Understanding risk factors for herpes zoster and postherpetic neuralgia in UK primary care: investigations to inform vaccine policy.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

Postherpetic neuralgia is the most common complication of herpes zoster. Identifying predictors for postherpetic neuralgia may help physicians screen herpes zoster patients at risk of postherpetic neuralgia and undertake preventive strategies. Peptic ulcer has been linked to immunological dysfunctions and malnutrition, both of which are predictors of postherpetic neuralgia. The aim of this retrospective case-control study was to determine whether adult herpes zoster patients with peptic ulcer were at greater risk of postherpetic neuralgia. Adult zoster patients without postherpetic neuralgia and postherpetic neuralgia patients were automatically selected from a medical center's electronic database using herpes zoster/postherpetic neuralgia ICD-9 codes supported with inclusion and exclusion criteria. Consequently, medical record review was performed to validate the diagnostic codes and all pertaining data including peptic ulcer, Helicobacter pylori (H. pylori) infection and ulcerogenic medications. Because no standard pain intensity measurement exists, opioid usage was used as a proxy measurement for moderate to severe pain. In total, 410 zoster patients without postherpetic neuralgia and 115 postherpetic neuralgia patients were included. Multivariate logistic regressions identified 60 years of age and older, peptic ulcer and greater acute herpetic pain as independent predictors for postherpetic neuralgia. Among etiologies of peptic ulcer, H. pylori infection and usage of non-selective nonsteroidal anti-inflammatory drugs were significantly associated with the increased risk of postherpetic neuralgia; conversely, other etiologies were not significantly associated with the postherpetic neuralgia risk. In conclusion, 60 years of age and older, peptic ulcer and greater acute herpetic pain are independent predictors for postherpetic neuralgia in adult herpes zoster patients.

Herpes zoster patients can develop persistent pain after rash healing, a complication known as postherpetic neuralgia. By preventing zoster through vaccination, the risk of this common complication is reduced. We searched Medline and Embase for studies assessing risk factors for postherpetic neuralgia, with a view to informing vaccination policy. Nineteen prospective studies were identified. Meta-analysis showed significant increases in the risk of postherpetic neuralgia with clinical features of acute zoster including prodromal pain (summary RR 2.29, 95%CI: 1.42-3.69), severe acute pain (2.23, 1.71-2.92), severe rash (2.63, 1.89-3.66) and ophthalmic involvement (2.51, 1.29-4.86). Older age was significantly associated with postherpetic neuralgia; for individual studies, relative risk estimates per ten-year increase ranged from 1.22-3.11. Evidence for differences by gender was conflicting, with considerable between-study heterogeneity. A proportion of studies reported an increased risk of postherpetic neuralgia with severe immunosuppression (studies, n=3/5) and diabetes mellitus (n=1/4). Systemic lupus erythematosis, recent trauma and personality disorder symptoms were associated with postherpetic neuralgia in single studies. No evidence of higher postherpetic neuralgia risk was found with depression (n=4) or cancer (n=5). Our review confirms a number of clinical features of acute zoster are risk factors for postherpetic neuralgia. It has also identified a range of possible vaccine-targetable risk factors for postherpetic neuralgia, yet aside from age-associated risks, evidence regarding risk factors to inform zoster vaccination policy is currently limited.

Postherpetic neuralgia (PHN) following acute herpes zoster remains a significant cause of neuropathic pain, especially in older patients. Treatment results of this severe and long-lasting pain syndrome are often disappointing. To examine the effect of antivirals, and other potential risk factors, on PHN risk among zoster patients, researchers used prospectively collected data from …

