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Recommendations for the Managementof Herpes Zoster Robert H. Dworkin,1,2 Robert W. Johnson,18 Judith Breuer,19 John W. Gnann,5,7 Myron J. Levin,8 Miroslav Backonja,9
Robert F. Betts,3 Anne A. Gershon,4 Maija L. Haanpa¨a¨,22 Michael W. McKendrick,20 Turo J. Nurmikko,21
Anne Louise Oaklander,10 Michael N. Oxman,12 Deborah Pavan-Langston,11 Karin L. Petersen,14
Michael C. Rowbotham,14 Kenneth E. Schmader,15 Brett R. Stacey,16 Stephen K. Tyring,17 Albert J. M. van Wijck,23
Mark S. Wallace,13 Sawko W. Wassilew,24 and Richard J. Whitley6
Departments of 1Anesthesiology, 2Neurology, and 3Medicine, University of Rochester, Rochester, and 4Department of Pediatrics, ColumbiaUniversity, New York, New York; Departments of 5Medicine and 6Pediatrics, University of Alabama at Birmingham, and 7Birmingham Veterans Affairs Medical Center, Birmingham, Alabama; 8Department of Pediatrics, University of Colorado, Denver; 9Department of Neurology, University ofWisconsin, Madison; 10Department of Neurology, Harvard University, and 11Department of Ophthalmology, Harvard Medical School, Boston,Massachusetts; Departments of 12Medicine and 13Anesthesiology, University of California, San Diego, and 14Department of Neurology, Universityof California, San Francisco; 15Department of Medicine, Duke University, Durham, North Carolina; 16Department of Anesthesiology, University ofOregon, Portland; 17University of Texas Health Science Center, Houston; 18Department of Anesthesiology, University of Bristol, Bristol, 19Skin VirusLaboratory, Queen Mary College, London, 20Department of Infection and Tropical Medicine, Royal Hallamshire Hospital, Sheffield, and 21Department of Neurological Science, University of Liverpool, Liverpool, United Kingdom; 22Departments of Anesthesiology and Intensive Careand Neurology, Helsinki University Hospital, Helsinki, Finland; 23Pain Clinic, University of Utrecht Medical Center, Utrecht, The Netherlands; and24Dermatologische Klinik, Klinikum Krefeld, Krefeld, Germany The objective of this article is to provide evidence-based recommendations for the management of patients
with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and
costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and
the authors' clinical and research experience relevant to the management of patients with HZ were reviewed
at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the
use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the
treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In
addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may
further reduce pain and other complications of HZ.
After a primary varicella-zoster virus (VZV) infection tious Diseases is to improve the care of patients with (termed "varicella" or "chickenpox"), the virus estab- HZ by providing practical, evidence-based recom- lishes latency in dorsal root and cranial nerve ganglia.
mendations that take into account clinical efficacy, Herpes zoster (HZ), also known as "shingles," results adverse effects, impact on quality of life, and costs from reactivation of VZV and its spread from a single of treatment. Pharmacologic management is empha- ganglion to the neural tissue of the affected segment sized, because few nonpharmacologic approaches have and the corresponding cutaneous dermatome [1].
been evaluated in randomized controlled trials. These The objective of this supplement to Clinical Infec- recommendations apply only to the acute phase ofHZ; detailed recommendations for the treatment ofpostherpetic neuralgia (PHN), the most commoncomplication of HZ, appear elsewhere [2, 3]. We de- Reprints or correspondence: Dr. Robert H. Dworkin, Dept. of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box scribe the pathogenesis, epidemiological aspects, clin- 604, Rochester, NY 14642 ([email protected]).
ical aspects, and complications of HZ, and then we Clinical Infectious Diseases
review the literature on the treatment of HZ and pre- 2006 by the Infectious Diseases Society of America. All rights reserved.
sent specific treatment recommendations.
Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S1
of IFN-a in adjacent epithelial cells [5, 6]. Thereafter, the virusovercomes the innate defenses, and vesicles appear. Production Pathogenesis of HZ of cytokines and up-regulation of capillary endothelial adhesion Epidemiological Aspects of HZ factors attract migratory T cells that may further spread virus Clinical Aspects of HZ before they contain viral replication [5].
Cell-free virus, which is present only in skin vesicles, is nec- Differential Diagnosis and Laboratory Testing essary for the infection of sensory nerve endings in epithelia.
Complications of HZ This results in virus migration up sensory axons to establish HZ Ophthalmicus with Delayed Contralateral latency in sensory ganglia [7]. The final assembly and envel- opment of newly synthesized virions occurs within specialized wrapping cisternae located in the trans-Golgi network [8, 9].
The concave face of each wrapping cisterna is rich in VZV glycoproteins and becomes the viral envelope. The convex side Postherpetic Itch is rich in cellular proteins, such as cation-independent mannose Methods Used for Developing Treatment 6-phosphate receptors, and the cisterna becomes a transport Data Sources and Study Selection vesicle containing the newly enveloped virion [8, 10]. In human Outcome Assessments embryo lung fibroblasts, the presence of cation-independent Treatment of Immunocompetent Patients mannose 6-phosphate receptors on the convex face of the wrap- Patient Education ping cisterna is postulated to route virions from the cell se- Antiviral Therapy cretory pathway to endosomes where the virions are sequestered Recommendations for Antiviral Therapy [8, 11, 12] (figure 1). VZV also spreads quickly to adjacent Supplementing Antiviral Therapy epidermal cells by inducing the fusion (mediated by glycopro- Oral Corticosteroids teins H, L, B, and E) of virally infected cells with uninfected Analgesic Treatments neighboring cells [9]. In contrast, the loss of cation-indepen- dent mannose 6-phosphate receptors in keratinocytes in the Recommendations for Supplementing Antiviral Therapy superficial epidermis allows for the accumulation of cell-free Treatment of Immunocompromised Patients virions, which are necessary for transmission and establishment HZ in the Setting of Malignancy or Organ Transplantation of latency [13].
HZ in HIV-Seropositive Patients A guinea pig model of latency and reactivation in vitro has Treatment of Complicated Presentations of HZ been developed. Neurons dissected from the myenteric plexus HZ Ophthalmicus and VZV Retinitis are propagated in culture. In this model, infection of sensory Vulnerable and Frail Elderly Patients nerve endings with cell-associated virus causes lytic infection, Pregnant and Nursing Patients whereas cell-free virus establishes latency [7]. Latently infected Neurologic Complications of HZ human ganglia show restricted expression of 6 genes—ORF4, Recommendations for Future Research ORF21, ORF29, ORF62, ORF63, and ORF66 [14–17]—none of which code for glycoproteins, with 1 report of detection of open reading frame (ORF) 18 transcripts [16]; the same patternof expression is found in latently infected guinea pig somaticneurons [7]. The addition of cell-associated virus, the product PATHOGENESIS OF HZ
of the ORF61 gene, or its herpes simplex virus (HSV) homo- Nasopharyngeal replication of VZV, which occurs immediately logue ICP0 to the guinea pig gut model results in VZV reac- after primary infection, is followed by spread to adjacent lym- tivation and lytic infection [7]. ORF 61 protein is absent from phoid tissue, where the virus infects memory CD4+ T cells, cell-free virions, which are able to establish latency in the gut which are abundant in tonsilar lymphoid tissue [4]. Trafficking ganglia. More recently, direct transfer of VZV has been dem- of memory cells expressing cutaneous homing antigen and onstrated from infected peripheral blood mononuclear cells to CCR4 to the skin is thought to deliver virus to cutaneous ganglion tissue implanted into SCID-hu mice. Direct transfer epithelia within a few days of infection [4]. The localized rep- of virus to the ganglion and establishment of latency by this lication in epithelial cells is facilitated by down-regulation of route may, therefore, be possible [18].
IFN-a within the infected cells and failure of induction of In situ hybridization has shown the latent VZV genome to adhesion molecules [5]. At the same time, cell-to-cell spread be localized in ∼1%–7% of sensory ganglion neurons, at !10 of virus appears to be contained for the first week by production copies/cell [19–21]. In addition to detection of messenger RNA S2 • CID 2007:44 (Suppl 1) • Dworkin et al.
pothesis is that phosphorylation of immediate-early protein 62by the protein kinase encoded by ORF66 prevents translocationof the former to the nucleus, which, in turn, interrupts thecascade of viral transcription and replication [17]. The additionof ORF 61 protein to the latently infected guinea pig neuronmodel results in translocation of immediate-early protein 62and the ORF 29 protein to the nucleus. This causes transcrip-tion of a, b, and g viral proteins and reestablishment of lyticinfection [7, 22].
The incidence of HZ increases with age and with other causes of decreased cellular immunity. Limiting dilution experimentshave established that reduced VZV T cell responder cell fre-quency characterizes all conditions associated with increasedVZV reactivation [24]. Much of the T cell response in latentlyinfected individuals is directed against glycoproteins E, H, B,and I, as well as against transcriptional activators encoded byORFs 4, 10, 62, and 63. Boosting of the cell-mediated immune response has been shown in mothers of children with varicella,suggesting that exposure to antigen may be important for main-taining immunity [25]. Two studies have shown that the in-cidence of HZ is lower in adults with greater contact with children in their daily lives, which was considered to be a sur-rogate for exposure to VZV [26, 27]. Proof that exposure toexogenous antigen is protective came with the recent dem-onstration that a live attenuated VZV vaccine reduced the in-cidence of HZ and the burden of disease, compared with pla-cebo [28].
Figure 1.
