FormalPara Key Summary Points

Global incidence of herpes zoster (HZ) is increasing; however, there is a lack of literature reviews evaluating the burden of disease of HZ in Southeast Asia.

Considering this, a systematic literature review was conducted to provide an up-to-date, comprehensive overview of the available data on the epidemiology, clinical management, and health economics of HZ in six countries in Southeast Asia: Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam.

There were substantial gaps in the literature reporting the nationwide incidence, prevalence, and economic toll of HZ in Southeast Asia, both in individual age groups and among vulnerable populations.

However, the abundance of clinical case reports highlighting numerous symptoms and the severity of complications across health centers suggests HZ healthcare resource utilization is substantial in the region.

Further research is needed to determine the disease awareness in the general population and healthcare professionals, as well as its impact in Southeast Asian societies to inform future strategies for HZ prevention.

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Graphical Plain Language Summary

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Introduction

Herpes zoster (HZ; i.e., shingles) is a painful, dermatomal rash caused by the reactivation of latent varicella zoster virus (VZV; i.e., chickenpox) in dorsal root ganglia [1, 2]. HZ episodes can lead to complications, most commonly long-term nerve pain (postherpetic neuralgia; PHN), and in rare cases can also result in vision loss and stroke which can greatly impact patients’ health-related quality of life [1,2,3,4].

Recent trends have shown that the incidence of HZ is increasing globally [3]. HZ incidence also increases with age and is more common among immunocompromised individuals (due to disease or therapy) [5, 6]. Global estimates of HZ cumulative incidence and incidence rates across North America, Europe, and the Asia–Pacific region in the general population at least 50 years of age are between 2.9–19.5 cases per 1000 individuals and 5.2–10.9 cases per 1000 person-years in people, respectively [7].

HZ can lead to a considerable economic burden to healthcare systems and society. In developed countries, the reported direct costs (e.g., healthcare utilization and medicinal costs) of HZ and its complications range from US $2.7 million to US $2.6 billion and from US $1.7 to US $241.5 million annually for indirect costs such as loss of productivity and absenteeism [8].

First-line therapy for HZ infection is early intervention with antivirals (e.g., acyclovir), and patients often require pain management [4]. Vaccination is the main strategy for the prevention of HZ [4, 8]. Two main types of vaccines are currently available: live attenuated VZV (e.g., zoster vaccine live, ZVL) and recombinant VZV glycoprotein E (e.g., recombinant zoster vaccine, RZV) which have shown efficacy in preventing HZ and improving patients’ quality of life [7, 8]. Despite this, few countries have implemented HZ vaccination in their national immunization programs [8].

It is important for health policymakers to be informed on the HZ burden of disease to facilitate the implementation of preventative strategies (e.g., vaccination). In 2017, a systematic literature review of HZ epidemiology in the Asia–Pacific region highlighted a lack of representation in data for Southeast Asian populations, which accounts for over 680 million individuals [9, 10].

To address this, we conducted an updated systematic literature review to provide a comprehensive, up-to-date overview of the available data on the burden of disease and clinical management of HZ in six Southeast Asian countries: Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. The aim of this review was to better understand the burden, patient pathway, and clinical management of HZ in these countries and identify any gaps in the literature.

Methods

Search Strategy

A systematic literature review was conducted in accordance with guidelines specified in the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses (PRISMA) guidelines to facilitate an accurate, reproducible, and robust methodology [11,12,13]. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The literature search was performed in three databases, Medline (via PubMed), Scopus, and Embase, with a preliminary search strategy developed in Medline and then adapted to other mainstream and local databases (gray literature). Publications derived from gray literature included local congress abstracts, manuscripts, and other reports in local languages unavailable in Medline, Scopus, and Embase. Our search strategy facilitated the inclusion of many articles published by local investigators and healthcare professionals which may have otherwise been missed in mainstream databases as a result of not being accessible in English or not being published in indexed journals.

Search terms for the different databases were combined using Boolean operators [14]. The keywords and MeSH terms used across the three databases are shown in Supplementary Table 1. There was no restriction for publication date and database searches were conducted until May 2022. The geographical scope of this review was restricted to six Southeast Asian countries: Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. Articles written in English or local languages were considered for inclusion.

Article Selection

Identified literature was screened in two steps. Initially, article titles and abstracts were screened for duplicate entries and relevancy using the inclusion and exclusion criteria shown in Supplementary Table 2. Then, the sifted articles underwent a full-text review to determine study eligibility and inclusion according to the same criteria. Additionally, references from eligible articles were manually reviewed for inclusion using the “snowballing” approach [15].

The literature searches and screening were conducted by two independent authors (PSM, AGH). All discrepancies were discussed and resolved throughout each step by both authors. The screening and article organization were performed in EndNote X9, and the data extraction and analysis were performed in Excel.

Data Extraction

Once eligible publications were identified, the relevant data were extracted into an Excel database. Extracted data included publication details (author, journal, and year), study location (city, country), study type/design and period of evaluation, population (age group), sample size, main objectives of the study, epidemiological outcomes, clinical outcomes, and health economic outcomes. Data extraction was then revised and validated by authors.

