|Year : 2006 | Volume
| Issue : 4 | Page : 235-243
|Herpes zoster in the immunocompromized populations
North Manchester General Hospital, Manchester, England, United Kingdom
B K Mandal
North Manchester General Hospital, Manchester, England
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mandal B K. Herpes zoster in the immunocompromized populations. Indian J Dermatol 2006;51:235-43
Herpes zoster (HZ) results from the reactivation of varicella-zoster virus (VZV) lying dormant in the dorsal root ganglia following an earlier primary infection (chickenpox), usually in childhood. There are wide variations in estimates of its incidence in general population - from 0.8 to 4.8 per thousand per year., These overall rates mask a dramatic increase in the incidence of HZ with age - from 2 to 3 cases per thousand/year among adults below 50 to 10 cases per thousand year in the over-eighties (1% per annum).
The increased incidence of HZ in the elderly is related to the selective decline in cell-mediated immunity against VZV due to advancing age. Predictably, the incidence of HZ is also high in individuals with defective cell-mediated immunity through disease or drugs. Humoral immunity does not have any role in VZV reactivation. Agammaglobulinaemic patients are no more likely to develop HZ than healthy persons. Absent or low concentration of circulating antibody may affect cutaneous dissemination but administration of VZV specific immunoglobulin does not prevent cutaneous dissemination of early localised zoster in the immunocompromized.,
This review focuses on the frequency and the timing of VZV reactivation in different immunocompromised populations, the clinical outcome and the current strategies for combating the problem.
| Incidence of HZ in Different Immunocompromised Populations|| |
Malignancies and HZ
Lymphoreticular malignancies . Lymphoreticular malignacies have figured prominently in earlier hospital-based series of HZ in the immunocompromized, reflecting both the frequency of such disorders in the general population and the intense immunosuppressive effects of treatments they received. The incidence in Hodgkin's disease increased steadily from 4.2% in an earlier report to between 22 and 25% by the eighties.,, The incidence is much higher in patients receiving combined radiotherapy and chemotherapy (cumulative incidence around 22% at 18 months) than in those receiving either radiotherapy or chemotherapy (around 8%). A strong correlation with radiation has been noted by several groups of workers.,, Often HZ occurs in the irradiated areas implying some form of local triggering influence. It is likely, however, that radiation, which is fairly intensive and covers a wide area, exerts its effect mainly through causing intense immunosuppression although additional local effect cannot be discounted.
It is thus of interest that patients with other solid malignant tumors treated with localized radiation, not associated with immunosuppression, e.g., parotid and testicular tumors, do not appear to have a higher incidence of HZ. On the other hand, HZ has become more frequent in patients with small-cell carcinoma of lungs who are treated intensively with combined chemotherapy and radiation.,
In non-Hodgkin's lymphoma, HZ is encountered less frequently than in Hodgkin's disease, with reported rates of 2.5%, 7.1% (15) and 8.7%. This is probably because such patients are usually treated with chemotherapy only and therefore have an incidence similar to that seen in advanced Hodgkin's disease patients who are treated similarly.
Aggressive treatment with high-dose chemotherapy followed by hematopoietic stem cell transplantation is gaining increasing acceptance in the management of Hodgkin's disease and non-Hodgkin's lymphoma. These patients develop profound immunosuppression and HZ rates are similar to those seen in other bone marrow transplant recipients.
Hematological malignancies. Among leukaemic patients, those with lymphocytic rather than myelocytic and chronic rather than acute forms of leukaemia, who are more vulnerable to HZ. In one series, HZ occurred in 8.3% among chronic lymphocytic leukaemia patients but 0-1.2% in other forms of leukaemia. A more recent retrospective survey found only six HZ cases among 750 consecutive cases of chronic lymphocytic leukaemia.