Objective:To investigate risk factors for postherpetic neuralgia, the neuropathic pain that commonly follows herpes zoster.Methods:Using primary care data from the Clinical Practice Research Datalink, we fitted multivariable logistic regression models to investigate potential risk factors for postherpetic neuralgia (defined as pain ≥90 days after zoster, based on diagnostic or prescription codes), including demographic characteristics, comorbidities, and characteristics of the acute zoster episode. We also assessed whether the effects were modified by antiviral use.Results:Of 119,413 zoster patients, 6,956 (5.8%) developed postherpetic neuralgia. Postherpetic neuralgia risk rose steeply with age, most sharply between 50 and 79 years (adjusted odds ratio [OR] for a 10-year increase, 1.70, 99% confidence interval 1.63–1.78). Postherpetic neuralgia risk was higher in women (6.3% vs 5.1% in men: OR 1.19, 1.10–1.27) and those with severely immunosuppressive conditions, including leukemia (13.7%: 2.07, 1.08–3.96) and lymphoma (12.7%: 2.45, 1.53–3.92); autoimmune conditions, including rheumatoid arthritis (9.1%: 1.20, 0.99–1.46); and other comorbidities, including asthma and diabetes. Current and ex-smokers, as well as underweight and obese individuals, were at increased risk of postherpetic neuralgia. Antiviral use was not associated with postherpetic neuralgia (OR 1.04, 0.97–1.11). However, the increased risk associated with severe immunosuppression appeared less pronounced in patients given antivirals.Conclusions:Postherpetic neuralgia risk was increased for a number of patient characteristics and comorbidities, notably with age and among those with severe immunosuppression. As zoster vaccination is contraindicated for patients with severe immunosuppression, strategies to prevent zoster in these patients, which could include the new subunit zoster vaccine, are an increasing priority.

Objective To investigate the relation of autophagy and postherpetic neuralgia in elderly patients, and provide new methods for prevention and treatment of postherpetic neuralgia. Methods One hundred thirty-five specimens were obtained from elderly patients with herpes zoster, containing 83 patients with herpes zoster plus neuralgia and 52 cases with non-neuralgia herpes zoster.The level of autophagy was determined by acridine orange-stain.The protein expressions of autophagy marker protein LC3 and autophagy related protein Beclin1 were detected by Western blot. Results Flow cytometer detection after acridine orange-stain showed that mean fluorescence intensity (MFI) of herpes zoster plus neuralgia patients was 0.775±0.068 and non-neuralgia herpes zoster patients was 0.342±0.025.The level of autophagy of non-neuralgia herpes zoster patients was significant lower than herpes zoster plus neuralgia patients (P<0.05). The expressions of autophagy marker protein LC3 and autophagy related protein Beclin1 detected by Western blot also showed the level of autophagy of non-neuralgia herpes zoster patients was decreased compared with herpes zoster plus neuralgia patients. Conclusions High level autophagy is risk factor for postherpetic neuralgia in elderly patients. Key words: Autophagy; Herpes, zoster; Neuralgia

Is peptic ulcer disease a risk factor of postherpetic neuralgia in patients with herpes zoster?

Antiviral treatment of herpes zoster is controversial because of uncertain benefits and relatively high costs. Most studies show that antiviral therapy lessens acute herpes zoster symptoms and postherpetic neuralgia (PHN). Current clinical recommendations support antiviral treatment of severely symptomatic herpes zoster in all adults, and mild herpes zoster in those 50 or 60 years of age or older. However, it is unclear if these recommended strategies are cost effective. Published studies of herpes zoster costs and the effect of antiviral therapy on costs and quality of life have significant variation in study design and results, as well as many shortcomings in the data. Thus, definitive economic recommendations cannot be made based on the present data. Another approach, which we have used, is to develop a 'reference case' analysis using decision-analysis techniques and the available data to estimate the incremental cost effectiveness of antiviral treatment in patients of differing age and herpes zoster severity. In the baseline analysis, parameter values and assumptions were consistently slightly biased against antiviral use. Effectiveness was measured in quality-adjusted life years (QALYs). We assumed that antiviral treatment did not change PHN risk, but decreased PHN duration in patients older than 50 years. PHN risk increased with age and with acute herpes zoster severity as seen in published data. Mild acute herpes zoster was assumed to have a utility value of 0.9 and severe acute herpes zoster a value of 0.7 on a scale where 0 = death and 1 = perfect health. Treating mildly symptomatic acute herpes zoster cost $US89,200/QALY gained in 40-year-olds, $US47,700/QALY in 60-year-olds and $US40,700/QALY in 70-year-olds (1995 values). Results were most sensitive to variation of antiviral costs (baseline $US134), but changes in acute symptom relief, PHN risk, duration, costs and utility, and antiviral effect on PHN duration increased costs/QALY above $US50,000 in 60- and 70-year-olds in extremes of parameter ranges. However, no variation resulted in treatment of mild illness in 40-year-olds to fall below $US50,000/QALY gained. Treatment of severe acute herpes zoster cost $US29,700, $US18,000 and $US16,500/QALY gained in 40-, 60- and 70-year-olds, respectively. Results were sensitive to variation of antiviral costs (> $US225) and acute symptom relief (< 21%) in 40-year-olds. Based on this analysis, antiviral therapy of herpes zoster seems economically justifiable for mildly symptomatic acute herpes zoster in patients aged 50 years and older, and for severely symptomatic acute herpes zoster in all adults.

