to HSV or VZV. The most frequent forms involve the epithelium, with 4 different patterns: punctuate and diffuse, dendritic, geographic, and marginal. Stromal forms of keratitis are mostly non‐necrotic, and usually resolve with a combination of oral antivirals and topical steroids. In contrast, a necrotic stromal keratitis usually requires intravenous antiviral therapy. Endothelial forms of HSV/VZV keratitis are far less frequent. Three different types may be observed: disciform, diffuse or linear, the latter one being the most aggressive. After the acute phase of HSV/VZV keratitis, preventive treatment with oral antivirals may be given according to the clinical history. For VZV, a vaccine is now available. Its effectiveness has been shown for the prevention of herpes zoster ophthalmicus, but its place in patients with recurrent VZV infections of the eye remains to be clarified.

Systemic varicella-zoster virus infection in two critically ill patients in an intensive care unit

Varicella-zoster virus (VZV) usually causes localized zoster in adults. However, in immunocompromised patients, it can cause systemic infection accompanied by complications such as pneumonia, encephalitis, and hepatitis. Although most of critically ill patients in intensive care unit (ICU) are immunologically compromised, they are usually not considered to be at risk for systemic VZV infection.We report two cases of systemic VZV infection occurring in critically ill patients in an ICU. One patient was a 69-year-old man with Streptococcus pneumoniae-induced purpurafulminans, and the other was a 75-year-old woman with severe acute pancreatitis. During the clinical course in the ICU, characteristic vesicles with umbilical fossa appeared diffusely and bilaterally on their face, trunk, and extremities. VZV-specific IgG levels were confirmed to be elevated compared to that of the pre-onset, and a diagnosis of recurrent VZV infection was made in both patients. The patients were treated at the same ICU but did not coincide with each other; therefore a cross-infection was unlikely. They were treated with intravenous acyclovir, but the latter patient eventually died of respiratory failure.VZV infection can cause a number of serious complications, and can lead to death in some patients. Early detection and proper treatment are needed to prevent the infection from spreading out and save the patients. It might be necessary to consider antiviral prophylaxis against VZV infection for a part of critically ill patients in ICU, although the effectiveness of this approach is yet to be established.

Low numbers and altered phenotype of invariant natural killer T cells in recurrent varicella zoster virus infection

Invariant natural killer T (iNKT) cells play an important role in the immune response against various infectious agents. In this study we investigated their role in human defense against the varicella zoster virus. We observed decreased numbers of iNKT cells in patients who failed to control latent varicella zoster virus infection, e.g. underwent several reactivations of the virus. The residual population of iNKT cells expressed significantly higher levels of inhibitory receptor CD158a that was further up-regulated in the course of acute viral infection. Both of these abnormalities might contribute to impaired control of varicella zoster virus in human.

Factors influencing varicella zoster virus infection after allogeneic peripheral blood stem cell transplantation: low‐dose acyclovir prophylaxis and pre‐transplant diagnosis of lymphoproliferative disorders

Varicella zoster virus (VZV) infection is one of the frequent opportunistic infections after allogeneic bone marrow transplantation, with a high incidence of 30-50%. However, no data have been reported on VZV infection after allogeneic peripheral blood stem cell transplantation (PBSCT). We report a retrospective analysis of VZV infection in 192 allogeneic PBSCT recipients. Twenty-seven patients (14%) received long-term prophylaxis of low-dose acyclovir (200 mg twice daily orally > or =3 months) for recurrent oral (n=21) or genital herpes simplex virus infection (n=5) or for a previous history of recurrent VZV infection (n=1). Forty-two patients (22%) developed VZV infections: localized (n=37) and disseminated infection (n=5). The incidence of VZV infection at 1 and 3 years was 19.3+/-3.3% and 36.8+/-5.2%, respectively. Complications included post-herpetic neuralgia (n=18, 43%), secondary bacterial infections (n=3), and intracranial hemorrhage (n=1) with 2 deaths. A higher risk factor for VZV infection was pre-transplant diagnosis of a lymphoproliferative disorder (LPD): chronic lymphocytic leukemia, Hodgkin's disease, or non-Hodgkin's lymphoma (P=0.021, 52.5% in LPD vs. 32.6% in non-LPD group). The use of low-dose acyclovir prophylaxis (P=0.043, 14.7% in acyclovir vs. 41.6% in nonacyclovir group) was found to be protective. Although no VZV infection episodes were noted during the period of acyclovir prophylaxis, 3 episodes of VZV infection were noted after acyclovir cessation. The incidence of VZV infection after PBSCT was high at 36.8%, with patients transplanted for LPDs at higher risk. The long-term use of low-dose acyclovir may be protective for VZV infection, although it does not completely prevent rebound of late VZV infection.