Intracellular transport and maturation of varicella-zoster virus Reducing the occurrence of HZ will be crucial to eliminating (VZV). A, Primary envelopment. VZV nucleocapsids assemble in the nucleus, transmission of VZV. The force of infection (i.e., the rate at bud through the inner nuclear membrane, and acquire a temporary envelopebefore entering the perinuclear cisterna, which is continuous with the lumen which individuals acquire infection after exposure) is estimated of the endoplasmic reticulum. The primary virion envelope fuses with the to be 20% for varicella leading to infection of children 2–4 membrane of the endoplasmic reticulum, delivering naked nucleocapsids years of age. By contrast, the estimated force of infection for into the cytosol. B, Glycoprotein transport and virion assembly. VZV gly- HZ causing varicella is 0.1% [29]. Thus, susceptible children coproteins are synthesized in the rough endoplasmic reticulum (RER) and are more likely to develop varicella from exposure to varicella become processed and transported to the Golgi complex via the intermediatecompartment (IC) independently of newly assembled nucleocapsids. From than from exposure to HZ. Nonetheless, HZ will become a the RER, the glycoproteins, together with adhered tegument proteins, are more common source of varicella as immunization programs transported to the trans-Golgi network (TGN), where they concentrate in eliminate varicella; this is already evident in cases of nosocomial the concave membrane of specialized wrapping TGN cisternae. The viral varicella in the United Kingdom, where many cases arise from nucleocapsids converge with the glycoproteins and tegument as the TGN contact with HZ rather than varicella [30].
sacs wrap around the nucleocapsids and fuse, giving rise to mature virionsThe VZV glycoprotein-rich membrane of the concave face of the wrappingcisterna becomes the viral envelope. The membrane of the convex face is EPIDEMIOLOGICAL ASPECTS OF HZ
rich in mannose 6-phosphate (Man-6-P) receptors and delimits a transportvesicle that encloses the newly enveloped virion. Man-6-P receptors on the Varicella typically occurs during childhood in temperate cli- membrane of the convex face of the wrapping cisterna are thought to route mates and during adolescence or early adulthood in tropical viral particles from the cell secretory pathway to endosomes where the areas [31]. Latency is typically lifelong, and HZ is caused by virions are degraded. Illustration reproduced with permission from [8].
viral reactivation from the latent state. Second episodes of HZoccur in ⭐5% of individuals but occur more frequently in those from the 6 ORFs mentioned, immunohistochemical studies who are immunocompromised. Primary infection produces have shown the presence of protein products from ORFs 4, 21, long-term immunity to varicella. Protection from reactivation 29, 62, 63, and 66 [17, 22, 23]. Moreover, these are located in depends on intact cell-mediated immunity, which declines with the cytoplasm of infected cells, whereas, in lytic infection, both age (immunosenescence), during certain diseases (e.g., HIV cytoplasmic and nuclear localization is evident. A working hy- infection and some malignancies), and as a result of immu- Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S3
nosuppressive therapy (e.g., after organ transplantation, che- decrease as the number of adults infected with latent wild-type motherapy, or steroid treatment). The survival of VZV in hu- virus decreases. Any increase in HZ incidence could be offset by mans for several million years attests to its success.
adult HZ vaccination, if its use becomes widespread. In a ran- Data from a number of sources consistently show that the domized clinical trial of HZ vaccination compared with placebo incidence of HZ increases with age. Although HZ is not rare among nearly 39,000 adults ⭓60 years of age, the incidence of in young individuals, the median age of patients with HZ is HZ was reduced by 51.3% [28].
∼64 years, whereas the median age of the US population is ∼46 If vaccination of adults is widely adopted and produces re- years. The incidence of HZ ranges from 1.2 to 3.4 cases per ductions in the incidence and burden of HZ in the community 1000 person-years in studies of immunocompetent individuals that are comparable to those found in this trial [28], there in the community, but it increases to 3.9–11.8 cases per 1000 could be a dramatic reduction in HZ incidence in the decades person-years among those 165 years of age [28, 32–36]. Some to come. Considering the potential impact of adult HZ vac- [37, 38], but not all [39, 40], recent studies have found the cination and the long-term effect of childhood varicella vac- incidence of HZ to be increasing, although the explanation is cination, future generations may largely be spared the most unclear. It is likely that the incidence of HZ will change further distressing complications of HZ.
over the coming decades, as a result of the increasing age ofthe population, changes in therapy for malignant and auto- CLINICAL ASPECTS OF HZ
immune diseases, and the increasing use of organ transplan- The reactivation of VZV in ganglia may be a frequent event. In tation, and, possibly, as a consequence of childhood varicella the presence of adequate VZV-specific immune responses—most importantly, T cell–mediated immunity—reactivation events are In the developed world and elsewhere, significant increases either prevented or quickly aborted. The outcomes of these re- are occurring in the percentage of people who are elderly. In activations, thus, remain subclinical, although immunological the United Kingdom, 2001 census data showed that the pop- evidence of their existence can be detected [43]. If the VZV ulation ⭓65 years of age numbered ∼9 million (16%), and the reactivation is not contained, as can occur with iatrogenic im- projection for 2025 is 13 million. Among those ⭓65 years of munosuppression or age-related immunosenescence, then viral age, the proportion of people ⭓85 years of age has increased replication ensues, resulting in ganglionitis and extensive infec- from 7% in 1971 to 12% in 2004. Data from the Scientific tion and destruction of neurons and supporting cells [44, 45].
Registry of Transplant Recipients draft analysis has shown a This significant infection and accompanying inflammatory re- year-by-year increase in the number of solid-organ transplants sponse is probably the origin of the prodromal pain that pre- in the United States, with ∼12,000 conducted in 1988 and twice cedes the characteristic dermatomal eruption of HZ. Approx- that number conducted in 2003; all these patients receive im- imately 70%–80% of patients with HZ describe prodromal pain munosuppressant medications (Scientific Registry of Transplant in the dermatome where skin lesions subsequently appear. Pro- Recipients, personal communication, 13 January 2004).
dromal pain may be constant or intermittent and frequent or Childhood vaccination to prevent varicella was introduced in sporadic, and it may or may not interfere with sleep. The pain the United States in 1995, and other countries adopting this often has a distinctive quality for each patient and is commonly strategy include Australia, Canada, Germany, Israel, Japan, and described as "burning," "shooting," "stabbing," or "throbbing." South Korea. Epidemiological models suggest that a significant Some patients describe the pain only when the involved area increase in HZ incidence could occur as a consequence of reduced is touched, whereas others complain primarily of pruritus. The opportunities for subclinical boosting, due to dramatic reduc- prodrome is typically 2–3 days in duration, but longer dura- tions in varicella incidence resulting from immunization [26, 41, tions, of ⭓1 week, are not uncommon. Significant and pro- 42]. To the extent that exogenous boosting enhances VZV-specific longed prodromal pain not uncommonly leads to medical in- cell-mediated immunity and delays reactivation of latent virus, vestigation for diseases characterized by pain in the area of the adults with a history of varicella in regions where varicella in- prodrome (e.g., angina, cholecystitis, glaucoma, nephrolithiasis, cidence has been markedly reduced by vaccination will be more and spinal nerve compression).
likely to develop HZ than will those living where varicella is more The cause of the dermatomal pain becomes obvious when common. The incidence of HZ may, therefore, increase signifi- the characteristic rash appears in that dermatome [1]. The in- cantly, peaking ∼20 years after the initiation of childhood vac- terval from the onset of the prodrome to the appearance of cination programs and only returning to prevaccination levels rash represents the time required for reactivated VZV to rep- after 40 years [42]. Although the attenuated Oka vaccine virus licate in the ganglion and to transit down the cutaneous nerve establishes neuronal latency in vaccine recipients, it appears to to the nerve endings at the dermal-epidermal junction. There reactivate and cause HZ much less frequently than does wild- is additional delay while VZV replicates in the skin and induces type VZV. Thus, it is expected that the incidence of HZ would sufficient necrosis and inflammatory response to cause the rash.
S4 • CID 2007:44 (Suppl 1) • Dworkin et al.
icles begins within 1 week of the onset of rash, if not sooner,and is followed 3–5 days later by lesion ulceration and crusting.
The appearance of new vesicles for 11 week should raise con-cern about an underlying immunodeficiency syndrome. Crustsusually are gone by the end of 3 or 4 weeks, but scarring andhypo- or hyperpigmentation may persist long after the HZresolves. Fewer than 20% of patients have significant systemicsymptoms, such as fever, headache, malaise, or fatigue. Lesionson mucous membranes, where the epidermis is fragile ratherthan thick and keratinized, do not usually form vesicles andcrusts but form shallow erythematous ulcers. Eruptions on themucosa may go entirely unnoticed.
HZ is a dermatomal illness that does not cross the midline except where the normal representation of segmental nervesdoes so to a limited extent. In immunocompetent patients, only Figure 2.
Thoracic herpes zoster (photograph provided by S.W.W.) a single dermatome is typically affected; however, normal var- iations in innervation can lead to limited involvement of ad- The rash associated with HZ has a brief erythematous and jacent dermatomes. In typical HZ, widespread involvement of macular phase, which is often missed, after which papules rap- multiple dermatomes, especially those that are widely separated, idly appear. These papules develop into vesicles within 1–2 days, does not occur. The rash is usually accompanied by the same and vesicles continue to appear for 3–4 days. At this point, pain experienced during the prodrome, but this acute pain can lesions of all types may be present (see figures 2–4). The lesions worsen, improve, or appear for the first time during the cu- tend to be grouped, and clusters are often seen where there are taneous phase of HZ. Pruritis may be as common as pain in branches of the cutaneous sensory nerve (e.g., in parasternal, patients with HZ, although it has received far less medical mid-axillary, and paraspinous areas, representing the anterior attention [46]. Some mild cases of HZ are characterized by and lateral branches of the anterior primary division as well as more pruritis than pain.
the posterior division of a thoracic nerve). Pustulation of ves- In the immunocompetent patient with HZ, there are nu- Figure 3.
Cervical herpes zoster (photograph provided by A.L.O.) Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S5
inconsequential, because the anamnestic immune response inthe immunocompetent host limits replication to the derma-tomal infection. However, when there is relative immune in-sufficiency, as may result from immunosenescence, there maybe vesicles and other viremia-related skin manifestations at adistance from the affected dermatome. The likelihood and ex-tent of so-called "cutaneous dissemination" increases with age(figure 6). However, even with advanced age, symptomatic in-fection of internal organs is very rare. In severely immuno-compromised patients with HZ, viremia can lead to life-threat-ening visceral infection.
Subclinical invasion of VZV into the CNS is not uncommon in HZ. One-third of immunocompetent patients without clin-ical symptoms of infection of the CNS had either PCR resultspositive for VZV or anti-VZV IgG present when a CSF samplewas obtained within the first weeks after the rash onset. Leu- Figure 4.
Herpes zoster ophthalmicus (photograph provided by D.P.-L.) kocytosis in the CSF was found in 46% of the patients. Sub- clinical HZ-associated changes in the brain stem were found merous additional potential findings associated with the pain on MRI in 53% of the patients with cranial or cervical HZ and rash. Motor nerves may be involved in 5%–15% of cases [60]. VZV is a common cause of aseptic meningitis, which can in which the nerves (especially those in muscles in the extrem- present with or without rash that may precede or follow the ities) can be examined adequately. By use of electromyography, meningeal symptoms. The course of the disease is benign, with it is possible to show that muscles are involved in 50% of cases complete recovery expected in 1–2 weeks [61].
[47]. Obvious paresis typically improves over time and may Second cases of HZ are uncommon in immunologically in- respond to physical therapy (figure 5). The geniculate ganglion tact hosts, presumably because an episode of HZ will boost also contains latent VZV derived from facial, aural, and oral immunity and thereby prevent subsequent symptomatic VZV lesions of varicella. Reactivation in the geniculate ganglion can reactivations. The available data suggest that second cases of lead to facial nerve (VII) paralysis (because sensory and motor HZ occur in ⭐5% of individuals, although this conclusion is nerves are conjoined in nerve VII), as a result of a bystander limited by the duration of follow-up, uncertainty of the di- effect. VZV and HSV account for the majority of cases of Bellpalsy (idiopathic facial paralysis). In the absence of skin lesions,the etiologic role of VZV or HSV reactivation is not clinicallyobvious and must be determined by use of laboratory methods[48–50]. It has been suggested that, because of the involvementof VZV or HSV, moderate or severe Bell palsy in adults shouldbe treated with antiviral therapy as well as adjunctive admin-istration of corticosteroids; results of controlled trials, however,have been conflicting [51–55].