In chronic lymphocytic leukaemia, fludarabine is currently the most commonly used drug (after prednisolone) and causes suppression of CD4+ T cells (particularly when combined with cyclophosphamide or chlorambucil). Patients on combination therapy are more at risk than on monotherapy. Very low CD4 counts (below 50 cells/mm 3) predict VZV reactivation - 26% of patients with CD4 cell count below this level developed HZ as compared to 6% among those with counts above 50/mm 3.
More recently, alemtuzumab, a monoclonal antibody specifically directed against CD52, present on T and B lymphocytes, has been used in chronic lymphocytic leukaemia. It causes profound and prolonged lymphopenia and the time to reconstitution of CD4 back to normal is almost 2 years. In treatment refractory cases, alemtuzumab has caused significant increase in infections that are typically seen in allogenic bone marrow transplant patients including HZ.
Acute leukaemias and chronic myeloid leukaemia in younger patients are often treated nowadays with myeloablative therapy followed by hematogenous stem cell transplantation and have rates of HZ similar to other bone marrow transplant recipients.
HZ in recipients of bone marrow transplantation (hematogenous stem cell transplantation)
Indications for bone marrow transplantation (BMT) are becoming a legion. The list is ever widening and includes different forms of leukaemia and other hematological disorders, lymphoreticular malignancies, autoimmune disorders like systemic lupus erythematosus and rheumatoid arthritis and more recently, different forms of solid tumors like breast and lung cancers. The goal is to ablate an abnormal marrow or destroy a malignancy by high dose radiation and chemotherapy, followed by regeneration of haematopoietic capacity through infusion of hematopoietic stem cells under cover of immunosuppression to prevent graft rejection.
Such patients have complete immune incompetence for a while and are extremely susceptible to infections, exogenous as well as endogenous. Predictably, the incidence of HZ is among the highest of all immunocompromised populations, ranging from 18 to 41% in different series.,,, Allogenic (non-twin) transplants and acute or chronic graft vs. host diseases (GVHD) are significant risk factors.
HZ in solid organ transplant recipients
Solid organs are now increasingly transplanted with success for treating patients with end-stage organ disease. One of the keys to the success is the use of potent immunosuppression to prevent rejection of the donor organ. Infection is one of the prices to pay and HZ has become a common problem in such patients.
The incidences vary from 3 to 10% in renal, 5-10% in liver, 8-12% in lung and 20-25% in heart transplants and depend on patient populations, organs transplanted, immunosuppressive regimens and antiviral prophylaxis protocols chosen and variable methodologies used for follow up. In a retrospective analysis of HZ among 869 solid organ transplants performed in the University of Alberta Hospital, Edmonton, Canada between 1994 and 1999, Gourishankar and colleagues found an overall incidence of 8.6% (liver 5.7%, renal 7.4%, lung 15.1% and heart 16.8%). A recent report from Korea recorded a particularly high incidence of 29% among 561 kidney transplants between 1982 and 2002, whereas, a report from India documented five cases of HZ (9.2%) among 54 renal allograft recipients. 12% of liver transplant patients developed HZ in a centre in Spain.
HIV infection and HZ
The increased vulnerability to HZ among people with HIV became apparent quite early in the epidemic and it is now known that HIV patients have an incidence rate of up to 10 times higher than the general population.,, An incidence rate of 35.6% has been noted in a HIV cohort in rural Uganda.
Since the introduction of highly active antiretroviral therapy (HAART), dramatic changes have occurred in the HIV scene - in many patients, immune deterioration has been prevented or halted or reversed. One would expect these developments to have a positive impact on HZ incidence. On the other hand, patients are living longer and are therefore subject to age-related immunosenesence that increases HZ incidence in the elderly. HAART itself has been recognised as a risk factor for an attack of HZ.
There are few reliable estimates of the incidence of HZ in the HAART era. A recent large study from Baltimore, USA found the incidence to be similar to one in the pre-HAART era. Others have found that the incidence of HZ was significantly higher in the pre-HAART era than in the post -HAART era.
HZ in patients with autoimmune and dermatological disorders
Immunosuppressive drugs are also used widely in a diverse range of autoimmune and dermatological disorders.