Factors Influencing Varicella-Zoster Virus (VZV) Infection after Allogeneic Peripheral Blood Stem Cell Transplantation: Low-Dose Acyclovir Prophylaxis and Pre-Transplant Diagnosis of Lymphoproliferative Disorders.

Introduction: Varicella-zoster virus (VZV) is a frequent opportunistic infection among long-term survivors after allogeneic stem cell transplantation with relatively high incidence of around 30 to 50%. A recent study reported that the cumulative incidence of VZV infection at 5 year reaches up to 63% after allogeneic bone marrow transplantation (Koc, BBMT 2000). It has been suggested that peripheral blood stem cell transplantation (PBSCT) may facilitate immune reconstitution compared to BMT. However, no data has been reported on VZV infection after allogeneic PBSCT. The current study attempted 1) to estimate the incidence of VZV infection, 2) to identify the risk factor for VZV infection, and 3) to analyze the clinical relevance of lymphocyte recovery on VZV infection after allogeneic PBSCT.Patients and methods: We report a retrospective analysis of VZV infection in 192 recipients of allogeneic PBSCT at Princess Margaret Hospital, Toronto, Canada transplanted between June 2001 and December 2005. The median duration of follow up among survivors was 26 months (2 to 60 months). The pre-transplant diagnoses included AML (77, 40%), ALL (18, 9%), CLL (20, 10%), CML (23, 12%), HD (2, 1%), MDS (15, 8%), myelofibrosis (10, 5%), MM (3, 2%), NHL (22, 12%), and renal cell carcinoma (2, 1%). Twenty-seven patients (14%) received long-term courses of low dose acyclovir prophyaxis (200mg bid po for more than 3 months) for recurrent oral (n=21) or genital HSV infection (n=5) after PBSCT or previous history of recurrent VZV infection before PBSCT (n=1).Results: Of 192 recipients, 42 patients (22%) developed VZV infection including localized (n=37) and disseminated infections (n=5). The cumulative incidence of VZV infection at 1, 2 and 3 years was 19.3±3.3, 27.0±4.1 and 36.8±5.2%, respectively. Eighteen patients (43%) developed post-herpetic neuralgia for 2 months' duration (1–21 months). Other complications included secondary bacterial infections (n=3) and intracranial hemorrhage complicated with visceral VZV infection (n=1). One risk factor was identified: pre-translpant diagnosis of a lymphoproliferative disorder (LPD; CLL, HD or NHL) (p=0.021, 52.5±11.7% in LPD group vs 32.6±5.7% in non-LPD group). The use of low dose acyclovir prophylaxis (p=0.007, 0.0% in acyclovir group vs 41.6±6.0% in non-acyclovir group) was found to be protective. While no VZV infection episode were noted in the patients on long-term acyclovir prophyaxis, 3 episodes of VZV infection were noted after cessation of acyclovir. Time-dependent Cox regression analysis confirmed these 2 factors as independent risk factors: 1) diagnosis of LPD (p=0.039, HR 1.965, 95% C.I. 1.033–3.731) and 2) the use of low dose acyclovir prophylaxis (p=0.048, HR 0.305 95% C.I. 0.094–0.991). However, no difference was noted between the group with and without VZV infection in serial lymphocyte counts which has been done before and 3,6,9,and 12 months after transplantation.Conclusion: The incidence of VZV infection after allogeneic PBSCT still remained quite high on 36.8% at 3 years with patients transplanted for LPDs at higher risk. The use of low dose acyclovir (200mg bid po) seemed to be protective from VZV infection, even though it may not completely prevent late VZV infection. The quantitative serial measurement of lymphocyte count could not predict the risk of VZV infection after allogeneic PBSCT.

Varicella-zoster virus.

Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness, characterized by fever, viremia, and scattered vesicular lesions of the skin. As is characteristic of the alphaherpesviruses, VZV establishes latency in cells of the dorsal root ganglia. Herpes zoster, caused by VZV reactivation, is a localized, painful, vesicular rash involving one or adjacent dermatomes. The incidence of herpes zoster increases with age or immunosuppression. The VZV virion consists of a nucleocapsid surrounding a core that contains the linear, double-stranded DNA genome; a protein tegument separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins. VZV is found in a worldwide geographic distribution but is more prevalent in temperate climates. Primary VZV infection elicits immunoglobulin G (IgG), IgM, and IgA antibodies, which bind to many classes of viral proteins. Virus-specific cellular immunity is critical for controlling viral replication in healthy and immunocompromised patients with primary or recurrent VZV infections. Rapid laboratory confirmation of the diagnosis of varicella or herpes zoster, which can be accomplished by detecting viral proteins or DNA, is important to determine the need for antiviral therapy. Acyclovir is licensed for treatment of varicella and herpes zoster, and acyclovir, valacyclovir, and famciclovir are approved for herpes zoster. Passive antibody prophylaxis with varicella-zoster immune globulin is indicated for susceptible high-risk patients exposed to varicella. A live attenuated varicella vaccine (Oka/Merck strain) is now recommended for routine childhood immunization.

Varicella-zoster virus.

Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness, characterized by fever, viremia, and scattered vesicular lesions of the skin. As is characteristic of the alphaherpesviruses, VZV establishes latency in cells of the dorsal root ganglia. Herpes zoster, caused by VZV reactivation, is a localized, painful, vesicular rash involving one or adjacent dermatomes. The incidence of herpes zoster increases with age or immunosuppression. The VZV virion consists of a nucleocapsid surrounding a core that contains the linear, double-stranded DNA genome; a protein tegument separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins. VZV is found in a worldwide geographic distribution but is more prevalent in temperate climates. Primary VZV infection elicits immunoglobulin G (IgG), IgM, and IgA antibodies, which bind to many classes of viral proteins. Virus-specific cellular immunity is critical for controlling viral replication in healthy and immunocompromised patients with primary or recurrent VZV infections. Rapid laboratory confirmation of the diagnosis of varicella or herpes zoster, which can be accomplished by detecting viral proteins or DNA, is important to determine the need for antiviral therapy. Acyclovir is licensed for treatment of varicella and herpes zoster, and acyclovir, valacyclovir, and famciclovir are approved for herpes zoster. Passive antibody prophylaxis with varicella-zoster immune globulin is indicated for susceptible high-risk patients exposed to varicella. A live attenuated varicella vaccine (Oka/Merck strain) is now recommended for routine childhood immunization.

Recurrent varicella-zoster virus infections in apparently immunocompetent children

Fourteen generally healthy children (5 females, 9 males, ages 18 months to 13 years) who have developed 2 to 5 attacks of chickenpox are described. Herpes zoster also occurred in 2 of 14 children. No case of chickenpox was severe or associated with complications. General studies of immunoglobulins, specific antibodies to immunization agents, complement and lymphocyte subpopulation number and function indicated that 1 of 14 had low serum IgA and 3 of 14 lacked antibody to 1 (n = 2) or 2 (n = 1) immunization agents. Varicella-zoster virus (VZV)-specific immune studies showed that the children developed VZV-antibody titers by enzyme-linked immunosorbent assay of 1:640 to 1:10 240. By immunoblot assay all appeared to develop a normal spectrum of antibodies to individual VZV proteins. All but one developed VZV cellular immune responses with stimulation indices ranging from 3.6 to 174. Sequential follow-up of 8 patients revealed 1 who became seronegative and 2 who lost VZV cell-mediated immune responses. Chickenpox may recur more frequently than is generally recognized. General and VZV-specific immune investigations are unlikely to indicate a reason.

Antibody avidity following varicella-zoster virus infections.

The avidity of IgG antibodies following varicella-zoster virus (VZV) infections was investigated using urea treatment of antigen-bound serum antibody by indirect radioimmunoassay (RIA) and immunoblotting techniques. Sequential sera from 16 patients with varicella and 17 patients with zoster were tested, as well as sera from 80 seropositive individuals without a recent history of VZV disease. Both types of assay showed that low-avidity antibodies predominate early after primary infection, but that antibody avidity increases markedly during convalescence. Using RIA, all sera taken up to 12 weeks after the onset of varicella showed greater than 50% reduction in antibody titre after treatment with 8 M urea but thereafter the proportion of urea resistant antibody increased with time. In contrast, after recurrent infection, high avidity antibodies were found to predominate at all times. Only 6 of 47 sera tested from zoster cases showed greater than 30% reduction after urea treatment and all these were taken within 2 weeks after onset of rash. Immunoblotting also showed that the highly immunogenic p32/p36 nucleoproteins appear to induce predominantly low avidity antibodies, even after recurrent VZV infection. The results of this study indicate that treatment with 8 M urea in RIA for IgG antibodies may be a simple and reliable method for distinguishing primary and anamnestic antibody responses against VZV.