Reactivation in the geniculate ganglion can produce skin lesions in the mucocutaneous distribution of its peripheralnerves, including the ear and the side of the tongue. Thesefindings, together with facial paralysis, constitute Ramsay Huntsyndrome, in which various vestibulocochlear manifestationsoccur when cranial nerve VIII is affected by a bystander effect[56, 57]. Satisfactory recovery of muscle function decreases withthe age of the patient and the severity of the paralysis at onset.
Symptomatic reactivation in other cranial nerves has been doc- Figure 5.
T8 motor neuropathy in an otherwise healthy 59-year-old man who presented with vesicles in the T8 distribution 4 weeks before umented [58, 59].
this photo was taken. The patient was treated with an antiviral agent Reactivation of VZV in sensory ganglia may be accompanied for 7 days and with analgesics as needed. As the rash resolved, this by extraneural spread, and viremia is frequently detected by bulge became apparent; it is consistent with motor damage by varicella- PCR early after the onset of rash. Viremia disappears most zoster virus to the muscles of the abdomen (photograph provided by rapidly in patients who receive antiviral therapy and is typically S6 • CID 2007:44 (Suppl 1) • Dworkin et al.
Figure 6.
Disseminated herpes zoster (photograph provided by S.K.T.) agnoses, and incomplete information about comorbid disease to one-tenth that observed in adults 55–65 years of age [32– 34, 67]. In general, HZ in children is less severe than that in There is great interest in the concept of VZV reactivation older patients and is much less likely to result in severe acute causing dermatomal pain in the absence of skin lesions, termed and prolonged pain [67, 68]. Recognized risk factors for HZ "zoster sine herpete." This concept has been supported by se- occurring during childhood are a history of maternal varicella rologic and PCR evidence of concurrent VZV reactivation dur- during the pregnancy or a history of primary varicella in the ing acute pain syndromes [62–65]. In addition, a variety of first year of life, which are situations that can be assumed to otherwise unexplained local sensory and motor abnormalities result in blunting of VZV-specific immune memory during have been ascribed to VZV reactivation without skin manifes- primary exposure of the child to VZV. Presumably, HZ in chil- tations. Consequently, it has been suggested that patients with dren reflects some interference with the normal immune mech- unexplained and atypical local pain syndromes might benefit anisms that maintain latency of VZV—for example, transient from antiviral therapy against VZV. A prospective study of 56 immune suppression after Epstein-Barr–virus or cytomegalo- patients with such complaints in a general practice setting, virus infection [57].
together with 81 matched control blood donors, was under- Differential diagnosis and laboratory testing.
taken; none of the study subjects developed a rash, and the rash has appeared, the diagnosis of HZ is generally apparent presence of positive serologic test results (for IgM, IgG, and from the clinical presentation. However, the recently completed IgA) and positive PCR results from circulating leukocytes was trial of a vaccine to prevent HZ found that 20% of suspected very similar to that seen in the control group [66], indicating cases could not be confirmed by PCR [28]. This reflects, in that the presence of unexplained dermatomal pain did not part, intentional overdiagnosis to include mild and atypical identify clinical or subclinical reactivations. Thus, the routine cases. Nevertheless, multiple studies from clinical diagnostic use of antiviral agents for this purpose is not supported, and laboratories indicate that as many as 10% of specimens sub- there is the added concern that such therapy might abort ap- mitted from patients with presumed HZ instead contain HSV propriate investigation of the etiology of the pain.
[69, 70]. Important elements in establishing the diagnosis by Although HZ incidence increases with age, observation include (1) painful or abnormal sensory prodrome as a reflection of the VZV-specific immune senescence that (not always present); (2) dermatomal distribution; (3) grouped characterizes aging, HZ also occurs in children. It has been vesicles (however, in some cases, only papules will be observed); reported that children 10–14 years of age have a frequency of (4) multiple sites filling the dermatome, especially where di- HZ (50–100 cases per 105 children per year) that is one-fifth visions of the sensory nerve are represented; (5) lack of history Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S7
Figure 7.
Zosteriform herpes simplex in an elderly woman who presented with what she called "her recurrent shingles." Vesicles in a lumbosacral distribution had recurred many times over the past several years, and this outbreak began 1 week before the photo was taken. A viral culturedemonstrated herpes simplex virus type 2. The patient was otherwise healthy, except for hypertension (photograph provided by S.K.T.).
of a similar rash in the same distribution (to rule out recurrent rapid (∼3 h) and relatively inexpensive; the sensitivity is ∼90%, zosteriform herpes simplex; see figure 7); and (6) pain and and the specificity is 95%. The sensitivity decreases when the allodynia in the area of the rash. Allodynia, which is common lesions are beyond the vesicular stage, and the procedure cannot in both HZ and PHN, is pain evoked by a stimulus that does be used on crusts. Specimens must be properly obtained for not normally cause pain—for example, light brushing of the optimal laboratory diagnosis. Immunohistochemical analysis affected area with a cotton swab.
can be formatted to diagnose HSV infection, as well as VZV Important alternative diagnoses that can be confused with infection, from the slide submitted. Culture of the virus is very HZ include zosteriform herpes simplex and contact dermatitis, specific, but the result is delayed (1–2 weeks), and VZV is especially toxic dermatitis from plant exposure (which tends detected from only 60%–75% of specimens. It is not useful for to be seasonal). Moreover, the vaccine trial revealed that atypical very long beyond the vesicular stage of the rash [71, 72].
disease (absence of pain or minimal pain, limited area of der-matomal involvement, failure of vesicles to appear) is not un- COMPLICATIONS OF HZ
common [28]. Atypical manifestations of HZ can also occurin immunocompromised patients. These features can include Acute VZV encephalitis is a rare complication prolonged course, lesions that are intermittently recurrent, in- of HZ that usually occurs a few days after the onset of rash volvement of multiple dermatomes, and lesions that appear as but has been reported from days to weeks before or after the chronic crusts or verrucous nodules. When atypical lesions are skin eruption [73]. It should be recognized, however, that CSF present (whether in an immunocompetent patient or an im- pleocytosis is present in ∼50% of individuals with uncompli- munocompromised patient), or when there is potential con- cated HZ, reflecting the local leptomeningitis that regularly fusion as to whether VZV or HSV is the pathogen (e.g., when accompanies the disease. Encephalitis has occasionally been there are lesions in the sacral area), diagnostic laboratory tests documented in the absence of apparent cutaneous HZ and in should be utilized.
patients who received appropriate antiviral therapy during the PCR is the most sensitive and specific test, but it is expensive, acute episode of HZ. Immunocompromised patients are clearly and it takes at least 1 day to obtain results. However, DNA at increased risk for the development of encephalitis [73, 74].
amplification is useful for the analysis of "old" and crusted Other markers of increased risk for CNS involvement include lesions. Immunohistochemical analysis of a skin scraping is HZ in a cranial nerve dermatome or the presence of cutaneous S8 • CID 2007:44 (Suppl 1) • Dworkin et al.
dissemination. The clinical presentation is most often an acute vasion of the spinal cord by VZV, with virus spreading along or subacute delirium accompanied by few focal neurologic signs central axons of infected primary sensory neurons. As in the [73]. Other findings can include headache, meningismus, fever, brain, close neuronal packing allows spread to adjacent neu- ataxia, and seizures. The rate of death due to HZ-associated rons. Involvement of descending spinothalamic tracts or of encephalitis varies from 0% to 25%, probably according to the anterior horn can cause weakness, and involvement of ascend- extent of immune compromise, with an average mortality rate ing sensory tracts (posterior column or lateral spinothalamic of ∼10% [73].
tract) causes sensory loss at levels below the affected dermatome Chronic VZV encephalitis is seen almost exclusively in im- [84]. In severe cases, the myelopathy can progress to a partial munocompromised patients, especially patients with AIDS who Brown-Se´quard syndrome or total cord transection. Myelitis have marked depletion of CD4+ T cells [75]. The onset of most often follows thoracic HZ, with weakness developing in encephalitis may occur months after an episode of HZ; 30%– the same spinal cord segment as the rash. Neurologic symptoms 40% of these patients have no recognized history of cutaneous begin to develop an average of 12 days after the onset of the VZV infection, which makes the diagnosis more difficult. The rash [85]. However, VZV myelitis in patients with no history clinical presentation is usually subacute, with headache, fever, of antecedent HZ has also been reported [86, 87]. Immuno- mental status changes, and seizures. Patients may have focal compromised patients are at increased risk for post-HZ mye- neurologic defects, including aphasia, hemiplegia, and visual- litis, and the syndrome is well described in patients with AIDS field cuts [76]. MRI demonstrates plaque-like lesions in deep [88]. The most common initial manifestation is bladder dys- white matter, changes consistent with demyelination, and late function (e.g., urinary retention), which is often accompanied development of ischemic or hemorrhagic infarcts of cortical by weakness of the lower extremities, asymmetric reflexes, and and subcortical gray and white matter [77]. CSF examination sensory disturbances [85]. MRI has been useful in diagnosing reveals mononuclear pleocytosis. VZV DNA has been amplified myelitis, with abnormal signal evident in the cord at the level by PCR from the CSF of patients with chronic encephalitis of inflammation [89]. However, it should be noted that sub- [65]. Pathologic studies reveal multifocal leukoencephalopathy, clinical MRI and CSF abnormalities have also been reported with lesions in the white matter near the gray-white junction, [60]. The prognosis for recovery of neurologic function is small-vessel vasculitis, and demyelination [78]. Patients often have a clinical course of progressive deterioration and death, Acute retinal necrosis caused by VZV has although anecdotal reports have suggested some benefit from been described in immunocompetent patients. More aggressive high-dose intravenous acyclovir therapy [78, 79].
variants of this disease have been recognized in patients with HZ ophthalmicus with delayed contralateral hemiparesis.