HZ occurs commonly in systemic lupus erythematosus (SLE) patients. Lee and colleagues found a high incidence of 30.6% among 49 children with SLE while others have reported incidences of 13.1%, 13.5%, 13.9%, 15% and 19%, Immunosuppressive therapy (especially cyclophosphamide, azothiaprine and high dose corticosteroids), presence of lupus nephritis and other severe manifestations and of anti-Sm antibody are associated with a greater risk of HZ. The patients may have intrinsic defects in controlling VZV reactivation.
Wung and colleagues have reported an incidence rate of 10% among a cohort of 180 Wegener's granulomatosis - renal dysfunction and female gender were strong risk factors.
Methotrexate, azathioprine, and cyclosporin are important disease modifying anti-rheumatic drugs (DMARD) that are used commonly in treatment of rheumatoid arthritis. Corticosteroids are also commonly used to bridge the time until DMARDs are effective. Rheumatoid arthritis patients are thus often significantly immune compromised. Antonelli and colleagues reported HZ incidence of 14.5 cases/1000 patient years in methotrexate-treated patients as compared the general population incidence of 1.3-4.8 cases/1000 patient years. Yamauchi and colleagues found an incidence of 25% among a population of rheumatoid arthritis patients in Japan.
Immunosuppressant drugs are also used in treatment of severe eczema (corticosteroids, cyclosporin, azothiaprine or mycophenolate mofetil) and severe psoriasis (methotrexate). Information on the occurrence of HZ in such patients is lacking and longitudinal studies would be of interest. More recently, efalizumab (a monoclonal antibody that suppresses T-cell activation) and TNF blocker infliximab have been licensed for use in chronic plaque psoriasis. Both have potential for immunosuppression (infliximab increases reactivation of tuberculosis) and thereby of VZV reactivation.
Tacrolimus is a potent immunosuppressant when used systemically and has wide applications in solid organ transplantations, especially liver. Topical tacrolimus has now been licensed for use in severe atopic eczema. Systemic absorption is negligible. Particular attention has been paid to skin infection as a potential complication of topical treatment. Herpes simplex and less commonly HZ, molluscum, and warts have been reported by some workers., However, no evidence of increased cutaneous infection was found in a detailed controlled study.
Corticosteroids and HZ
Corticosteroids are powerful anti-tumour and immunosuppressant drugs and are used widely in oncology, transplant medicine, and immune disorders, in high doses and for prolonged periods. Their role in causing VZV reactivation in such patients is in no doubt. However, there is little evidence of an increased frequency of HZ in patients who are on low dose corticosteroid therapy. Certainly, patients taking low dose prednisolone on alternate days are at no greater risk.
| Timing of VZV Reactivation|| |
HZ may occur as early as 1 month but more commonly occurs several months after bone marrow transplantation.,, A similar situation exists in the other two major groups of therapeutically induced immunosuppressed populations, i.e., lymphoreticular malignancy patients and solid organ transplant recipients. In Guinee and colleagues' series on Hodgkin's disease, the incidence of HZ rose sharply only after 6 months and peaked at around 12 months. Following solid organ transplantation, earlier reports described the onset as between 100 days and 8 months and a recent report found a median onset of 9 months. Exposure to antiviral drugs may be delaying the onset of HZ further.
Thus, VZV reactivation occurs maximally after the period of most intense immunosuppression. In contrast, reactivation of HSV occurs typically during this period. The reason for this is unclear. Perhaps, the net state of immunosuppression has not been prolonged enough to favor reactivation of infections such as VZV, cytomegalovirus and Pneumocystis carinii . However, reactivation of the latter two organisms require a degree of immunosuppression that is not necessary for VZV reactivation, as exemplified by its increased occurrence among otherwise healthy elderly people.