Herpes zoster (HZ) results from recrudescence of varicella zoster virus latent since primary infection (varicella). The overall incidence of HZ is ∼ 3/1000 of the population per year rising to 10/1000 per year by 80 years of age. Approximately 50% of individuals reaching 90 years of age will have had HZ. In ∼ 6%, a second attack may occur (usually several decades after the first). Patients with HZ can transmit the virus to a non-immune individual causing varicella. HZ is not contracted from individuals with varicella or HZ. Reduced cell-mediated immunity to HZ occurs with ageing, explaining the increased incidence in the elderly and from other causes such as tumours, HIV and immunosuppressant drugs. Diagnosis is usually clinical from typical unilateral dermatomal pain and rash. Prodromal symptoms, pain, itching and malaise, are common. The most common complication of HZ is postherpetic neuralgia (PHN), defined as significant pain or dysaesthesia present ≥ 3 months after HZ. PHN results from damage and secondary changes within components of the nervous system subserving pain. Some motor deficit is common; severe and long-lasting paresis may rarely accompany HZ. More than 5% of elderly patients have PHN at 1 year after acute HZ. Predictors of PHN are, greater age, acute pain and rash severity, prodromal pain, the presence of virus in peripheral blood as well as adverse psychosocial factors. Therapy for acute HZ is intended to reduce acute pain, hasten rash healing and reduce the risk of PHN and other complications. Antiviral drugs are close to achieving these aims but do not entirely remove risk of PHN. Oral steroids show no protective effect against PHN. Adequate analgesia during the acute phase may require strong opioid drugs. Nerve blocks and tricyclic antidepressants (TCAs) may reduce the risk of PHN although firm evidence is lacking. PHN requires thorough evaluation and development of a management strategy for each individual patient. Initial therapy is with TCAs (e.g., nortriptyline) or the anticonvulsant gabapentin. Topical lidocaine patches frequently reduce allodynia. Strong opioids are sometimes required. Topical capsaicin cream is beneficial for a small proportion of patients but is poorly tolerated. NMDA antagonists have not proved beneficial with the exception of ketamine. Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in some cases. HZ is a common condition. Severe complications such as stroke, encephalitis and myelitis are relatively rare whereas sight threatening complications of ophthalmic HZ are more common. PHN is common, distressing and often intractable. Good management improves outcome.