AIDS and include VZV retinitis, progressive outer retinal Stroke is a rare but serious complication of HZ that has been necrosis, and rapidly progressive herpetic retinal necrosis reported in both immunocompetent and immunocompromi- (RPHRN) [90–92]. The RPHRN syndrome is seen almost ex- sed patients [80], including both children and adults [81]. The clusively in patients with AIDS who have CD4+ T cell counts pathogenesis of this unusual disorder is thought to be direct of !100 cells/mm3 [92, 93]. This form of VZV retinitis may VZV invasion of large cerebral arteries by extension of virus occur concurrently with active HZ or, more frequently, may from smaller vessels that traverse the trigeminal-innervated me- develop weeks or months after the acute episode of HZ has ninges. This produces a necrotizing arteritis that can result in resolved. RPHRN can occur after HZ ophthalmicus or after vascular thrombosis or hemorrhage. The most frequently de- HZ involving a remote dermatome. The retinitis begins with scribed presentation is headache and contralateral hemiplegia multifocal necrotizing lesions involving the peripheral retina.
occurring in a patient with a history of recent HZ ophthalmicus, Most patients present with unilateral involvement, but pro- although a variety of other stroke syndromes have been re- gression to bilateral disease occurs frequently [91, 92]. Fun- ported. The mean interval from acute HZ to onset of neurologic doscopic examination reveals granular, yellowish, nonhemor- symptoms in adults is ∼7 weeks, although intervals as long as rhagic lesions that rapidly extend and coalesce, often resulting 6 months have been reported. CSF examination reveals mono- in retinal detachment. There is a relative lack of intraocular nuclear cell pleocytosis, and imaging studies (CT or MRI) show inflammatory changes. RPHRN rapidly progresses to confluent changes consistent with brain infarction. Arteriography is usu- full-thickness retinal necrosis (which differs from the slow pro- ally diagnostic and demonstrates segmental inflammation, nar- gression seen with CMV retinitis) and results in blindness in rowing, and thrombosis of the proximal branches of the middle 75%–85% of involved eyes [92, 93]. The etiologic role of VZV or anterior cerebral artery [82]. The mortality rate among adults in most cases of RPHRN has been established by demonstrating is 20%–25%, with a high probability of permanent neurologic VZV in choroid, vitreous fluid, and retinal biopsy specimens, sequelae among survivors [83].
by means of culture or PCR [90]. HSV occasionally causes an HZ myelitis is thought to result from direct in- identical syndrome [92, 94].
Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S9
In some patients, pain does not resolve when the impossible to ignore. The combination of chronic pruritis and HZ rash heals but, rather, continues for months or years. This profound sensory loss after HZ leads to rare cases of severe persisting pain is termed PHN, and it is the most common self-injury, when the protective pain sensations that deter pro- complication of HZ. Patients typically describe several different longed scratching are lost [117]. Pruritis associated with HZ is types of pain, including continuous burning or throbbing pain, neuropathic and does not respond to antihistamines or treat- intermittent sharp or electric shock–like pain, and allodynia ments for inflammatory pruritis. There are no clinical trials, [95]. Although multiple definitions of PHN have been used, but clinical experience suggests that postherpetic itch can be the results of recent studies suggest that pain persisting for at resistant to most treatments that are efficacious for PHN but least 120 days after rash onset may be considered to be a val- can respond to those that suppress ectopic neuronal firing— idated definition of PHN for research purposes [96–98]. There for example, local anesthetics.
have been no systematic attempts to investigate the prevalenceof PHN, and estimates of the number of cases in the United METHODS USED FOR DEVELOPING
States have ranged up to 1 million [99]. Numerous studies have established that older age is a potent risk factor for PHN; greater Data sources and study selection.
The consensus meeting on acute pain intensity, greater severity of the rash, and presence which the treatment recommendations were based was spon- and greater severity of a painful prodrome preceding the rash sored by the International Association for the Study of Pain are additional well-replicated risk factors [98, 100–103].
Neuropathic Pain Special Interest Group, the Neuropathic Pain There is considerable agreement that both peripheral and Institute, and the VZV Research Foundation. Participants were central processes contribute to PHN and that PHN is a het- selected on the basis of research and clinical expertise relevant erogeneous disorder [104–106]. For example, patients with to HZ and its management and represent the fields of anes- prominent allodynia often have minimal sensory loss and re- thesiology, geriatrics, infectious diseases, internal medicine, port pain relief after local application of analgesics, which sug- neurology, ophthalmology, outcomes research, pain manage- gests that preserved, and possibly sensitized, primary afferent ment, and virology. Relevant publications were identified by nociceptors that remain connected to the skin and their chron- Medline searches, examination of reference lists of published ically sensitized central targets are responsible for initiating and articles and book chapters, and the personal knowledge of the maintaining pain and allodynia in these patients [105, 107].
authors. Before the meeting, all participants were provided cop- Pathologic findings associated with PHN include degeneration ies of systematic literature reviews and meta-analyses [118– of affected primary afferent neuronal cell bodies and axons, 121], existing guidelines relevant to the management of HZ atrophy of the spinal cord dorsal horn, scarring of the dorsal [122–125], and published randomized clinical trials, discussed root ganglion, and loss of epidermal innervation, all of which below. This literature and the authors' clinical and research are more prominent on the affected side [44, 108–110].
experience were reviewed during the consensus meeting, which Chronic pain has substantial effects on quality of life, and was chaired by the first 2 authors. Information on additional physical disability and emotional distress are common in patients randomized trials that were not identified before the meeting with PHN [94]. The US Food and Drug Administration has was provided on request after the meeting. Recommendations approved 3 medications for the treatment of PHN (gabapentin, for practice guidelines [126], best-evidence synthesis [127], and lidocaine patch 5%, and pregabalin), and the results of random- narrative systematic reviews [128] were followed in developing ized controlled trials have also demonstrated the efficacy of tri- recommendations for the management of HZ and summarizing cyclic antidepressants (TCAs) and opioid analgesics in treating the literature on which they are based. The initial version of PHN [2, 3]. Nevertheless, a substantial percentage of patients are the present article was prepared by the first 5 authors, revised often refractory to these treatments used alone or in combination by the other authors, and recirculated until all authors agreed [111] and require treatment in settings specializing in pain man- with the text.
agement. The results of controlled trials provide no basis for the Recommendations for first-line pharmacologic treatments use of antiviral therapy in treating patients with PHN [112, 113], are based on positive results from multiple randomized clinical although it has been suggested that higher dosages should be trials. The methods and results of these trials, in combination studied in larger samples [114, 115].
with the clinical experience of the authors, provide the basis Like pain, pruritis not infrequently per- for specific recommendations regarding these treatments. Be- sists after HZ resolves [116]. Postherpetic itch can occur along cause recommendations for first-line treatments are consistent with PHN or independently of it, which suggests different with the results of multiple trials and the clinical experience of mechanisms. Patients with chronic pruritis report substantial the authors, they are made with a high degree of confidence.
disability, not only because of the unpleasant sensations but Recommendations for additional treatments that should be also because of the disruptive need to scratch that is virtually considered in combination with first-line treatment are based S10 • CID 2007:44 (Suppl 1) • Dworkin et al.
on the results of single clinical trials, inconsistent results of timal levels of mental, physical, and social activity. Patients multiple trials, or uncontrolled trials, considered together with should be told to keep the rash clean and dry to reduce the the clinical experience of the authors. These recommendations risk of bacterial superinfection, to avoid use of topical anti- are made with moderate confidence that these treatments biotics and of dressings with adhesive that can cause irritation should be considered because they may provide additional ben- and delay rash healing, and to inform their physician if a sec- efits when used in combination with first-line treatment.
ondary increase in temperature develops, which is often an Treatment effects on viral clearance, indication of bacterial infection. For some patients, discomfort acute pain, PHN (as reflected by the presence of either per- may be reduced by sterile wet dressings.
sisting pain of any intensity or persisting pain of moderate orgreater intensity [129]), and other complications of HZ were considered. In developing specific treatment recommendations, The efficacy of antiviral therapy in patients with HZ has been these efficacy outcomes were considered together with safety demonstrated by multiple randomized controlled clinical trials.
and tolerability as well as drug interactions, to evaluate the Acyclovir (800 mg 5 times daily for 7–10 days), famciclovir overall risk-benefit ratio of treatment.
(500 mg 3 times daily for 7 days, the approved dosage in United It was not possible to formally consider the cost-effectiveness States; 250 mg 3 times daily is approved in some other coun- of treatment, because of limited data and differences related to tries), and valacyclovir (1000 mg 3 times daily for 7 days) have geographic region and third-party coverage. Clinicians should been approved by the US Food and Drug Administration for familiarize themselves with medication acquisition costs and the treatment of HZ. These antiviral agents are phosphorylated the reimbursements provided by their patients' insurance plans, by viral thymidine kinase and cellular kinases to a triphosphate to protect their patients' finances and encourage treatment form that inhibits viral replication.
Acyclovir was the first antiviral agent developed to treat HZ, and 4 clinical trials examined the recommended oral dosage of TREATMENT OF IMMUNOCOMPETENT
800 mg 5 times daily for 7–10 days beginning within 72 h of rash onset [130–136]. Two clinical trials were conducted in The principal goals of the treatment of HZ are reduction of which various dosages of famciclovir were compared with either pain in immunocompetent patients and cessation of viral rep- acyclovir [137] or placebo [138, 139]. A single published clinical lication in immunocompromised patients and those with oph- trial of 2 dosages of valacyclovir compared with acyclovir in thalmic HZ. All patients should have a medical and psycho- patients ⭓50 years of age [140] was accompanied by an un- social history evaluation and targeted physical examination published trial of valacyclovir compared with placebo in pa- performed to confirm the diagnosis, document comorbid ill- tients !50 years of age. In addition, 2 trials in which famciclovir nesses, and provide a basis for treatment. Prompt referral to and valacyclovir were compared with acyclovir [141, 142] and an ophthalmologist is required for all patients with ocular in- 1 trial examining various dosages of famciclovir compared with volvement, whether immunocompetent or immunocompro- acyclovir [143] were conducted in patients with HZ who were mised. Elderly patients may be socially isolated, have cognitive followed for only 1 month from rash onset.
impairment or depression, or have had recent adverse major VZV replication is also inhibited by brivudin, an antiviral life events (e.g., bereavement), all of which may impact treat- agent that has been compared with acyclovir in 2 clinical trials ment compliance and response to treatment. Anxiety or de- [144, 145] and with famciclovir in a recent large trial [146].
pression may also develop secondary to severe HZ, which may Brivudin (125 mg once daily for 7 days) has been approved further complicate treatment and disease resolution.
for the treatment of HZ in several countries.
These clinical trials demonstrated that orally administered acyclovir, brivudin, famciclovir, or valacyclovir reduces the du- The treatment of HZ should occur in conjunction with ap- ration of viral shedding and new lesion formation and accel- propriate education and support from the health care provider.
erates rash healing in patients with HZ. In general, these agents Careful explanation of the disease, including the risk of viral decrease the severity and duration of acute pain, and it is there- transmission to individuals who have not had chickenpox, and fore also likely that antiviral therapy reduces the adverse impact of the proposed treatment plan is essential for adherence to of the acute phase of HZ on quality of life.
therapy and is beneficial to patient well-being; for example, The effect of antiviral therapy on the development of PHN providing reassurance and education can dispel myths and fears has attracted particular attention because of the clinical im- about HZ and its implications for the patient's health. En- portance of preventing chronic pain. By inhibiting viral rep- couragement, reassurance, and advice on quality of life are also lication, antiviral therapy likely reduces neural damage, which important and include supporting adequate nutrition and op- is thought to contribute prominently to the development of Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S11
PHN. For this reason, the delay in instituting antiviral therapy into tissues that are sites of HZ complications and the lower should be as short as possible, to limit additional neural damage sensitivity of VZV compared with HSV make higher blood beyond what may have occurred before rash onset.
levels of antiviral medications important.