It is of interest that VZV reactivation seems to be occurring at a time when immune reconstitution has just begun. In BMT and cancer chemotherapy patients, cellular immune response begins to appear by the ninth month and usually returns to normal by the end of the year (unless complicated by GVHD) and partially so in solid organ transplants, where some degree of immunosuppression is maintained to prevent rejection.
The picture appears to differ in HIV-infected populations. In a way, the declining cellular immune response in people with HIV mimics the age-related immunosenesence seen among the elderly - albeit in a much more compacted time frame. In HIV patients, early reports highlighted HZ as an early clinical event and the World Health Organization categorized HZ in Stage II of their proposed clinical staging. The epidemic of HZ that came soon after the HIV epidemic began in Manipur, India, further supported the status of HZ as an early clinical event in the natural history of HIV. As early as 1987, comments appeared on the paradox of its apparent rarity among AIDS patients despite their profound immunosuppression.
Later studies evaluating the relationship between CD4 count and the risk of HZ have yielded mixed results. Two studies demonstrated an increased risk with decreasing CD4 cell count., In contrast, a study among homosexual men in San Francisco and another in Uganda, failed to reveal any association between HZ and duration of HIV. Gebo and colleague found that moderate degree of immunodeficiency (CD4 cells 50-200/mm 3) put the patient at increased risk of HZ whereas profound immunodeficiency (CD4 cells below 50/mm 3) did not. More intriguing in this context are the spate of reports of HZ as immune reconstitution disease (IRD) among patients whose immune functions have improved following HAART.,,,,,,,
Perhaps, there exists a threshold for immune responsiveness below which cutaneous manifestations of HZ do not appear and VZV reactivation remains subclinical unless it disseminates to distant organs. In therapeutic immunosuppression this threshold is reached rapidly, hence the rarity of HZ during the early months following cancer therapy, BMT and solid organ transplant recipients. HZ starts to appear when immune responsiveness has again recovered to above this threshold. In contrast, in HIV patients there is a slow decline in immune responsiveness giving ample opportunity for VZV to reactivate and cause HZ until it declines below the threshold and HZ becomes much less common. HZ begins to reappear as IRD when immune responsiveness improves again following HAART.
Thus, the late occurrence of HZ among cancer therapy and transplant patients may be an expression of IRD.
Hope - Simpson originally hypothesized that immunity to VZV is maintained in normal individuals through subclinical release of virus acting as antigenic boost. Serological studies have shown that subclinical HZ occurs frequently in transplanted patients., Reports of disseminated visceral zoster presenting as acute abdomen but without rash in BMT patients suggests that viraemia is not rare.,,
| Morbidity and Mortality of HZ in the Immunocompromized|| |
It is clear from the published reports that HZ in the immunocompromised is rarely life-threatening. There was no death in the Manchester series and in the NIH series only one death can be attributable directly to HZ. Several series have reported zero mortality., In most others it has been below 5%).,, A higher death rate (6.7%) was found by Locksly among BMT pts.
On the other hand, complications are much more common among the immunocompromized than in the general population.
Cutaneaous dissemination (defined as presence of more than 20 vesicles outside the primary and immediately adjacent dermatomes) is common and affects up to 40% of patients. There are wide variations according to patient populations studied. Among the earlier hospital based series it was present in 15% of NIH patients and 44% of Manchester patients. Cutaneaous dissemination occurs more commonly among bone marrow transplant recipients (36.4%) and in about 40% of patients with lymphoreticular malignancies. On the other hand, there were no cases of cutaneous dissemination in two large series of solid organ transplant recipients and HIV patients and 0-14.6% in SLE patients,,, and 0% in rheumatoid arthritis. Up to 10% of patients with cutaneous dissemination may develop visceral development, in form of pneumonitis, meningoencephalitis or hepatitis.