Herpes zoster (HZ) results from recrudescence of varicella zoster virus latent since primary infection (varicella). The overall incidence of HZ is ∼ 3/1000 of the population per year rising to 10/1000 per year by 80 years of age. Approximately 50% of individuals reaching 90 years of age will have had HZ. In ∼ 6%, a second attack may occur (usually several decades after the first). Patients with HZ can transmit the virus to a non-immune individual causing varicella. HZ is not contracted from individuals with varicella or HZ. Reduced cell-mediated immunity to HZ occurs with ageing, explaining the increased incidence in the elderly and from other causes such as tumours, HIV and immunosuppressant drugs. Diagnosis is usually clinical from typical unilateral dermatomal pain and rash. Prodromal symptoms, pain, itching and malaise, are common. The most common complication of HZ is postherpetic neuralgia (PHN), defined as significant pain or dysaesthesia present ≥ 3 months after HZ. PHN results from damage and secondary changes within components of the nervous system subserving pain. Some motor deficit is common; severe and long-lasting paresis may rarely accompany HZ. More than 5% of elderly patients have PHN at 1 year after acute HZ. Predictors of PHN are, greater age, acute pain and rash severity, prodromal pain, the presence of virus in peripheral blood as well as adverse psychosocial factors. Therapy for acute HZ is intended to reduce acute pain, hasten rash healing and reduce the risk of PHN and other complications. Antiviral drugs are close to achieving these aims but do not entirely remove risk of PHN. Oral steroids show no protective effect against PHN. Adequate analgesia during the acute phase may require strong opioid drugs. Nerve blocks and tricyclic antidepressants (TCAs) may reduce the risk of PHN although firm evidence is lacking. PHN requires thorough evaluation and development of a management strategy for each individual patient. Initial therapy is with TCAs (e.g., nortriptyline) or the anticonvulsant gabapentin. Topical lidocaine patches frequently reduce allodynia. Strong opioids are sometimes required. Topical capsaicin cream is beneficial for a small proportion of patients but is poorly tolerated. NMDA antagonists have not proved beneficial with the exception of ketamine. Transcutaneous Electrical Nerve Stimulation (TENS) may be effective in some cases. HZ is a common condition. Severe complications such as stroke, encephalitis and myelitis are relatively rare whereas sight threatening complications of ophthalmic HZ are more common. PHN is common, distressing and often intractable. Good management improves outcome.

Objective: To analyze the clinical features and risk factors of herpes zoster and the risk factors of postherpetic neuralgia (PHN). Methods: A total of 2 840 patients diagnosed with herpes zoster in Peking University People's Hospital from January 2021 to April 2022 were included. The patients with herpes zoster were aged (59±16), and of which 1 314 (46.3%) patients were male. The patients were divided into PHN group and non-PHN group according to whether the patients with herpes zoster developed PHN. And there were 442 (15.6%) patients developed PHN aged (68±12), and of which 189 (42.8%) were male. The information and medical history of PHN group and non-PHN group were collected. The information of the use of glucocorticoids, immunosuppressive agents, biological agents and targeted medicine within 2 months before herpes zoster occurred, history of surgery within 6 months before herpes zoster occurred, and the duration of PHN were collected. Logistic regression analysis was used to analyze the risk factors of PHN. Results: Out of 2 840 patients, 2 056 (72.4%) with herpes zoster aged 50 years and above. Intercostal nerves was mostly involved in patients with herpes zoster, with a total of 1 532(53.9%). Hypertension (465 cases, 16.4%) accounted for the highest number of patients with chronic diseases, followed by diabetes (337 cases, 11.9%) and coronary heart disease (283 cases, 10.0%). Rheumatoid arthritis (41 cases, 1.4%) accounted for the highest number of patients with connective tissue diseases, followed by Sjogren's syndrome (31 cases, 1.1%), systemic lupus erythematosus (28 cases, 1.0%). Logistic regression analysis showed that age≥50 years old (OR: 4.581; 95%CI: 3.131-6.705),lesion on the upper limb and shoulder (OR: 1.858; 95%CI: 1.129-3.059), hypertension (OR: 1.963; 95%CI: 1.513-2.546) and immunosuppressive treatments (OR: 2.170; 95%CI: 1.254-3.753) were independent risk factors for PHN (all P<0.05). Conclusions: Herpes zoster mostly occurs in people aged 50 and above, and mainly affected intercostal nerves. The most common complications are hypertension and rheumatoid arthritis. Age≥50, lesion on upper limbs and shoulders, hypertension, and immunosuppressive treatments may be independent risk factors of PHN.