The results of meta-analyses [119, 120, 147] and many [133, All of the controlled clinical trials of antiviral therapy have 135–140, 145, 146], but not all [130, 131, 134], randomized initiated treatment within 72 h of rash onset, an arbitrary in- controlled trials have demonstrated that antiviral therapy for clusion criterion that does not necessarily reflect the cessation HZ significantly reduces the duration or incidence of prolonged of viral replication. Because patients often do not recognize the pain. For example, in controlled trials using the recommended significance of their symptoms or because there are delays in dosages, the median time to complete loss of pain in patients scheduling their evaluation, HZ is often not diagnosed this with pain at rash healing was 63 days with famciclovir, versus rapidly in clinical practice; obtaining medication can be an 119 days with placebo [138]; the median time to complete additional delay. Thus, patients are often unable to initiate cessation of pain was 38 days for valacyclovir, versus 51 days treatment within this narrow window. Unfortunately, because for acyclovir [140]. Although the effect of acyclovir on chronic the efficacy of antiviral therapy initiated ⭓4 days after rash pain has been less clear because of negative results from some onset has not been systematically studied, there is no evidence trials [131, 148], the results of 2 meta-analyses suggest that it base for such treatment. However, there is no difference in pain may be superior to placebo in reducing the overall duration of outcomes when antiviral therapy is initiated before 48 h versus pain and the incidence of PHN [119, 120].
48–72 h after rash onset [150], and the results of 2 uncontrolled Although the results of each of the antiviral clinical trials studies revealed no significant differences in the persistence of taken singly can be challenged, the preponderance of the find- pain between patients who initiated treatment within 72 h and ings provides strong support for the use of antiviral therapy those who initiated treatment at a later time [151, 152]. Con- not only to hasten resolution of the acute phase but also to sidered together, these data are not inconsistent with there being attenuate the development of chronic pain in patients with HZ.
a benefit from antiviral therapy initiated beyond 72 h after rash Acyclovir, famciclovir, and valacyclovir are well tolerated and safe [1]. However, brivudin (which is not available in the United A few studies have examined whether the benefit of antiviral States) must not be used to treat patients receiving 5-fluoro- therapy is augmented when its duration is extended beyond 7 uracil (or other 5-fluoropyrimidines), because its main metab- days [140, 153, 154]. The results of these studies suggest that olite inhibits catabolism of fluorinated pyrimidine derivatives.
any benefit of extending treatment duration beyond 7 days may This drug interaction can cause severe and potentially fatal bone be minimal, but this conclusion requires further investigation.
marrow suppression. The most common adverse effects asso-ciated with antiviral therapy are nausea (occasionally with vom- Recommendations for Antiviral Therapy
iting) and headache, which occur in no more than 10%–20% Topical antiviral therapy lacks efficacy in patients with HZ and of patients, a rate generally similar to that found in patients is not recommended. Systemic antiviral therapy is strongly rec- treated with placebo [138, 140, 144].
ommended as first-line treatment for all immunocompetent In head-to-head comparisons of effects on cutaneous and patients with HZ who fulfill any of the following criteria (see pain end points, no differences were found between famciclovir table 1): (1) ⭓50 years of age; (2) have moderate or severe and valacyclovir [149] and brivudin and famciclovir [146].
pain; (3) have moderate or severe rash; or (4) have nontruncal Some evidence suggests that these 3 agents may be somewhat involvement. In patients who have a low risk for complications superior to acyclovir in reducing the likelihood of prolonged of HZ—for example, those who are younger with mild acute pain [137, 140, 145]. In choosing among antiviral agents, factors pain and rash and truncal involvement—the potential benefits in addition to efficacy should be considered. Acyclovir, which of treatment are unknown but may be meaningful because such is available in generic forms, is less expensive than the antiviral patients can still develop PHN. Acyclovir, famciclovir, and val- agents still protected by patent. However, dosing for brivudin acyclovir are all exceptionally safe, which contributes to a fa- is once daily, and dosing for famciclovir and valacyclovir is 3 vorable balance of potential benefit versus risk. It is, therefore, times daily, making these 3 antiviral agents considerably more recommended that antiviral therapy be considered even for convenient than acyclovir, the optimal use of which requires patients whose risk of developing PHN and other complications dosing every 5 h because of its pharmacokinetics. Furthermore, of HZ is likely to be low.
when choosing an antiviral agent, it is also important to con- There are no systematic data addressing the effectiveness of sider the higher and more reliable levels of antiviral activity antiviral therapy administered outside of the clinical trial set- achieved in blood with the use of oral brivudin, famciclovir, ting. Nevertheless, in clinical practice, brivudin, famciclovir, or valacyclovir, compared with oral acyclovir. The existence of and valacyclovir can be expected to have greater overall effec- barriers to the entry of antiviral agents from the bloodstream tiveness than acyclovir, on the basis of their potentially superior S12 • CID 2007:44 (Suppl 1) • Dworkin et al.
Oral antiviral medications for herpes zoster.
Precautions and contraindications 800 mg 5 times daily (every 4–5 h) Dosage adjustment required for patients with renal 125 mg once daily Contraindicated for patients treated with 5-fluoro- uracil or other 5-fluoropyrimidines, because ofdrug interaction associated with severe andpotentially fatal bone marrow suppression 500 mg 3 times daily (approved Dosage adjustment required for patients with renal dosage in United States; in some other countries, 250 mg 3times daily is approved) 1000 mg 3 times daily Dosage adjustment required for patients with renal insufficiency; thrombotic thrombocytopenicpurpura/hemolytic uremic syndrome reported atdosages of 8000 mg daily in immunocompro-mised patients a Not available in the United States.
efficacy [137, 140, 145], the greater patient compliance asso- VZV resistant to acyclovir (mediated by absent or altered ex- ciated with their more convenient dosing, and their higher and pression of thymidine kinase) has been reported in immuno- more reliable levels of antiviral activity in blood, which is im- compromised but not in immunocompetent patients.
portant because of the existence of barriers to the entry ofantiviral agents from the bloodstream into tissues that are sites Supplementing Antiviral Therapy
of HZ complications.
Although the reduction in chronic pain demonstrated by most In patients presenting 172 h after rash onset, the potential antiviral trials is both statistically and clinically significant, an- benefits of initiating antiviral therapy are unknown but might tiviral therapy does not prevent PHN in all patients. In antiviral be meaningful, given the minimal risks of treatment with acy- trials, ∼20% of patients 150 years of age continue to have pain clovir, famciclovir, and valacyclovir. The presence of new ves- 6 months after their rash, despite treatment beginning within icles or complications of HZ may identify patients with con- 72 h of rash onset [119, 139, 140, 149]. Although it is possible tinuing viral replication who could benefit from treatment. It that new antivirals with greater efficacy will be developed, a is, therefore, recommended that the initiation of antiviral ther- different strategy for preventing PHN is to supplement antiviral apy be considered for patients presenting 172 h after rash onset with continued new vesicle formation or when there are cu- Two well-designed clinical trials dem- taneous, motor, neurologic, or ocular complications. Advanced onstrated that the addition of a 3-week tapering dosage of a age and severe pain (which are potent risk factors for PHN) corticosteroid did not contribute significantly, beyond the ben- are additional factors that can prompt consideration of initi- efits achieved by acyclovir alone, in reducing prolonged pain ating antiviral therapy 172 h after rash onset.
[148, 153]. However, the addition of the corticosteroid did have In patients who still have new vesicles forming or who have cutaneous, motor, neurologic, or ocular complications after 7 beneficial effects on acute pain and some cutaneous end points days of antiviral therapy, close monitoring is recommended to in both of these trials; in one of the trials, the times to unin- assess the need for further evaluation. Because the potential terrupted sleep, return to normal daily activity, and cessation benefits are unknown but may be meaningful, and given the of analgesic therapy were all significantly accelerated in patients minimal risks of treatment, it is also recommended that con- who received combination therapy [148]. Individuals with con- sideration be given to extending the duration of antiviral ther- traindications to the use of corticosteroids, including hyper- apy for 17 days for these patients. In patients who have been tension, diabetes, and peptic ulcer disease, were excluded from given an incorrect diagnosis or who develop toxicity, antiviral these studies. Nevertheless, adverse effects of corticosteroids therapy should be discontinued immediately.
were reported, including gastrointestinal symptoms, edema, When rash healing has not occurred in a normal fashion in and granulocytosis.
an immunocompetent patient with HZ, further evaluation by No randomized placebo-controlled an infectious diseases specialist is recommended. Infection with trials of oral treatments for acute pain in patients with HZ have Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S13
been published. However, the well-replicated finding that more- multiple studies have demonstrated their efficacy in patients severe acute pain is a risk factor for PHN, as well as research with chronic neuropathic pain [157], including PHN [171– on the pathophysiologic mechanisms of PHN, provide the basis 176]. The US Food and Drug Administration has approved for hypothesizing that the combination of antiviral therapy with gabapentin for the treatment of PHN and pregabalin for the effective relief of acute pain may further lessen the risk of PHN treatment of PHN and painful diabetic polyneuropathy. The beyond that achieved with antiviral therapy alone [155]. TCAs combination of their generally satisfactory tolerability, safety, have well-established efficacy in the treatment of PHN and and lack of drug interactions distinguish them from other oral other neuropathic pain syndromes [156, 157], and TCAs may, medications used in the treatment of neuropathic pain. A recent therefore, have an analgesic effect in HZ. The results of a pla- proof-of-concept study has demonstrated analgesic effects of a cebo-controlled trial of amitriptyline (25 mg once daily for 3 single 900-mg dose of gabapentin versus placebo in patients months beginning within 48 h of rash onset) and a reanalysis during the acute phase of HZ [177], and it has also been re- examining the subgroup of patients also treated with an an- ported that open-label treatment of a sample of 64 patients tiviral suggested that amitriptyline reduced the incidence of with HZ, by use of the combination of gabapentin and the PHN at 6 months by at least 50% [158, 159].
antiviral agent valacyclovir, appeared to reduce the incidence The effect of amitriptyline on acute pain was not assessed of PHN at 3 and 6 months after rash onset, compared with in this study, and because treatment continued for 3 months the results of published studies of antiviral monotherapy [178].
after rash onset, it cannot be determined whether the reduction Further evidence that these medications have the potential to in PHN incidence was the result of early treatment. Amitrip- reduce acute pain in HZ is provided by the results of studies tyline and other TCAs have generally poor tolerability and a of acute postoperative pain, in which perioperative adminis- potential for serious adverse effects, including sudden cardiac tration of gabapentin, compared with placebo, reduced pain or death [160, 161]. A screening electrocardiogram is recom- opioid requirements [179].