Here we summarize descriptively the three study endpoints: epidemiology of HZ (incidence, cumulative risk, and prevalence of HZ and disease complications), clinical management of HZ (symptoms, diagnosis, treatment, prognosis, and quality of life), and health economics of HZ (healthcare resource utilization, hospitalization rates, antiviral use, and cost of medical care) in Southeast Asia (Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam).

Quality Assessment

The risk of bias for the observational studies included in this review was assessed using the STROBE (Strengthening the Reporting of OBservational studies in Epidemiology) [16] checklist of essential items, modified according to Sanderson et al., and Fowkes and Fulton [17, 18]. Briefly, we used an algorithm (Web-appendix-2), programmed into a spreadsheet to estimate a summary risk of bias considering five criteria: the methods for selecting study participants, measuring exposure and outcome variables, to control confounding, design-specific sources of bias, and statistical analyses. Disagreements were resolved by author consensus.

Results

Included Studies

A total of 524 publications were identified from the initial literature search, and following removal of duplicate records, 464 publications were screened by title and abstract in accordance with the inclusion and exclusion criteria in Supplementary Table 2. Subsequently, 346 records were excluded, and full text articles were retrieved for the remaining 118 publications which were then assessed for eligibility using the same inclusion and exclusion criteria. Overall, 59 publications were deemed eligible after review, and an additional 13 references were identified from gray literature “snowballing” amounting to a total of 72 publications included in the study. A summary of the screening and eligibility evaluation phases is shown in Fig. 1.

Fig. 1
figure 1

Flowchart of the screening and eligibility evaluation during study selection. The flowchart was generated following PRISMA recommendations. A total of 72 publications that reported HZ data from six Southeast Asian countries (Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam) were included in the study. HZ herpes zoster, PRISMA Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses

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Study Characteristics

A summary of the number of publications included per country is shown in Fig. 2. Out of six countries from Southeast Asia included in the search strategy, the majority of publications were identified in Singapore (n = 23; [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]) and Thailand (n = 21; [42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62]), while fewer were obtained from Indonesia (n = 8; [63,64,65,66,67,68,69,70]), Malaysia (n = 7; [71,72,73,74,75,76,77]), Philippines (n = 6; [78,79,80,81,82,83]), and Vietnam (n = 6; [84,85,86,87,88,89]). One multinational study included data from all six countries [10].

Fig. 2
figure 2

Number of publications included per country in Southeast Asia. A total of 72 publications from six Southeast Asian countries (Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam) were included in the review. The distribution of publications per country was quantified. One publication was considered “multinational” as it reported data from multiple countries

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The spectrum of study types and distribution of all studies according to the three review objectives (epidemiology, clinical management, and health economics) are shown in Fig. 3. Most publications were either cross-sectional studies or case reports with data mostly related to HZ epidemiology and clinical management.

Fig. 3
figure 3

Number of publications per study type and objective. A total of 72 publications from six Southeast Asian countries (Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam) were included in the review. The distribution of publications is shown according to a study type and b endpoint. Individual publications could be included in more than one study objective. aCohort and case–control. SLR systematic literature review

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Quality Assessment of Included Studies

The methodological quality and risk of bias in the included observational studies was assessed using a modified version of the STROBE tool in Supplementary Table 3. Several studies could not be assessed as they were derived from a congress abstract or scientific poster (n = 11), or only the abstract was available in English (n = 2); these studies were not excluded because of the importance and relevance of these publications to this systematic review. Overall, of the remaining 31 publications assessed, 6 articles displayed risk of high bias, 22 moderate bias, and 3 low bias. Whereas, 3 studies demonstrated high quality methodology, 22 moderate quality, and 6 low quality. Of the 6 studies with low quality, sources of bias included a lack of follow-up (potential for misdiagnoses), lack of clear diagnosis or case definition, lack of representation for the general population, and small sample sizes.

Epidemiology of Herpes Zoster in Southeast Asia

VZV Seroepidemiology

HZ infection is caused by the reactivation of latent VZV, often many years after primary infection which typically occurs during childhood [1]. We identified a total of 12 studies which reported VZV seroprevalence in Southeast Asia (Singapore, n = 4; Thailand, n = 4; Indonesia, n = 1; Malaysia, n = 1; Philippines, n = 1; and 1 multinational study) [10, 19, 20, 30, 31, 50,51,52,53, 67, 71, 78].

One study in Singapore published in 2014 reported increasing VZV seropositivity with age (N = 3293), from 84% in individuals aged 18–29 years to 96.4% in those aged 70–79 years [30]. Three additional older studies reported an overall VZV seropositivity of 42.8% (N = 500, age 6 months–45 years) in 1989–1990 [19], 89.8% (N = 576, age 18–25 years) in 1993–1997 [20], and 76% (N = 2189, age 16–36 years) in 2000–2005 [31].

In Thailand, three studies also highlighted an increasing seroprevalence with age in the general population: from 10.2% (age < 1 year) to 96.1% (age 30–39 years) in a 1994 study (N = 559; overall seroprevalence 61.4% [51]), from 15.5% (age 9 months–4 years) to 75.9% (age 20–29 years) in a study from 1997 to 1998 (N = 2093; overall seroprevalence 52.8% [52]), and from 12% (age 6 months–3 years) to 100% (age > 25 years) in a 1998–2000 study (N = 350) [53]. A fourth study of 383 medical students aged 18–25.8 years in 2008–2009 reported that 92% were VZV seropositive [50].