Chronic obstructive pulmonary disease (COPD) has been reported as a potential risk factor for developing herpes zoster (HZ). We aimed at comparing incidence rates of HZ between people with versus without COPD in the US. This retrospective cohort study used data from Optum's de-identified Clinformatics Data Mart database from 1/1/2013 through 12/31/2018. We identified two cohorts of people ≥40 years without prior HZ, HZ vaccination, postherpetic neuralgia (PHN) or HZ ophthalmicus: those with (COPD+) and those without (COPD-) a COPD diagnosis. Adjusted incidence rate ratios (aIRRs) of HZ and PHN were calculated using generalized linear models, controlling for the propensity score of being diagnosed with COPD and relevant demographic and clinical characteristics. People in the COPD+ cohort (n = 161 970) were considerably older, had more comorbidities and were more likely to use corticosteroids than those in the COPD- cohort (n = 9 643 522). The incidence rate of HZ was 5.7-fold higher in the COPD+ versus COPD- cohorts (13.0 vs. 2.3 per 1000 person-years [PY]; aIRR, 2.77; 95% confidence interval [CI], 2.69 to 2.85; P < 0.001). The unadjusted incidence rate of PHN was 1.7-fold higher in the COPD+/HZ+ versus COPD-/HZ+ cohort (64.8 vs. 37.1 per 1000 PY), but not after adjustment (aIRR, 1.07; 95% CI, 0.79 to 1.45). HZ and PHN incidence rates increased with age. After adjustment, COPD+ adults had a 2.8-fold increased risk of developing HZ. These results may help to increase awareness about potential risk factors for HZ and highlight the need for vaccination among those at increased risk.

Introduction: Patients with inflammatory bowel disease (IBD) are at an increased risk for vaccine preventable infections such as herpes zoster (HZ). Immunosuppressed populations are at increased risk for complications from HZ such as post-herpetic neuralgia (PHN). The aim of this study was to determine if complications of HZ are more frequent in patients with IBD than in the general population. Methods: This was a retrospective age matched cohort study using the Optum Research Database from 2007 through 2020 using pharmacy and administrative data. We identified patients with IBD who had > 2 medical claims for IBD and had 12 months baseline coverage and 3 months after index date which was defined as a diagnosis of HZ. We then identified complications of HZ (PHN, ophthalmic, neurologic, or disseminated) that occurred up to 90 days after the index date. We compared patients with IBD with HZ compared to patients without IBD or on a medication used to treat IBD with HZ, and evaluated 90-days risk of HZ complications. Cases were matched based on age, gender, and index year. We evaluated medication exposure within the past month for any oral medication and 3 months for any patients on a biologic. We also evaluated immunization with a HZ vaccine within the past year. Using a composite primary outcome of any HZ complication, we compared patients with IBD and age matched controls. Secondary outcomes evaluated individual HZ complications such as PHN. Results: 16,969 patients with IBD met the inclusion criteria and were matched to controls. Patient with IBD had higher Charlson comorbidity scores compared to those without IBD (2.13 vs. 1.31 p value < 0.0001) (Figure 1A). Patients with IBD were more likely to have any HZ complications than matched controls [2811 (17.49%) vs 2220 (13.8%) p value < 0.0001]. They were also more likely to be hospitalized, have disseminated HZ, develop PHN, or neurologic complications compared to matched controls (Figure 1B). Those with higher comorbidity scores were more likely to have HZ complications (2.68 vs. 2.01 p value < 0.0001). In logistic regression analysis, Hispanic ethnicity, anti-TNF therapy, thiopurine use, prednisone and increased age were all associated with an increased risk for any HZ complication. Conclusion: Our study shows that patients with IBD are more likely to have complications of HZ compared to controls and these complications are common. Efforts are needed to increase HZ vaccine uptake among patients with IBD to potentially prevent HZ complications.Figure 1.: A. Baseline Demographic B. HZ outcomes within 90 days after index. C. Demographic of patients with IBD with and without HZ complication.