Subclass Distribution of the Serum and Intrathecal IgG Antibody Response in Varicella-Zoster Virus Infections

The subclass distribution of the varicella-zoster virus (VZV)-specific IgG antibody response was studied in serum samples from 22 patients with primary varicella and 34 with recurrent VZV infections and in cerebrospinal fluid (CSF) samples from 22 patients with recurrent infection who presented with symptoms of aseptic meningitis. IgG1 and 3 were the dominant subclasses among patients with primary and recurrent infections; IgG1 was also prevalent in the CSF samples. The VZV IgG subclass distribution patterns did not allow differentiation between primary and recurrent infections. However, seroconversions for IgG2, 3, or 4 were observed among patients with recurrences who were negative for specific IgM, suggesting that qualitative tests for serum IgG subclass antibody could be helpful for diagnosis in such cases. Herpes simplex virus-specific IgG was found in CSF samples from several patients with meningitis. The results suggest that calculation of the antibody to albumin index is better than IgG subclass antibody assays for discriminating the causative agent in these cases.

Cytomegalovirus, varicella-zoster virus, and Coxsackie B virus-specific IgM antibody responses in children with cancer

Cytomegalovirus (CMV)-, varicella-zoster virus (VZV)-, and Coxsackie B virus (CBV)-specific IgM antibody responses were studied in children with cancer during CMV, VZV, or enterovirus infections, respectively. High concentrations of specific IgM antibody apparently persisted in some instances for more than 6 months after primary CMV, primary VZV, or enterovirus infection; in other instances primary CMV or VZV infection were accompanied by undetectable or low-concentration specific IgM antibody responses. Low-concentration or undetectable specific IgM antibody responses were seen during recurrent CMV and recurrent VZV infection. Detection of a high-concentration CMV-, VZV-, or CBV-specific IgM antibody response in a single serum obtained from a child with malignant disease thus lacked specificity and sensitivity as a diagnostic marker for recent infection with one of these viruses. Moreover, detection of a specific IgM response did not differentiate primary and recurrent CMV or VZV infection in such a child. These findings have important implications for the serological diagnosis of virus infections in children with cancer.

Immunity to varicella-zoster viral glycoproteins, gp I (gp 90/58) and gp III (gp 118), and to a nonglycosylated protein, p 170.

Humoral and cellular immunity against two major glycoproteins (gp) of varicella-zoster virus (VZV), gp I (gp 90/58) and gp III (gp 118), and against a nonglycosylated phosphoprotein (p 170) was demonstrated in human subjects. Primary VZV infection was accompanied by the development of IgG to gp I (mean titer 1:200), gp III (mean titer 1:132), and p 170 (mean titer 1:331). Increased IgG antibody production to each of the VZV proteins occurred during recurrent VZV infection with mean titers to gp I of 1:29512, to gp III of 1:15848, and to p 170 of 1:15848. Persistent high titers to gp III (mean titer 1:891) and to p 170 (mean titer 1:2238) were observed in 75% and 88% of VZV-immune subjects, respectively. T lymphocytes which proliferated on stimulation with gp I, gp III, and p 170 developed with primary VZV infection. VZV-immune subjects had mean transformation indices of 4.2 +/- 0.70 SE to gp I, 4.7 +/- 1 SE to gp III, and 3 +/- 0.39 SE to p 170. Among individual subjects, humoral and cellular immunity was not always detected to all three of the VZV proteins. Resolution of primary VZV infection and maintenance of VZV latency did not require a host response to each of these major viral proteins.

Cell-mediated immunity to varicella-zoster virus after allogeneic marrow transplant.

The cellular immune response of normal persons and marrow transplant recipients to varicella-zoster virus (VZV) antigen was measured with use of the lymphocyte transformation response. Ninety-nine of 100 normal persons with previous VZV infection had a stimulation index of greater than or equal to 4.8, while 10 susceptible persons had responses of less than or equal to 3.0. Before transplant, responses were lower than normal in patients with leukemia in relapse (P = 0.001), but not in patients with leukemia in remission or with aplastic anemia. Throughout the first 100 days after transplant, lymphocyte response was depressed (P less than 0.0005), especially among recipients of antithymocyte globulin during days 41-80 (P less than 0.05). Patients with aplastic anemia had higher responses than those with leukemia during days 20-60 (P less than 0.02). By one year, most responses were normal. Long-term survivors who had recurrent VZV infection had positive responses more often than those without recurrent infection (P = 0.01). The lymphocyte response to VZV antigen parelleled, and thus may predict, periods of increased susceptibility to VZV infection.