Less data were identified for Indonesia, Malaysia, and the Philippines. In Indonesia, one study published in 2000 in a Javanese community (N = 1103) reported an increase in VZV seropositivity from 30% in individuals aged 4 years to 72% in those aged 30–32 years [67]. In Malaysia and the Philippines, two studies were identified that investigated VZV seroprevalence among healthcare workers which reported 84.4% (N = 64, mean age not reported) and 82% (N = 174, age 20–25 years) VZV seropositivity, respectively (study periods not stated) [71, 78].

A 2017 systematic literature review of HZ epidemiology in the Asia–Pacific region with data from multiple studies indicated that VZV seropositivity increased with age in Singapore, Thailand, Indonesia, Malaysia, and the Philippines and no studies were identified in Vietnam, similar to the findings above [10].

Incidence and Prevalence of Herpes Zoster

Studies reporting the national incidence or prevalence of HZ at a national level were lacking among countries in Southeast Asia. The included studies reporting HZ incidence and prevalence are summarized in Table 1.

Table 1 General characteristics of included studies relating to HZ incidence and prevalence
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In the systematic literature review of HZ epidemiology in the Asia–Pacific region, including a total of 14 countries from which six are found in Southeast Asia (Singapore, Thailand, Indonesia, Malaysia, the Philippines, and Vietnam), the estimated overall incidence rate of HZ was 3–10 per 1000 person-years, similar to that of other countries worldwide [10]. However, studies relating to Southeast Asia were sparse, and the only country in Southeast Asia for which incidence data were reported was Thailand. These data came from the Thailand Bureau of Epidemiology, which reported an increasing incidence of HZ from 6.44 to 7.65 cases per 100,000 individuals from 2001 to 2014, respectively; and Aunhachoke et al., who reported the incidence rate at 0.26 cases per 1000 individuals in 2008 [10, 61].

A total of five publications identified reported the prevalence of HZ across Singapore (n = 2), Indonesia (n = 2), and the Philippines (n = 1) [39, 40, 65, 66, 79]. All were derived from a single center, and most patients were over 40 years of age with similar proportions in genders.

Of two studies identified in Singapore, one conducted at the Communicable Disease Centre reported that 3% of hospitalizations during 1993–1994 (N = 2262) were related to HZ, of which 52.2% were male, and most patients were elderly (mean age 50.4 years) [40]. Similarly, the second study at an emergency department at Tan Tock Seng Hospital (N = 157,527) in 2007 reported that 5.3% of dermatological cases were HZ (N = 4061; mean age 37.9), of which 51.2% cases were male, accounting for 0.14% of all visits to the emergency department [39].

In Indonesia, one study at a hospital reported between 105 and 125 cases of HZ annually during 2009–2011 [65]. A second Indonesian study in 2013 reported 0.68% (N = 4099) of patients at a single dermatology clinic in Manado were admitted with HZ, with the majority of cases in people aged 45–64 years (78.6%); 42.9% of cases were male [66]. In the Philippines, HZ accounted for 0.7% of outpatients at a hospital in Manila (N = 221), with no noticeable differences in gender; and most (19.5%) patients were aged 51–60 years (mean age 42.6 years) [79].

While there were no studies reporting the incidence and prevalence of HZ in Vietnam, one article described the clinical characteristics of 71 patients at a hospital dermatology department: 53.5% of patients were male and most patients were aged over 50 years (70.41%) and 22.53% were over 70 years old [85].

Herpes Zoster Complications

HZ infection can lead to further complications in patients, most commonly PHN, but in rare cases these can include blindness and stroke [1, 3, 4]. In our review, nine studies reporting the proportion of HZ infections resulting in complications were identified from Singapore (n = 4; [37, 38, 40, 41]), Thailand (n = 4; [43, 59,60,61]), and the Philippines (n = 1; [79]), as summarized in Table 2. As with the prevalence data, these studies were mostly derived from single centers. Of the studies available, PHN, ophthalmic involvement or HZ ophthalmicus (HZO), and secondary bacterial infections were frequently reported.

Table 2 Proportion of patients with HZ-related complications
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In Singapore, three studies were conducted at the National Skin Center (NSC). One in 2008–2010 reported that 10.2% of patients with HZ (N = 421) developed early complications, of which more than 50% had ophthalmic involvement (e.g., conjunctivitis and periorbital swelling), and 16.4% developed PHN; patients over 60 years of age were also at a significantly higher risk of developing PHN [37]. The second NSC study in 2010–2013 noted that 83% of HZ-infected patients (N = 347) presented with acute HZ, 10.7% subacute HZ, and 6.3% with PHN [41], and the third NSC study, which occurred in 1994–1995 (N = 164), reported that PHN was more common in patients over 50 years of age compared with those under 30 years of age [38]. Another study of 67 hospitalized patients with HZ in 1993–1994 reported that most patients (58%) were over 50 years of age, and 85% of all patients included developed complications (bacterial superinfection [61.2%], cutaneous dissemination [31.3%], ocular involvement [14.9%], and neurological complications [19.4%]) [40].