mended to assess cardiac conduction abnormalities before be- Considered together, the efficacy of gabapentin and prega- ginning TCA treatment of patients 140 years of age who have balin for the treatment of PHN and other chronic neuropathic neuropathic pain [162]. Two selective serotonin and norepi- pain syndromes, the beneficial effects of gabapentin on a variety nephrine reuptake inhibitors—venlafaxine and duloxetine—are of acute pain conditions, and recent animal model data [180], better tolerated than TCAs and have recently been demon- suggest that these medications might reduce acute pain in pa- strated to have efficacy in patients with diabetic polyneuropathy tients with HZ and possibly further reduce the risk of PHN [163, 164]. However, until the efficacy of these antidepressants beyond that achieved with antiviral therapy administered alone.
is demonstrated for patients with PHN, there is little basis for However, in preliminary data analyses from a randomized trial predicting that they would prevent its development when used [169], gabapentin titrated to a maximum dosage of 1800 mg in patients with HZ.
daily did not differ from placebo in reducing acute pain in HZ Opioid analgesics would be expected to reduce acute pain within the first 2–3 weeks after rash onset. This may suggest in patients with HZ because of their diverse mechanisms of that dosages of gabapentin higher than the 1800 mg admin- action in the peripheral nervous system and CNS as well as istered daily in this study are necessary for treatment of HZ or their demonstrated efficacy in patients with both inflammatory that treatment with pregabalin would be preferable because it and neuropathic pain [165, 166], including PHN [167, 168].
can be titrated to an effective dosage more rapidly than ga- Opioid analgesics are often used in combination with weak bapentin [181], which is an important consideration when analgesics, such as acetaminophen and nonsteroidal anti-in- treating patients whose acute pain can begin suddenly and can flammatory drugs (NSAIDs), but the efficacy of such combi- often be severe. Although both gabapentin and pregabalin are nations has not been systematically studied in patients with HZ used in the treatment of epilepsy, other anticonvulsant medi- or chronic neuropathic pain. Preliminary analyses of a recent cations are not recommended for patients with HZ, because of randomized trial showed that controlled-release oxycodone was their lack of proven efficacy in PHN, poor tolerability, or risks superior to placebo in relieving acute pain in patients with HZ of clinically significant adverse events.
within the first 2–3 weeks after rash onset, but the sample size Sympathetic and epidural nerve blocks precluded an evaluation of the effect of treatment on PHN have been used for the treatment of severe pain in patients [169]. Tramadol, a weak m-opioid agonist that also inhibits the with HZ for many years, but few controlled studies have ex- reuptake of norepinephrine and serotonin, is efficacious in pa- amined their effects on acute pain or PHN [182–184]. The tients with PHN [170] but has not been studied as a treatment results of a recent randomized trial involving patients with HZ treated with oral antiviral therapy demonstrated that a single Gabapentin and pregabalin act at the a -d subunit of voltage- epidural injection of steroids and local anesthetics relieved acute gated calcium channels to reduce neurotransmitter release, and pain within the first month after rash onset significantly better S14 • CID 2007:44 (Suppl 1) • Dworkin et al.
than did the standard of care but did not reduce the risk of tant to prescribe these medications to achieve a constant level developing PHN [185]. Treatment with multiple epidural in- of analgesia (e.g., every 6 h) rather than to use as-needed dosing jections of local anesthetic and methylprednisolone without for increased levels of pain. These commonly used medications, antiviral therapy during HZ was associated with a reduction in however, have not been studied for the treatment of HZ. For the incidence of PHN, compared with that associated with pain that is moderate to severe in intensity, which is often intravenous acyclovir and prednisolone [186]. Given the well- accompanied by disturbed sleep, treatment with a strong opioid established efficacy of antiviral therapy in patients with HZ, analgesic (e.g., oxycodone or morphine) is recommended on however, the results of this study have limited clinical relevance, the basis of the consistent efficacy of this class of medications because antiviral therapy was withheld from the patients who in patients with inflammatory and neuropathic pain (table 2).
received epidural injections. Continuous epidural infusion of Various approaches may be used to treat HZ-associated pain local anesthetic with intermittent additional epidural anesthetic with the numerous short- and long-acting opioid analgesics boluses was superior to continuous infusion of saline and in- that are available. One approach is to begin treatment with a termittent anesthetic boluses in reducing the time to complete short-acting medication at an oxycodone equianalgesic dosage cessation of pain in patients with HZ treated with acyclovir of 5 mg given 4 times daily as needed. Commonly used short- [187]. Although treatment of patients with HZ by use of mul- acting opioid analgesics include oxycodone alone or in com- tiple epidural injections or continuous epidural infusions is bination with acetaminophen or aspirin. Once an effective unlikely to be feasible in most settings, these data suggest that dosage is determined, treatment can be switched from a short- aggressive analgesia can be efficacious in patients with HZ.
acting to a long-acting medication, which is more convenient A trial of intravenous VZV hyperim- for patients and may also provide a more consistent level of mune globulin versus placebo in patients 150 years of age with pain relief; for exacerbations of pain, treatment with a short- a dermatologic diagnosis of HZ treated with intravenous acy- acting opioid can be continued on an as-needed basis, in com- clovir found a reduction in the incidence of pain 5 weeks after bination with the long-acting opioid. One of the most common rash onset; however, the effect of treatment on chronic pain adverse effects of opioid analgesics is constipation, which can could not be determined because of the short follow-up du- be managed with preemptive laxative and stool-softener ther- ration [188]. Percutaneous electrical nerve stimulation admin- apy. The risk that substance abuse will develop in patients who istered 3 times each week for 2 weeks in patients with HZ was do not have a history of substance abuse is unknown, but is superior to famciclovir for some but not all cutaneous and thought to be low in older individuals with HZ.
acute pain end points, and for PHN severity but not incidence If moderate to severe pain in patients with HZ has not re- [189], but the absence of adequate blinding in this study limits sponded rapidly to treatment with an opioid analgesic, the interpretation of the data. Although topical capsaicin may have prompt addition of one of the following 3 classes of oral med- benefit in some patients with PHN [190], there is no basis for ications in combination with the opioid analgesic should be its use in patients with HZ, in whom it can be expected to considered, even though few studies have examined whether exacerbate pain.
the risk of PHN is reduced by such treatment: (1) gabapentinor pregabalin; (2) TCAs, especially nortriptyline; or (3) corti- Recommendations for Supplementing Antiviral Therapy
costeroids (e.g., prednisone), if there are no contraindications Even if the risk of developing PHN is not reduced by combining (table 2). For those patients with moderate or severe pain who antiviral therapy with analgesic or corticosteroid treatment in are unable to tolerate an opioid analgesic, treatment with these patients with HZ, effective relief of acute pain is a very desirable 3 classes of medications, alone and in combination, can be treatment goal. Pain should be assessed and treated promptly, and the choice of treatment approaches depends on the pa- Gabapentin and pregabalin can both cause sedation, and tient's pain severity and underlying conditions and on any prior tolerability may be improved with initial doses given only at response to specific medications. The principles of state-of-the- bedtime and subsequent dosage increases administered 3 times art pain management, such as the use of standardized pain daily for gabapentin and twice daily for pregabalin. The first 2 measures, scheduled analgesia, and consistent and frequent fol- weeks after rash onset can be expected to be associated with low-up to adjust dosing to the needs of the patient, should be the greatest benefit of treatment. Aggressive titration to rapidly applied to the management of pain in patients with HZ. It is reach the maximum dosages of 3600 mg of gabapentin daily important to recognize that HZ pain changes over time and and 600 mg of pregabalin daily must be balanced against the can become more severe as the acute infection progresses [191].
risk of greater adverse effects. Final dosages of gabapentin and Patients with mild to moderate pain may be managed with pregabalin should be determined by relief of pain or the de- acetaminophen or NSAIDs, alone or in combination with a velopment of unacceptable adverse effects that do not resolve weak opioid analgesic (e.g., codeine) or tramadol. It is impor- within 1 or 2 days.
Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S15
Although most clinical trials of TCAs for the treatment of disseminated HZ in immunocompromised patients demon- neuropathic pain have examined amitriptyline, it is not rec- strated that treatment halts disease progression and reduces the ommended for elderly patients, because of the risk of significant duration of viral replication [193, 194]. Subsequent studies of adverse events. In a randomized double-blind trial, nortrip- bone marrow transplant recipients proved that acyclovir, in tyline was found to provide equivalent analgesic benefits for addition to promoting faster disease resolution, is highly ef- patients with PHN, when directly compared with amitriptyline, fective at preventing VZV dissemination [195, 196]. Because but was better tolerated [192]. Nortriptyline is, therefore, pref- most VZV-related fatalities result from disseminated infection, erable, although desipramine can be considered for patients the ability to prevent dissemination has markedly reduced the with excessive sedation from nortriptyline. Nortriptyline treat- rate of death due to HZ in transplant recipients.
ment can be initiated at a dosage of 25 mg (or less for frail or Intravenous acyclovir remains the therapy of choice for VZV elderly patients) at bedtime and then titrated by 25 mg daily disease in severely immunocompromised patients, including every 2–3 days as tolerated, until relief of pain or a maximum (1) allogeneic hematopoietic stem cell transplant recipients dosage of 150 mg daily is reached. Patients must understand within 4 months of transplantation, (2) hematopoietic stem that TCAs have an analgesic effect that is independent of their cell transplant recipients with moderate to severe acute or chronic graft-versus-host disease, or (3) any transplant recipient Corticosteroids can be considered as soon as possible after receiving aggressive antirejection therapy. In addition, any diagnosis for patients with at least moderately severe pain and transplant recipient with suspected visceral dissemination (e.g., no contraindications. In addition, corticosteroids should be encephalitis or pneumonitis) should receive intravenous acy- considered for patients with VZV-induced facial paralysis and clovir. The recommended dose is 10 mg/kg (or 500 mg/m2) cranial polyneuritis to improve motor outcomes, peripheral every 8 h. When the infection is controlled, intravenous ad- nerve damage from foraminal compression, or evidence of CNS ministration can be stopped, and oral antiviral medication can involvement, although the benefit of such treatment has not be initiated for the remainder of the course of therapy.
been systematically studied. Contraindications (e.g., hyperten- For immunocompromised patients, treating HZ with oral sion, diabetes, gastritis, osteoporosis, and psychosis) and risks antiviral agents on an outpatient basis is an attractive approach, associated with the use of corticosteroids must be carefully although data are limited. One small study randomized 27 al- evaluated. Treatment with corticosteroids should be initiated logeneic hematopoietic stem cell transplant recipients with HZ only in combination with antiviral therapy. There is no evidence to receive either oral or intravenous acyclovir. No VZV dis- base for the use of topical corticosteroids for treatment of pa- semination occurred in either group, and no differences in tients with HZ, and such treatment is not recommended.
healing or clinical outcome were apparent [197]. Published data For patients with pain that is inadequately controlled by from clinical trials of famciclovir and valacyclovir for the treat- antiviral agents in combination with oral analgesic medications ment of HZ in immunocompromised patients remain limited, and/or corticosteroids, referral to a pain specialist or pain center but a growing body of clinical experience suggests that these is recommended to evaluate eligibility for neural blockade. Al- medications are safe and effective in this setting [198, 199]. For though long-term benefits of neural blockade in HZ have not less severely immunosuppressed patients, oral therapy with acy- been established, these procedures can reduce severe acute pain, clovir (800 mg 5 times daily), valacyclovir (1000 mg 3 times and their risk-benefit ratio is therefore likely to be favorable.
daily), or famciclovir (500 mg 3 times daily), coupled with Patients with the most severe lesions and pain may benefit from close clinical observation, is a reasonable option. The higher hospitalization and administration of epidural analgesics.
plasma drug concentrations achievable with famciclovir andvalacyclovir, along with their simplified dosing schedule, favor TREATMENT OF IMMUNOCOMPROMISED
the use of these medications rather than oral acyclovir. Brivudin is not recommended for immunocompromised patients, even Patients with disorders of cell-mediated immunity (due to dis- though it is effective [200], because of its potentially fatal in- ease or medical interventions) are at increased risk for devel- teraction with 5-fluorouracil and other 5-fluoropyrimidines opment of HZ. Those patients with the greatest degree of im- used in cancer chemotherapy. Because of the risk of ocular munosuppression are at highest risk for VZV dissemination involvement, intravenous acyclovir and evaluation by an oph- and visceral organ involvement. Populations at special risk in- thalmologist is recommended for highly immunocompromised clude patients with lymphoproliferative malignancies, organ patients who present with HZ ophthalmicus [201].
transplant recipients, patients receiving systemic corticoste- HZ in HIV-seropositive patients.