Vasculopathy is the underlying pathology of CNS disease by VZV. It usually affects large vessels in immunocompetent individuals but predominantly small vessels in the immunocompromised host. In some patients, both large and small vessels are involved. The resultant neurological picture can be very diverse. Gray et al . described five clinico-pathological patterns in AIDS patients: (i) multifocal encephalitis predominantly affecting white matter, (ii) ventriculitis, (iii) acute haemorrhagic myeloradiculitis, (iv) focal necrotizing myelitis, and (v) vasculopathy of leptomeningeal arteries causing infarcts. Neurological manifestations often occur months after HZ or without preceding HZ and can be rapidly fatal.
Abdominal involvement (usually hepatitis, less commonly pancreatitis and gastritis) can be dramatic and may present as 'acute abdomen.' This may precede any rash or occur without it, thus causing considerable diagnostic difficulty and delay in instituting vital antiviral drugs. Most such reports have involved BMT patients.,,,,,, An unexplained elevated transaminase may precede HZ.
Among AIDS patients, another devastating example of VZV reactivation has come to light recently - the progressive outer retinal necrosis syndrome. It is a clinical variant of necrotizing herpetic retinopathy. Its course and clinical features distinguish it from HSV-related acute retinal necrosis and CMV retinopathy. A third of the patients may not have any history of cutaneous HZ. Prognosis is poor despite aggressive antiviral therapy; disease progression and recurrences are common.
The most troublesome problems of HZ in the immunocompromized are of course local ones - e.g., postherpetic neuralgia (PHN), delayed healing or locally progressive disease.
Some of the observed frequencies of PHN are 15% in SLE, 18% in malignancy, 23% in HIV, 24% in BMT and a striking 42.7% in solid organ transplant recipients. These contrast with the 9% incidence noted in a general population series.
Delayed healing of the local lesions or their persistence and progression are common. Lesion formation commonly continues for up to two weeks and scabbing may not take place until 3-4 weeks into the disease course. Local tissue destruction can be considerable with disfiguring scarring. Others have found chronic verrucous skin lesions, long-standing chronic zoster in children with HIV and oro-dental problems.
| Diagnosis|| |
Clinical diagnosis is sufficient in most cases but laboratory help is necessary when skin lesions are atypical or the patient has visceral disease. Laboratory diagnostic techniques include Tzanck smears, electron microscopy, antigen detection, virus culture and demonstration of viral DNA by polymerase chain reaction (PCR).
Demonstration of multinucleate giant cells in the scraping of the base of a lesion (Tzanck smear) has a low sensitivity, direct immunoflorescent staining of the same is more useful but time consuming; cell culture even more so.
Real-time PCR assays provide results within 4 hours compared to a median of 4.4 days for culture and immunoflorescence. Detection of VZV DNA in blood by PCR is proving most useful in patients presenting with visceral zoster and can be life-saving in severely immunocompromized patients presenting with acute abdomen.,
In neurological disease, magnetic resonance imaging scanning, angiography and virological analysis of cerebrospinal fluid (CSF) are necessary to achieve diagnosis. VZV vasculopathy patients do not always have VZV DNA in CSF but diagnosis can be confirmed by demonstrating anti-VZV antibody.
| Treatment|| |
Efficacy of acyclovir in HZ was initially demonstrated in immunocompromized patients. A number of studies proved the ability of intravenous acyclovir in reducing the complications of HZ in these patients. There is no evidence from controlled studies about its efficacy if started after 72 hours into the illness but most clinicians would do so if skin lesions are active or progressing.
Intravenous acyclovir necessitates hospitalisation and thus poses problem when dealing with uncomplicated HZ in an otherwise well immunocompromized patient at home or in the outpatient setting. Oral acyclovir has not been evaluated in such patients.
Although the newer drugs, famciclovir and valacyclovir have better bioavailability and thus should be superior to acyclovir, neither has been assessed against intravenous acyclovir in controlled studies, in treatment of HZ in the immunocompromized. However, the evidence that valacyclovir 1G 3 times a day for 7 days produced similar, if not superior, area under the curve peak and trough levels compared to IV acyclovir in immunocompromized patients, supports the use of this drug on an outpatient basis.