The number of HZ complications among Thailand patients was particularly high; 21.2% of surveyed Thai patients (N = 118; 69.5% female) in 2013–2014 reported HZ-related complications (disseminated HZ [8.4%], eye or ear involvement [8.4%], and secondary bacterial infection [5%]) [60]. Consistent with this, the proportions of patients with PHN and HZO were high at three other sites in Thailand, with reports of 16.8% with PHN (N = 399) in 1995–2000 [59], 17.79% with PHN (N = 208) in 2001 [43], and 19.4% with PHN and 7.2% with HZO (N = 180) in 2007–2008 [61]. One of these studies noted that most PHN cases occurred in patients aged 61–70 years [43].

At a hospital in the Philippines during 2003–2007 (N = 221), HZ-associated pain (75.1%; e.g., acute pain and PHN), ophthalmic involvement (5%), and secondary bacterial infections (6.79%) were the three most commonly reported HZ complications [79]. However, the proportion of HZ cases reporting PHN (2.26%) was lower than reports in other Southeast Asian countries described above.

Two additional studies in Indonesia and Malaysia also reported that PHN was more common in older individuals. One at a dermatology department in Indonesia in 2019 where 53.3% of patients with HZ and PHN were 60 years of age or older (N = 30) [70], and the other at a hospital in Malaysia where 49% (N = 88) with PHN were 61–70 years old in 2007–2020 [77].

Rarer complications associated with HZ in Southeast Asia were reported in multiple case studies (n = 22), as summarized in Supplementary Table 4. Most case reports were from Singapore (n = 9) and Thailand (n = 6) and many reported accompanying comorbidities. Complications reported included segmental zoster paresis [21], pseudohernia [22], disseminated herpes simplex virus and VZV co-infection [24], herpetic necrotizing retinopathies [25], asymmetrical oligoarthritis with possible zoster-associated arthritis [26], syndrome of inappropriate antidiuretic hormone secretion [28], and neovascular glaucoma [75]. Four case reports also presented further complications secondary to HZO: one case of HZO with optic neuritis [45], and a second affecting the trigeminal tract and brainstem nuclei, each in Thailand [47]. Furthermore, five cases with orbital apex syndrome were reported in Singapore and Malaysia [27, 29, 73, 74].

Comorbidities and Risk Factors

According to meta-analyses investigating risk factors for HZ, the presence of comorbidities is associated with an increased risk of developing HZ [90, 91]. Of the 72 publications included here, 23 studies described the association of HZ infection in subpopulations of individuals with specific comorbidities or risk factors, notably in immunocompromised patients with human immunodeficiency virus (HIV), diabetes mellitus (DM), and systemic lupus erythematosus (SLE).

Of these studies, six reported the proportion of individuals with comorbidities in a population of patients with HZ. Two single-center studies reported 17.4% (N = 421, Singapore; [37]) and 28% (N = 221, Philippines; [79]) of patients diagnosed with HZ had a comorbidity. A third study in Singapore of 67 hospitalized patients with HZ reported that 28.4% were immunocompromised (due to renal transplant, malignancy, HIV, or rheumatoid conditions) and 35.8% had other underlying medical conditions [40]. In Vietnam, one study found that hypertension was reported in 22.54%, muscular conditions in 4.23%, DM in 2.82%, digestive diseases in 8.45%, and dyslipidemia in 2.82% of patients with HZ [85]. Finally, in Thailand, one study of 208 medical records of patients with HZ reported that 21.05% of 37 patients who developed PHN were immunocompromised compared with 17.06% in individuals with healthy immunity [43]. One article in Thailand also reported the occurrence of comorbidities among a population of patients with complications of HZO. Of 160 patients with HZO in 2005–2008, 14.4% had hypertension, 6.9% had DM, and of 65 patients tested, 33.8% (22/65) had HIV [44].

The remaining studies investigated the occurrence of HZ within populations of patients with chronic disease or compromised immunity (e.g., patients with HIV, DM, and SLE), and are summarized below.

Human Immunodeficiency Virus

Six studies included proportional data on patients with HIV and HZ infection in Thailand (n = 4), Indonesia (n = 1), and Vietnam (n = 1).

Three of the studies identified for Thailand investigated the prevalence of cutaneous diseases in patients with HIV at a single health center. HZ infection was reported to occur in 9.17% (N = 120) of patients with HIV in 2000 [54], 16.1% (N = 248) in 1993–1994 [42], and 10.9% (N = 129) in 1998–1999 [56]. Another study conducted in a hospital in Thailand reported that 14% of 399 patients with HZ had HIV in 1995–2000 [59].

Outside of Thailand, one study of 843 patients at a HIV clinic in Indonesia during 2008 reported that 1.9% of patients with HIV had HZ, which represented 13.2% of patients with skin complaints (n = 121) [69]. One study at a rehabilitation center in Vietnam reported that 20% of 235 patients with HIV had HZ in 1996 [84].