Herpes zoster (HZ) and postherpetic neuralgia (PHN) are common diseases in a pain clinic. In Korea, the rate of clinical visits due to the incidence of herpes zoster was 7.93-12.54/1000 annually [1]. PHN is a painful neuropathy and the most common complication of HZ. A complete recovery from PHN is difficult for doctors despite of proper HZ treatment. In spite of the treatment, some patients suffered from severe PHN for several years. Therefore, the most important aspects are the risk factor of PHN and the method of prevention of PHN. In this issue of the Korean Journal of Pain (KJP), Jung et al. [2] reported the incidence of HZ in Cheonan, Korea. The results show that patients 50 years and older have a higher incidence of HZ, and the most common site of HZ was the thoracic nerve (47.9%), followed by the trigeminal nerve (21.4%). The incidence rate was similar to the affected site of PHN (thoracic area: 52.9%, trigeminal area: 15.6%) in Korea [3]. In patients who suffer from HZ, the risk factors of PHN are old age, presence of a painful prodrome, severe pain of HZ, severe rash, and immuno-compromised status [4,5,6]. In patients with HZ over 60 years, up to 25% progressed to PHN [7]. The proportion of PHN increases steadily from young ages up to 80-84 years [8]. Therefore, patients who are elderly and possess the risk factor with HZ must undergo more intensive treatment. The main treatment of HZ is medication and interventional therapy. Taking antiviral medication beginning within 72 hrs of rash onset is usually recommended [7,9,10]. Two meta-analyses suggest that the antiviral medication can reduce the overall duration of pain and incidence of PHN [11,12]. Epidural injection with a steroid within 2 months of HZ development is also recommended for the prevention of PHN [13]. In the previous survey of Korea, epidural injection was the most commonly performed interventional treatment in PHN patients [3]. Other interventions such as paravertebral block, peripheral block and sympathetic block are clinically effective for the treatment of HZ and PHN. For evidence-based medicine of interventional treatment of HZ and PHN, the investigations of randomized controlled trials regarding the interventions will be necessary. In this issue, Jeon et al. [10] described the prevention and treatment of HZ and PHN. They mention that vaccination against varicella zoster virus (VZV) can be the first line for the prevention of HZ and PHN. A previous review article reported that vaccination of VZV reduced morbidity from HZ and PHN [14]. Vaccination of VZV reduced the occurrence of herpes zoster by approximately 70% in individuals aged 50-59 years old [15]. In persons 60 years or older, the vaccination reduced the burden of illness from HZ by 61.1% and the risk of PHN by 66.5% [16]. Therefore, the vaccination of patients over 50 years old can be effective for the prevention of HZ and PHN. Although PHN is difficult to treat, early and intensive treatment of patients with HZ can reduce the occurrence of PHN. In healthy elderly people, a vaccination of VZV can also decrease the incidence of HZ and PHN.

Approximately one in three persons will develop herpes zoster during their lifetime, and it can lead to serious complications such as postherpetic neuralgia. However, evidence on burden of herpes zoster and postherpetic neuralgia in Japan is limited. This prospective, observational, multicenter, physician practice‐based cohort study was conducted in Kushiro, Hokkaido, Japan (Clinicaltrials.gov identifier NCT01873365) to assess the incidence and hospitalization rates of herpes zoster, and the proportion, clinical burden and risk factors for postherpetic neuralgia in adults aged 60 years or more. Within the study area, 800 subjects developed herpes zoster and 412 were eligible for the study. Herpes zoster incidence was 10.2/1000 person‐years and higher among women and older subjects. Subjects with herpes zoster required on average 5.7 outpatient consultations. Herpes zoster‐associated hospitalization rate was 3.4% (27/800). The proportion of postherpetic neuralgia and other complications was 9.2% (38/412) and 26.5% (109/412), respectively. Statistically significant association with the development of postherpetic neuralgia was male sex (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.17–5.38), age of 70–74 years (OR, 3.51; 95% CI, 1.09–11.3), immunosuppressive therapy (OR, 6.44; 95% CI, 1.26–32.9), severe herpes zoster pain at first consultation (OR, 3.08; 95% CI, 1.10–8.62) and rash on upper arms (vs no rash on upper arms; OR, 3.46; 95% CI, 1.10–10.9). Considerable herpes zoster and postherpetic neuralgia burden exists among elderly in Japan, and there may be predictive factors at the first visit which could be indicative of the risk of developing postherpetic neuralgia.