Prospectively acquired roids, and patients with AIDS.
data to guide clinicians when selecting antiviral therapy for HZ HZ in the setting of malignancy or organ transplantation.
in HIV-seropositive patients are currently limited. Nearly 300 Initial clinical trials with intravenous acyclovir for localized or HIV-infected patients with HZ were enrolled in controlled stud- Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S17
ies comparing orally administered acyclovir (800 mg 5 times HZ will have involvement of the ocular structures and develop daily) with sorivudine (40 mg once daily) [202, 203]. Times to chronic disease; in one recent study, 20% of patients with HZ cessation of new vesicle formation, total crusting, and resolu- uveitis were found to be legally blind in the involved eye [213].
tion of HZ-associated pain were 3–4 days, 7–8 days, and ∼60 The list of complications is protean: scarred lid malfunction days, respectively [203]. Although sorivudine was never mar- or loss; paralytic ptosis; conjunctivitis; episcleritis; scleritis; in- keted, these studies clearly confirmed the efficacy and safety of fectious or neurotrophic keratitis; iridocyclitis; hemorrhagic oral antiviral therapy for HZ in patients with HIV infection.
retinitis; acute retinal necrosis; choroiditis; papillitis; retrobul- Famciclovir was judged to be effective and safe for treatment bar neuritis; optic atrophy; Argyll Robertson pupil; partial or of HZ in patients with AIDS when evaluated in a small, open- complete third, fourth, or sixth nerve palsy (always self-re- label clinical trial [204]. Valacyclovir has not been systematically solving); isolated pupillary paralysis; internuclear ophthalmo- evaluated as a treatment for HZ in HIV-infected patients, al- plegia; acute and chronic glaucoma; orbital apex syndrome; though preliminary data [199] and anecdotal clinical experience PHN; and sympathetic ophthalmia [210, 214–218].
suggest therapeutic benefit. Patients who have HZ ophthal- Therapy for HZ ophthalmicus is similar to that for HZ else- micus should always be treated to reduce the risk of serious where in the body but should include the care of an ophthal- ocular complications, even when presenting 172 h after rash mologist familiar with the disease. Treatment includes the fol- onset [205, 206]. Because of the documented risk of relapsing lowing [217, 218]: (1) approved dosages of famciclovir or infection, VZV disease in HIV-seropositive patients should be valacyclovir for 7–10 days, preferably started within 72 h of treated until all lesions have healed, which is often longer than rash onset (with intravenous acyclovir given as needed for ret- the standard 7- to 10-day course. What impact VZV therapy initis), to resolve acute disease and inhibit late inflammatory may have on the risk of subsequent complications, such as CNS recurrences [136, 219–222]; (2) pain medications, as discussed infection or retinitis, is unknown. Adjunctive therapy for HZ above; (3) cool to tepid wet compresses (if tolerated); (4) an- with corticosteroids has not been evaluated in HIV-infected tibiotic ophthalmic ointment administered twice daily (e.g., patients and is not currently recommended. Long-term ad- bacitracin-polymyxin), to protect the ocular surface; (5) topical ministration of anti-VZV medications to prevent recurrences steroids (e.g., 0.125%–1% prednisolone 2–6 times daily) pre- of HZ is not routinely recommended for HIV-infected patients.
scribed and managed only by an ophthalmologist for corneal Although rare, acyclovir-resistant VZV has been reported in immune disease, episcleritis, scleritis, or iritis; (6) no topical immunocompromised patients, especially those with HIV in- antivirals, because they are ineffective; (7) mydriatic/cycloplegia fection, and results from mutations in the thymidine kinase as needed for iritis (e.g., 5% homatropine twice daily); and (8) gene. The presence of atypical lesions or a failed clinical re- ocular pressure–lowering drugs given as needed for glaucoma sponse should prompt evaluation for drug susceptibility to de- (e.g., latanaprost once daily and/or timolol maleate ophthalmic termine whether resistance has developed. When acyclovir re- gel forming solution every morning). Systemic steroids are in- sistance occurs, treatment with alternative medications (e.g., dicated in the presence of moderate to severe pain or rash, intravenous foscarnet or cidofovir) is required.
particularly if there is significant edema, which may cause or- Management of acute pain in HZ and PHN is similar in bital apex syndrome through pressure on the nerves entering immunocompromised and immunocompetent patients, al- the orbit [218]. The dosage is commonly 20 mg of prednisone though NSAIDs that are not cyclooxygenase II–specific inhib- administered (together with an oral antiviral agent) orally 3 itors are contraindicated in thrombocytopenic patients.
times daily for 4 days, twice daily for 6 days, and then oncedaily every morning for 4 days.
TREATMENT OF COMPLICATED
Therapy for chronic problems includes the following: (1) PRESENTATIONS OF HZ
lubricating, preservative-free artificial tear gels or tears admin- HZ ophthalmicus and VZV retinitis.
HZ ophthalmicus is istered 4 times daily, antibiotic ointment administered once second only to thoracic HZ in frequency [207]. Two surveys daily, and, possibly, lateral tarsorrhaphy to protect the corneas of all cases of HZ occurring between 1935 and 1959 in Roch- (which are often hypesthetic/anesthetic as a result of neuronal ester, Minnesota, found a trigeminal HZ incidence of 9%–16% damage) from breakdown; (2) continuous-wear, therapeutic [208, 209], which is within the 8%–56% range found in other soft contact lenses and antibiotic drops (e.g., polymyxin-tri- studies [32, 210, 211]; some of these estimates, however, may methoprim given 4 times daily as needed for corneal ulcera- have been biased by a greater tendency for patients with facial tion); (3) topical steroids and antibiotics for inflammatory dis- or periocular rashes to seek medical attention. A trigeminal HZ ease (iritis, episcleritis, scleritis, and immune keratitis); (4) incidence of ∼10.7% was found for the 660 evaluable cases of dilation for iritis; (5) glaucoma therapy as needed; and (6) HZ in the placebo group of the Shingles Prevention Study [212].
surgical management as needed—for example, for amniotic Without antiviral therapy, 50%–72% of patients with periocular membrane transplantation, tissue-adhesive seal ulcers, kera- S18 • CID 2007:44 (Suppl 1) • Dworkin et al.
toprosthesis, and glaucoma trabeculectomy. Chronic pain man- in a frail elderly individual who is living alone and experiences agement is generally similar to that for PHN in other der- functional decline.
matomes and includes gabapentin or pregabalin, TCAs, opioid Hence, when HZ occurs in this population, it is important analgesics, and lidocaine gel (which is preferable to the lidocaine to modify pharmacotherapeutic approaches and augment non- patch for periophthalmic use). Local nerve blocks or sympa- pharmacotherapeutic approaches to management. Starting dos- thetic blocks can be used for pain that is refractory to first- ages of medications should be lower than those recommended line therapy, although there are no controlled studies of these for younger individuals, and the dosage should be titrated more slowly, particularly for opioid analgesics, gabapentin, prega- The optimal antiviral therapy for VZV-induced, rapidly pro- balin, TCAs, and NSAIDs. These individuals experience sig- gressive herpetic retinal necrosis in immunocompromised pa- nificant age- and disease-related declines in glomerular filtra- tients remains undefined. Responses to intravenous acyclovir tion rate, so the dosages of renally excreted medications (e.g., or ganciclovir have been inconsistent and disappointing, with antiviral agents, gabapentin, and pregabalin) must be adjusted, 49%–67% of involved eyes progressing to no light perception as is discussed further below [238]. Furthermore, these indi- [91, 226]. Several case reports have reported improved pres- viduals are at high risk for adverse drug effects because of ervation of vision in patients treated with a combination of multiple comorbidities, age-related changes in pharmacoki- intravenous ganciclovir plus foscarnet, with or without intra- netics and dynamics, use of multiple medications, and frequent vitreal antivirals [227–232]. Cidofovir has also been used suc- inappropriate prescribing [239]. The choice of medications cessfully in a small number of patients [233, 234]. The optimal should take into account the patient's diseases, medication reg- duration of induction therapy and options for long-term main- imen, and adverse event experiences. For example, NSAIDs tenance therapy have not been established.
should be avoided in elderly individuals with congestive heart Acute retinal necrosis in immunocompetent patients is a less failure and chronic kidney disease. For nonpharmacotherapeu- virulent disease and responds better to antiviral therapy. For tic approaches, it is critically important for the practitioner to such patients, acyclovir is clearly beneficial for preserving useful recognize that these treatments are just as important as the use vision [235]. A suggested antiviral regimen for acute retinal of medications. Nonpharmacologic approaches include main- necrosis in the otherwise healthy host is intravenous acyclovir taining physical activity, enhancing nutrition, maintaining or (10–15 mg/kg every 8 h for 10–14 days) followed by oral val- increasing social contact, and providing assistance for problems acyclovir (1 g 3 times daily for 4–6 weeks), although this treat- with basic and instrumental activities of daily living during the ment approach has not been studied in a controlled fashion.
acute episode. These interventions usually require a multidis- Vulnerable and frail elderly patients.