Diabetes Mellitus

Only one study reported incidence of HZ among patients with DM. This was a nested case-controlled study during 2005–2014 from a single hospital in Bangkok, Thailand which reported an incidence rate of 3.96 per 1000 person-years (2.8% cumulative incidence; N = 1428) [57]. Of the 40 HZ-infected patients with DM in this study, 12.5% experienced recurrent HZ (two episodes in four patients, and three episodes in one patient), and 35% developed symptoms of PHN. Hypertension, number of hypoglycemic agents used, and use of herbal remedies were reported as significant risk factors for developing HZ in patients with DM, whereas greater body mass index was protective [57]. The proportion of DM in patients with HZ was also reported by various single-center studies in Thailand and Singapore and ranged from 2.5% to 9% [37, 44, 59].

Systemic Lupus Erythematosus

Three studies from the Philippines reported HZ prevalence in patients with SLE. In one study of 65 patients with SLE who developed HZ (N = 195, mean age 36.8 years), four patients experienced recurrent HZ infection and two experienced disseminated HZ [82]. Mean onset of HZ after SLE diagnosis was 6.1 years, and cyclophosphamide and mycophenolate mofetil treatment was associated with greater occurrence of HZ, whereas hydroxychloroquine was reported to substantially reduce the risk of HZ by 87% [82]. In a separate study (N = 458, mean age 35.6 years), 21% of all patients developed HZ at least once and recurrent HZ infection was reported in eight patients with SLE [81]. The third study investigated SLE cases in patients with a recorded pregnancy, of which 2% developed HZ (N = 99) [83].

Another study was identified in Malaysia, which reported similar proportions of HZ infection (16.2%) in patients with SLE (N = 229, mean age 34.4 years) and found that steroid treatment (prednisolone ≥ 60 mg daily) and hematological manifestation were significant risk factors of HZ infection [76].

Other Comorbidities

Other comorbidities reported in association with HZ or VZV in Southeast Asia included cancer (n = 2), central nervous system infections (CNS; n = 4), and organ transplants (n = 2).

Two studies reported malignancies, occurring in 0.75% (N = 399) and 5.9% (N = 421) of patients with HZ at centers in Thailand (1995–2000; [59]) and Singapore (2008–2010; [37]), respectively.

Four studies investigated VZV association with patients who developed CNS infections; one identified in Singapore and three in Vietnam. In Singapore (2013–2016), one study of suspected CNS infections (N = 155) reported that 87 cases had identifiable etiology related to infection, of which 6.9% were VZV positive [32]. Whereas in Vietnam, one study during 2017–2019 reported that VZV was the suspected cause of CNS infections in 1.8% of patients (N = 380) [86]. Likewise, two other Vietnamese studies found that 1.4% (N = 352) and 6% of 113 patients with suspected meningitis or encephalitis were VZV positive in 2007–2008 and 2017–2019, respectively [87, 89].

Two studies in Thailand investigated VZV infections in pre- and post-kidney transplant patients. Of 181 pre-kidney transplant patients during 2006–2011, 99.4% had latent VZV infection [55]. While in a study of 1032 post-kidney transplant patients in 2003–2013, 22 (2%) were diagnosed with disseminated VZV, of which 2 were recently exposed to VZV and 4 with an increased immunosuppression regimen [58].

Patient Pathway and Clinical Management of HZ

In total, we identified 48 publications reporting data related to the patient pathway and clinical management of HZ in Singapore (n = 17; [20,21,22,23, 25,26,27,28,29,30,31, 35, 37, 38, 40, 41, 74]), Thailand (n = 14; [44,45,46,47,48,49, 52, 53, 57,58,59,60,61,62]), Indonesia (n = 6; [63, 64, 66,67,68, 70]), Malaysia (n = 6; [71,72,73, 75,76,77]), the Philippines (n = 4; [79, 80, 82, 83]), and Vietnam (n = 1; [85]).

Prodromal Symptoms

HZ prodromal symptoms, prior to the manifestation of skin lesions, reported across Southeast Asia included pain, itching, paresthesia, and insomnia (Supplementary Table 5). Prodromal pain was reported in all relevant studies and occurred in 24–90% of patients with HZ [38, 41, 60, 79, 85]. Two studies in Singapore also reported itching (15.9–27%) as well as paresthesia (12%), and insomnia (4.3%) [38, 41]. No studies in Malaysia or Indonesia reported proportions of patients with prodromal symptoms.

Clinical Presentation

In total 11 studies indicated the anatomical distribution of HZ skin lesions at onset and during disease progression. Skin lesions were more frequently found in the thoracic dermatome (39–64%) and ranged from 10% to 23.5% in lumbar, 3.6–23.8% in cervical, 3–36% in cranial, and 5–10.7% in sacral dermatomes [37, 38, 40, 41, 59,60,61, 66, 77, 79, 85]. A full list of studies describing the distribution of HZ lesions are shown in Supplementary Table 6. Two studies, in the Philippines and Singapore, reported the occurrence of skin lesions at multiple dermatomes (1.35% and 17.8%, respectively) [37, 79].