Among new drugs under study, soruvudine [1-beta-D-arabinofuransyl-E-(2-bromovinyl)uracil] has been found to be superior to acyclovir for reducing the times to the cessation of new vesicle formation in a study among HIV-infected patients.
Not surprisingly, VZV resistant to acyclovir has now been encountered in patients on long-term therapy with the drug. Such cases should be treated with foscarnet.
| Prevention|| |
Ideally HZ should be prevented in the immunocompromized but the necessary tools are lacking.
How effective is prophylactic acyclovir?
Oral acyclovir has been used widely in transplant and cancer chemotherapy centres, primarily to prevent HSV and CMV diseases during the period of intense immunosuppression. Routine antiviral prophylaxis for prevention of CMV disease may reduce the mortality from HZ but did not affect the incidence. The duration of acyclovir prophylaxis was probably not long enough to cover median time of VZV reactivation but protected against disseminated visceral disease during the period of intense immunosuppression.
One answer would be to use acyclovir for longer periods. Thomson and colleagues reported the use of low dose oral acyclovir (400 mg bd) in 247 allogenic transplant recipients until immunosuppression was discontinued and CD4 cell count exceeded 200/mm 3. Viral reactivation was effectively suppressed during the period of prophylaxis with only one case of breakthrough HZ. In all, 64 patients discontinued prophylaxis and HZ developed in 26 of them, giving a cumulative incidence of HZ 1 year after stopping acyclovir of 39% and at 3 year, 44%. Such infections were usually mild and localized.
In another randomised double-blind study, acyclovir (800 mg bd) for 1 year post-transplant significantly reduced VZV infections at 1 year after transplantation. The hazard ratio for zoster at 1, 3, and 5 years were 0.16, 0.52, and 0.76, respectively, the differences were not statistically significant. There was no statistically significant difference in reconstitution of VZV-specific T-helper cell responses. Post-study HZ occurred predominantly in patients with continued need for systemic immunosuppression. Such patients may benefit from longer periods of prophylaxis.
ACV thus postpones HZ rather than prevents it and some have questioned the practicality and cost-effectiveness of prolonged ACV prophylaxis.
Does vaccination have a role?
In June 2005, Oxman and colleagues demonstrated that a high-potency VZV vaccine decreased the incidence of HZ and its associated morbidity in immunocompetent individuals over 60 years of age. The efficacy of the vaccine is probably due to enhancement of waning specific cell-mediated immune responses. Hata and colleagues gave heat-inactivated live-attenuated varicella vaccine to transplant recipients 30 days before and 30, 60, and 90 days post-transplant and monitored for 1 year. HZ developed in seven of 53 vaccinated patients (13%) and in 19 of 58 unvaccinated patients (33%) - P =0.01. In vitro T-cell proliferation response to VZV was significantly greater in the vaccinated than in unvaccinated at 120 days and persisted at 6 months and 1 year, though not significantly. Further studies are clearly needed in this area.
HZ causes significant morbidity in the immunocompromised population in forms of PHN, locally destructive disease and cutaneous dissemination. Intensely immunosuppressed patients are additionally at risk from visceral diseases that are potentially fatal, particularly if the presentation is atypical. Prompt IV acyclovir helps prevent visceral dissemination. A low threshold is necessary for its empiric use in highly immunocompromised patients presenting as 'acute abdomen' because characteristic skin lesions may not be present or develop later. Demonstration of viral DNA in blood helps rapid diagnosis in such cases.
In uncomplicated local disease, IV acyclovir can perhaps be substituted by oral valacyclovir, thereby obviating the need for hospitalization.
Low dose oral acyclovir protects against VZV reactivation during its use only, so effective prevention of HZ requires continued prophylaxis until reasonable immune reconstitution has occurred, i.e., for 12 months in BMT recipients. In those who need continuing immune suppression this may not be practical or cost-effective.
Whether pre-operative high-dose VZV vaccine can bridge this gap by accelerating the immune reconstitution process remains to be seen.
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