The health status of ciplinary approach that involves nursing, social work, physical older adults varies widely, from well elderly individuals who therapy, occupational therapy, and the family.
have no diseases or functional problems to chronically ill elderly The clinical course of vulnerable and frail elderly individuals individuals who have multiple comorbidities and disabilities.
needs to be monitored more closely than does that of well elderly Vulnerable elderly individuals are people ⭓65 years of age who individuals, to detect inadequate responses to therapy and early are at increased risk for death or functional decline in a 2-year functional decline and to step up interventions, if needed. Phar- period, as defined by older age, poor self-rated health, and macotherapeutic and nonpharmacologic approaches require par- decreased functional status [236]. Frail elderly individuals, a ticular attention in individuals with dementia. HZ pain and acute subset of vulnerable elderly individuals, are at the highest risk inflammation may worsen cognition in these individuals with for death and functional decline and are characterized clinically dementia, who then may require additional assistance in ob- by weakness, easy exhaustion, low levels of physical activity, taining proper treatment and performing activities of daily liv- slow walking speed, undernutrition/weight loss, and functional ing. The management of HZ pain is more complicated in pa- decline [237]. Importantly, functional status is a more impor- tients with dementia, because of the risk for adverse cognitive tant predictor of death and functional decline than are specific effects of opioid analgesics, gabapentin, pregabalin, and TCAs.
clinical conditions. These individuals have markedly dimin- In addition, traditional pain measures (e.g., the 0–10 numerical ished physiologic reserves for responding to stressors, including rating scale) used to track response to analgesics are not useful such acute illnesses as HZ. Cutaneous dissemination and, pos- in assessing patients with advanced dementia [240]. Finally, sibly, visceral dissemination seem to be more common in el- when frail elderly individuals are residents of nursing homes, derly individuals. Moreover, the pain and acute inflammation prompt recognition and initiation of antiviral treatment of HZ of HZ puts vulnerable and frail elderly individuals at risk for can prevent the spread of VZV to susceptible individuals, such physical inactivity, poor oral intake with resultant undernutri- as younger nurses and aides in the facility [241].
tion, cognitive impairment, depression, and functional decline.
Pregnant and nursing patients.
Maternal varicella can be The insult of HZ can trigger a change of living environment transmitted to the fetus and cause significant morbidity, but Management of Herpes Zoster • CID 2007:44 (Suppl 1) • S19
congenital varicella has never been documented in association RECOMMENDATIONS FOR FUTURE RESEARCH
with maternal HZ. There are no adequate studies of the effects Major advances have been made in the prevention and treat- that antiviral therapy during pregnancy has on the developing ment of HZ and PHN. To further reduce the personal and child, although rates of birth defects reported in registry data social burden of HZ, additional research on the natural history for acyclovir and valacyclovir are reassuring (similar data are of HZ is necessary and should include studies of the following: not available for famciclovir and brivudin) [242]. Because the (1) the impact of varicella and HZ vaccination on epidemio- safety of antiviral therapy during pregnancy has not been firmly logical aspects of HZ and its complications; (2) the risk factors established, pregnant women with HZ should be treated only for HZ and its complications—for example, the role of im- in cases in which the potential benefits of antiviral therapy to munosenescence, nervous system senescence, greater HZ se- the mother outweigh the potential risks to the fetus. The ma- verity, and medical comorbidity in explaining why older pa- jority of pregnant women with HZ are expected to have a tients with HZ have a greater risk of developing PHN; (3) relatively low risk of developing PHN, because of their age.
methods for the early identification of HZ by patients and However, patients with severe rash, severe acute pain, or HZ health care providers, so that treatment is initiated as promptly ophthalmicus can be treated with acyclovir and valacyclovir, as possible in those who are at risk for the development of especially during the late stages of pregnancy, when any po- complications; (4) methods for identifying HZ before the rash tential risks to the fetus should be lower. However, during the appears and in patients with very mild rashes; (5) methods for early stages of pregnancy, the potential benefit of antiviral ther- identifying patients with zoster sine herpete; (6) the mecha-nisms of pain in HZ and PHN and of the transition from acute apy to the mother must be great enough to outweigh the un- pain to PHN; and (7) the role of VZV in neurologic and other known but potentially greater risk to the fetus. Antiviral therapy is not routinely recommended for eclamptic, preeclamptic, or Additional research on the prevention and treatment of HZ diabetic pregnant women.
and on the prevention of its complications, especially PHN, is Because acyclovir is excreted in breast milk, antiviral therapy also necessary and should include studies of the following: (1) should be administered to nursing mothers with caution and improved (e.g., lipophilic) antiviral therapy for HZ; (2) treat- only in circumstances in which the benefits are well established ments for acute pain in patients with HZ (e.g., to determine (e.g., within 72 h of rash onset). Severe acute pain in pregnant whether NSAIDs are efficacious); (3) strategies to prevent PHN, patients with HZ can be safely treated with opioid analgesics, ideally based on improved knowledge of pain mechanisms; (4) but this must then be considered in the management of the novel strategies to block reactivation of VZV or to eliminate latent infection within neurons; (5) research on extending the Neurologic complications of HZ.
The role of antiviral use of the live attenuated HZ vaccine to frail elderly individuals, agents in the management of neurologic complications of HZ immunocompromised patients, and individuals !60 years of has not been evaluated in a controlled fashion. For those dis- age; (6) the development of noninfectious (inactivated) HZ eases in which viral replication likely plays an important role vaccines for use in immunocompromised individuals; (7) the in pathogenesis (e.g., meningitis, encephalitis, and myelitis), development and evaluation of epitope-specific recombinantDNA vaccines for HZ that would selectively stimulate VZV- therapy with intravenous acyclovir is recommended; this ap- specific cell-mediated immune responses; (8) methods for iden- proach is supported by benefits noted in anecdotal experience.
tifying which patients would benefit from antiviral therapy ini- For such conditions as delayed contralateral hemiparesis, in tiated 172 h after rash onset; and (9) methods for identifying which the role of active viral replication is less clear, the value which patients would benefit from antiviral therapy extending of antiviral therapy is uncertain, but the potential benefits of for 17 days. Both of the latter 2 objectives should be a priority antiviral therapy outweigh any potential risks [243].
for research on HZ.
Dosages should be adjusted if renal insuf- We anticipate that ongoing and planned research will address ficiency is present when acyclovir (creatinine clearance, !25 these questions and that clinical trials will identify additional mL/min), famciclovir (creatinine clearance, !60 mL/min), or treatments with efficacy in the prevention and treatment of HZ valacyclovir (creatinine clearance, !50 mL/min) is used. Be- and PHN, and we therefore recommend that these clinical rec- cause brivudin undergoes hepatic as well as renal excretion, ommendations be updated within 5 years.
dosage reduction for renal insufficiency is less critical, but he- patic function must be considered when this antiviral agent is used. Dosages of gabapentin and pregabalin should be reduced We dedicate these recommendations to the memory of Richard T. Perkin, when renal function is impaired.
whose passion for supporting research and education to reduce the suffering S20 • CID 2007:44 (Suppl 1) • Dworkin et al.
caused by chickenpox, herpes zoster, and postherpetic neuralgia is an en- 4. Ku CC, Padilla JA, Grose C, Butcher EC, Arvin AM. Tropism of during inspiration. We thank Paul Lambiase and Mary Gleichauf of the varicella-zoster virus for human tonsillar CD4+ T lymphocytes that University of Rochester Office of Professional Education for invaluable express activation, memory, and skin homing markers. J Virol 2002;
The consensus meeting on which these recom- 5. Ku CC, Besser J, Abendroth A, Grose C, Arvin AM. Varicella-Zoster mendations are based was supported by unrestricted grants to the Uni- virus pathogenesis and immunobiology: new concepts emerging from versity of Rochester Office of Professional Education from the International investigations with the SCIDhu mouse model. J Virol 2005; 79:2651–8.
Association for the Study of Pain Neuropathic Pain Special Interest Group, 6. Ku CC, Zerboni L, Ito H, Graham BS, Wallace M, Arvin AM. Varicella- the Neuropathic Pain Institute, and the VZV Research Foundation.
zoster virus transfer to skin by T cells and modulation of viral rep- This article was published as part of a sup- lication by epidermal cell interferon-a. J Exp Med 2004; 200:917–25.
plement entitled "Recommendations for the Management of Herpes Zos- 7. Chen JJ, Gershon AA, Li ZS, Lungu O, Gershon MD. Latent and lytic ter," sponsored by the International Association for the Study of Pain infection of isolated guinea pig enteric ganglia by varicella zoster virus.
Neuropathic Pain Special Interest Group, the Neuropathic Pain Institute, J Med Virol 2003; 70(Suppl 1):S71–8.
and the VZV Research Foundation.
8. Gershon AA, Sherman DL, Zhu Z, Gabel CA, Ambron RT, Gershon Potential conflicts of interest. All authors received an honorarium for
MD. Intracellular transport of newly synthesised varicella-zoster vi- participation in the consensus meeting from the University of Rochester rus: final envelopment in the trans-Golgi network. J Virol 1994; 68:
Office of Professional Education. R.H.D. has received research support, consulting fees, or honoraria in the past year from Allergan, Astellas 9. Cole NL, Grose C. Membrane fusion mediated by herpesvirus gly- Pharma, Cephalon, Dov Pharmaceuticals, Eli Lilly, Endo Pharmaceuticals, coproteins: the paradigm of varicella-zoster virus. Rev Med Virol EpiCept Corporation, Fralex Therapeutics, Johnson & Johnson, Merck, NeurogesX (also stock options), Novartis, Pfizer, Schwarz Pharma, US Food 10. Wang, ZH, Gershon MD, Lungu O, Zhu Z, Gershon AA. Trafficking and Drug Administration, US National Institutes of Health, and US Vet- of varicella-zoster virus glycoprotein gI: T(338)-dependent retention erans Administration; R.W.J. has received consulting or lecture fees from in the trans-Golgi network, secretion, and mannose 6-phosphate- DepoMed, Merck, Novartis, Sanofi Pasteur MSD, and Yamanouchi; J.B.
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from Astellas Pharma, GlaxoSmithKline, Merck, and Novartis; M.J.L. has 12. Westlund B, Dahms NM, Kornfeld S. The bovine mannose 6-phos- received consulting fees from GlaxoSmithKline and Merck and shares a phate/insulin-like growth factor II receptor: localization of mannose patent with Merck for the herpes zoster vaccine; M.B. has received research 6-phosphate binding sites to domains 1–3 and 7–11 of the extracy- support, consulting fees, or honoraria in the past year from Allergan, As- toplasmic region. J Biol Chem 1991; 266:23233–9.
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port, consulting fees, or honoraria in the past year from Eli Lilly, GW 15. Cohrs RJ, Barbour M, Gilden DH. Varicella-zoster virus (VZV) tran- Pharma, Medtronic, Merck, Pfizer, Schwarz BioSciences, and UCB Pharma; scription during latency in human ganglia: detection of transcripts K.L.P. has received consulting fees or honoraria in the past year from CV mapping to genes 21, 29, 62, and 63 in a cDNA library enriched for Therapeutics, Eli Lilly, Evotech, NeurogesX, Neuromed, Organon, and VZV RNA. J Virol 1996; 70:2789–96.
Roche; M.C.R. has received consulting fees or royalties in the past 12 16. Kennedy PG, Grinfeld E, Bell JE. Varicella-zoster virus gene expression months from Alnylam, Biogen, Eli Lilly, Hind Health Care, Metaphore, in latently infected and explanted human ganglia. J Virol 2000; 74:
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