The most common symptom associated with HZ skin lesions was pain (74.21–100%; Supplementary Table 7; [37, 38, 40, 41, 79, 85]) consistent with pain as the predominant prodromal symptom in Southeast Asian patients. Other commonly reported symptoms included tenderness (1.5–11.76%; [40, 79]), itching (9–30.77%; [40, 79]), fever (8.54–25.4%; [38, 40, 79, 85]), and fatigue (7–16.9%; [38, 85]).

At the NSC in Singapore in 2010–2013 (N = 347), pain or discomfort (85.9%), and blistering rashes with scarring (44.4%) were reported as the most unbearable symptoms [41]. Pain duration also increased with age within the same NSC cohort, with 2.2% of patients aged 50–59 years experiencing pain for longer than 6 months compared with 7.7% of patients over 80 years of age [41]. In the Philippines, one study reported that the mean duration of acute pain was 15.8 days [79].

The mean duration of symptoms before consultation was 4 days (1–21 days; N = 118) in Thailand (2013–2014) and 8 ± 2.1 days (N = 221) in the Philippines (2003–2007), respectively [60, 79]. The median time for skin lesions to heal was 11 days (N = 67) in one study in Singapore (1993–1994) [40]. A second Singapore study (N = 421) in 2008–2010 also noted that older patients required a significantly longer duration of time for HZ skin lesions to heal [37].

Impact of Herpes Zoster on Quality of Life

The symptoms of HZ, as described above, can have an impact on patients’ quality of life. We found three studies which reported patient-reported outcomes. One study using Thai Dermatology Life Quality Index (DLQI) questionnaires reported a 10.7 DLQI mean score, indicative of a moderate–severe impact on patients’ quality of life; 25 patients (N = 118) in this study had complications related to HZ including disseminated HZ, eye or ear involvement, and secondary bacterial infection [60]. A second study in Thailand used the EuroQol 5 Dimension survey (EQ-5D) to measure quality of life in patients with zoster (N = 180) and reported that the severity and duration of zoster-associated pain correlated significantly with quality of life and activities of daily living among patients [61]. The third study investigated pain in patients with HZ-related PHN (N = 30) in Indonesia, and found that 30% of patients reported the worst pain intensity and identified strong correlations in pain intensity with mood disturbance, working status, relationships with others, sleep, and disturbance on enjoyment of life according to the Zoster Brief Pain Inventory [70].

HZ Diagnosis and Treatment

Diagnosis of HZ for observational studies generally was based on clinical presentation and physical examination of the patient. Ancillary tests including Tzanck smears [49, 58, 60], enzyme-linked immunosorbent assays [30, 31, 52, 53, 67], and immunofluorescent staining of VZV antigens [49, 60] were also utilized in diagnoses, often in reports of rare or complicated cases involving HZ.

The therapies reported to treat HZ across identified publications are detailed in Supplementary Table 8. The majority of patients recorded at health centers across Southeast Asia received antiviral therapy (more than 80% in Singapore, Thailand, and Indonesia, and 61.9% in the Philippines), of which acyclovir was generally the predominant antiviral prescribed except for the Philippines, where valaciclovir was prescribed slightly more often (52.6% vs. 47.4% acyclovir) [41, 60, 66, 79]. Reported use of pain relief medications (e.g., paracetamol and gabapentin) ranged from 55.6% in Singapore to 76% in the Philippines [41, 79]. One study found that analgesic and psychotropic treatments effectively reduced pain in 71.4% of HZ-infected patients [37]. Correspondingly, pain relief was among the most desired outcomes (30%) from antiviral therapy, with the greatest being a reduction in skin-lesion duration [38]. One study investigating cases of HZO, which included patients with HIV (33.8%), hypertension (14.4%), and diabetes mellitus (6.9%) in Thailand, reported a 3-day median duration of rash onset to antiviral treatment [44].

HZ Vaccination Recommendations in Southeast Asia

The main strategy for HZ prevention is vaccination [4, 8]. The recommended populations for HZ vaccination in each Southeast Asian country are summarized in Table 3. Generally, recommendations for HZ vaccination are for individuals at least 50 years of age and/or patients with greater risk of HZ infection, except Indonesia for which vaccination is contraindicated in immunocompromised patients (non-HIV). There are no recommendations for HZ vaccination in Vietnam. The live-attenuated vaccine is recommended in Indonesia, Singapore, and Thailand; and the recombinant zoster vaccine in Malaysia. Use of both is recommended in the Philippines (with differing criteria of use).

Table 3 HZ vaccine recommendations in Southeast Asia
Full size table

Health Economics of Herpes Zoster in Southeast Asia

There was a distinct lack of HZ-related health economic and healthcare utilization data in Southeast Asia, with few relevant studies identified in Singapore (n = 3; [38, 40, 41]) Thailand (n = 2; [60, 61]), and the Philippines (n = 1; [79]).

In Singapore, one study in 1993–1994 reported mean duration of hospitalization among 67 inpatients with HZ, which was 5.7 days [40]. Another retrospective study at a hospital in Singapore, which included 164 HZ-infected patients from 1994 to 1995, reported that most general practitioner consultations (45%) occurred within 3 days post onset of skin lesions [38]. This study also reported that the majority of patients (43%) were only willing to pay for treatment if costs (reported in Singapore dollars, S$) were below S$200.00 compared with 30% who were willing to pay above S$200.00 [38]. Another study of patient medical records in 2010–2013 in Singapore reported the direct costs per patient with HZ and PHN (including medication, consultation, and hospitalization). For patients with PHN, costs were significantly greater at S$359.48 compared with S$186.70 for patients without PHN, and one instance of HZ was estimated to incur S$340.00 in societal costs [41]. Absenteeism from work (indirect cost) was also reported to have a substantial impact on overall costs, and was highest among people aged 50–59 years (S$210.56) and 60–69 years (S$63.98) [41].

In Thailand, a prospective cohort study of 180 patients with HZ reported that patients typically required only 1–2 outpatient visits within 6 months. However, 34 patients reported an increase in caregiver assistance in this period. Most patients were elderly (76.7%), 18.9% were HIV-positive, and 4.4% were receiving immunosuppressive treatment [61]. Family members acting as caregivers were reported to miss a median 5 days of work (1–8 days) [61]. This study also reported the mean direct healthcare cost for HZ was estimated to be (Thai baht) ฿3083.39 ± 5047.0 (US $90.41 ± 148.0) in 2010, less than in Singapore, but equivalent to 1.1% of annual income per capita in Thailand [61]. A separate Thailand study reported that the median cost of treatment people willing to pay was at ฿500, which represented 4.2% of the median monthly income in 2011 [60].

In the Philippines, only one study with relevant data was identified which reported that persistent pain was the main cause for follow-up examination (N = 221) [79]. No studies reported the direct or indirect costs of HZ in the Philippines, Indonesia, Malaysia, and Vietnam.

Discussion

The global disease burden of HZ is increasing worldwide. However, countries in Southeast Asia often lack representation or are misrepresented in studies investigating the health and economic impact of HZ. No studies from Southeast Asia were included in a recent 2021 SLR of HZ incidence worldwide but two were included in a 2014 SLR of HZ incidence and complications [3, 7]. While one SLR of HZ in the Asia–Pacific region included 125 publications from Southeast Asia, this represented only 10% of all included studies (N = 1250) [10].

Therefore, this review sought to provide a comprehensive overview of HZ disease burden specifically in Southeast Asia, and included available data on HZ epidemiology, clinical management, and economic impact from 72 publications. Not all countries in Southeast Asia were included in the search strategy (i.e., Brunei, Cambodia, East Timor, Laos, or Myanmar); however, the included countries (Indonesia, Malaysia, the Philippines, Singapore, Thailand, and Vietnam) are among the largest populations and geographical size, and are generally in similar sociodemographic and socioeconomic categories, hence are representative for the region.

According to our quality assessment, most studies identified in Southeast Asia were moderate–low quality with moderate–high risk of bias, consistent with most observational studies being retrospective, involving only a single center, or based on passive surveillance. A number of case studies were also included, which are inherently prone to high bias. However, the descriptive nature of such studies provided key insight into the patient pathway, clinical management endpoints, and presence of rare complications of HZ in the region. Furthermore, by accessing existing literature from international and local sources, we were able to obtain a greater understanding of the disease distribution of HZ in Southeast Asia and highlight significant gaps within the literature for future research.

Overall, more than 60% of all studies originated in Singapore or Thailand, with the fewest identified in the Philippines, Malaysia, and Vietnam. Over 30% of articles were either a case study or case series publication, indicating a lack of more robust studies.

There was also a substantial lack of studies reporting HZ incidence and prevalence, which could reflect that HZ is perceived as a lower health priority and that there might be low disease awareness, as HZ is not a mandatory notifiable disease in Southeast Asian countries. The lack of nationwide data on HZ incidence and prevalence resembles that of other reviews of HZ disease burden in Latin America and Gulf Cooperation Council (GCC) countries in the Middle East [92, 93].

Only two studies from Thailand were identified that reported HZ incidence. The data from both studies originated from the Thailand Bureau of Epidemiology, and so the quality of these data could not be evaluated. The incidence of HZ reported in Thailand was notably lower than global rates (2.9–19.5 cases per 1000 individuals) and when compared with data from other Asian countries [7, 10], which could suggest under-reporting or frequent misdiagnoses.

The prevalence of HZ was reported as 0.68–0.7% at individual dermatological clinics, 0.14% at a single emergency department (5.3% of dermatological cases), and 3% of admissions at one hospital; however, no data were reported in Thailand, Malaysia, and Vietnam. These studies showed a range in quality according to our assessment; however, most exhibited low quality statistical methodology and low quality methodology for measuring exposure and outcome variable. The proportion of hospitalizations related to HZ, reported solely in Singapore (3%), was substantially higher than hospitalization rates reported in Europe (6.99–10.95 per 100,000 individuals [0.007–0.011%]) [94,95,96]. However, the percentage of HZ-related emergency department visits (0.14% in Singapore) was similar to nationwide data reported in the USA (0.13–0.14% in 2006–2013) [97].

HZ can lead to the development of various disease complications, including PHN and HZO [3]. Most studies that reported complications among patients in Southeast Asia were derived from single and referral centers or were presented in case reports. A large variety of complications were reported; however, it should be noted that as these single and referral centers may receive more severe cases, there may be a risk of misrepresenting the overall case burden. Overall, between 10.2% and 21.2% of reported HZ cases developed or experienced complications in Singapore and Thailand, and PHN prevalence ranged from 2.26% to 19.4%, similar to reports globally [3]. However, when considering hospitalized patients with HZ, complications were reported in up to 85% of patients (in Singapore) [40]. The rates of occurrence of HZO (5–8.4%; excluding data from inpatient-only populations) or secondary bacterial infection (5–6.8%; excluding data from inpatient-only populations) were similar between Southeast Asian countries (Singapore, Thailand, and the Philippines).

Several studies reported a higher risk of complications among older individuals, and patients with HZ-related complications identified from case studies in Southeast Asia tended to have pre-existing comorbidities. A subset of studies reported the prevalence of comorbidities among patients with HZ, namely HIV, DM, and SLE. Of the studies that were viable for quality assessment, the majority were deemed moderate quality with a moderate risk of bias (8/10).

The proportion of patients with HZ reported with any comorbidity was 17.4–28%. The reported rates of HZ infection in patients with HIV or SLE were similar to other regions. For example, in the current review, 6.2% of patients with SLE experienced recurrent HZ and up to 21% developed at least one episode of HZ, in the range of 2.51–43% reported in North America and Asia [98,99,100,101]. Likewise, between 1.9% and 20% of patients with HIV in Southeast Asia were reported to develop HZ, with most studies originating in Thailand, consistent with recent reports of HIV-related opportunistic infections in Kenya [102]. While literature globally has discussed the relationship of the COVID-19 pandemic with HZ [103, 104], we only found one case study where a patient reported HZ with COVID-19 in Southeast Asia [63]. Other studies have highlighted the possible association between COVID-19 vaccination and HZ infection. In particular, a case series of seven Filipino patients who received the COVID-19 vaccine reported that five developed HZ following the first dose of the vaccine and two following the second dose [105]. Similar cases have been reported across Europe and Asia [106,107,108,109].

One study had reported that PHN was more common in immunocompromised versus immunocompetent patients. This may align with two studies conducted in England that reported higher rates of hospitalization and PHN among immunocompromised versus immunocompetent patients [110, 111]. These data are also consistent with reports in the USA showing that the incidence rates of HZ in immunocompromised individuals exceed rates estimated in immunocompetent individuals [112].

Regarding the clinical presentation of HZ, pain was the predominant burden, noted in 74.2–100% of patients, affecting many aspects of patients’ quality of life in both social and working aspects. Antiviral therapy was the most common strategy reported to treat HZ, consistent with European and US recommended treatment guidelines [113, 114]. European guidelines recommend the initiation of analgesics in patients with zoster-associated pain [114], but their use was only reported in 55.6–76% of patients in Southeast Asia.

Immunosuppressive conditions (e.g., HIV and cancer treatment) and immunosenescence due to the decline in cell-mediated immunity with age are the predominant risk factors of HZ infection [5, 6]. With reports of increasing global trends of HZ and future projections of an increase in the elderly population, the incidence and global health burden of HZ are correspondingly expected to rise [3]. Vaccination is the main strategy to prevent the onset of HZ and clinical trials have demonstrated positive results in the reduction of HZ and PHN in patients [4, 8]. HZ vaccination is currently recommended in five of the six countries included in this review. Despite this, HZ vaccination is not in widespread use in Southeast Asia, and is often not implemented in countries where the live attenuated vaccine or recombinant subunit vaccine is licensed [8]. However, recommendations for vaccination are undergoing evaluation and national guidelines are likely to change as new vaccines become available.

Information on the economic toll imposed by HZ in Southeast Asia was sparse, with only two studies in Singapore and Thailand providing estimates of the healthcare and societal costs related to HZ. Given that HZ can incur up to US $2.6 billion in healthcare costs annually in countries such as the USA where costs are also estimated to increase up to US $4.7 billion by 2030 for individuals aged 65 years or older [115, 116], further studies are needed to determine the impact across Southeast Asia.

Conclusions

This systematic literature review of HZ burden in Southeast Asia identified significant gaps in the literature. Studies in Malaysia, Indonesia, Vietnam, and the Philippines were particularly sparse. While Thailand and Singapore provided more data, a lack of HZ burden data was also evident. There was a lack of studies reporting nationwide incidence of HZ (by age and in vulnerable populations). However, we did identify an abundance of descriptive studies and case reports providing relevant insight into the patient pathway and clinical management among general and immunocompromised populations, suggesting that while HZ is not routinely captured in surveillance systems, it is prevalent in Southeast Asia.

The current evidence indicates a substantial health impact reported among both immunocompetent patients over 50 years of age and in patients with comorbidities across Southeast Asia. High rates of complications, symptoms, medicinal use, and reports of poorer quality of life suggest substantial healthcare resource utilization for patients with HZ, yet there is a significant paucity in health economic data in each country in Southeast Asia. Further research will be needed to better understand the burden of disease incurred by HZ in Southeast Asia and to inform potential preventative strategies in the region.