Knowledge, attitude, and practice toward herpes zoster (HZ) and HZ vaccination: Concept elicitation findings from a multi-country study in the Asia Pacific.

Herpes zoster (HZ) is a prevalent disease characterized by a painful rash. A multi­country study was conducted to elicit public and physician knowledge, attitude, and practice (KAP) toward HZ disease and vaccination for the assessment of local factors influencing HZ vaccine perceptions in four Asian-Pacific countries/territories One-to-one qualitative interviews were conducted in 2022, among the public (people aged ≥ 50 years, adults with parents aged ≥ 50 years, zoster vaccine live-vaccinated individuals aged ≥ 50 years in Republic of Korea, and HZ patients; n = 78) and physicians (general practitioners and specialists; n = 24). Themes surrounding KAP toward HZ and HZ vaccination were summarized using a thematic analysis. A substantial knowledge gap related to HZ was observed among the public, including its causes, long-term impacts, and the at-risk population. There was a low perceived risk of HZ and low general awareness of HZ vaccine availability, although country/territory-specific differences existed. Fear of HZ-associated pain contributed toward vaccination intent among HZ patients and adults with parents aged ≥ 50 years. HZ-naïve adults who were encouraged to receive the vaccine by others were not motivated to do so due to optimism bias. Physicians were perceived to be a reliable source of information. However, physicians did not always proactively discuss HZ vaccination due to time constraints and a perceived need to prioritize other vaccinations including influenza and pneumococcal vaccines. Initiatives are needed to improve public awareness of HZ and its complications, in terms of overall impact on individuals and society, and highlight the important role of physicians in recommending vaccination.

Management of complicated skin and soft tissue infections with a special focus on the role of newer antibiotics.

Complicated skin and soft tissue infections (cSSTIs) represent the severe form of infectious disease that involves deeper soft tissues. Involvement of methicillin-resistant Staphylococcus aureus (MRSA) further complicates cSSTI with increased hospitalization, health care costs, and overall mortality. Various international guidelines provide recommendations on the management of cSSTIs, with the inclusion of newer antibiotics. This literature-based review discusses the overall management of cSSTI, including appropriate use of antibiotics in clinical practice. Successful treatment of cSSTIs starts with early and precise diagnosis, including identification of causative pathogen and its load, determination of infection severity, associated complications, and risk factors. The current standard-of-care for cSSTIs involves incision, drainage, surgical debridement, broad-spectrum antibiotic therapy, and supportive care. In recent years, the emergence of newer antibiotics (eg, ceftaroline, tigecycline, daptomycin, linezolid, etc) has provided clinicians wider options of antimicrobial therapy. Selection of antibiotics should be based on the drug characteristics, effectiveness, safety, and treatment costs, alongside other aspects such as host factors and local multidrug resistance rates. However, larger studies on newer antibiotics are warranted to refine the decision making on the appropriate antimicrobial therapy. Local Antimicrobial Stewardship Program strategies in health care settings could guide clinicians for early initiation of specific treatments to combat region-specific antimicrobial resistance, minimize adverse effects, and to improve outcomes such as reduction in Clostridium difficile infections. These strategies involving iv-to-oral switch, de-escalation to narrow-spectrum antibiotics, and dose optimization have an impact on the overall improvement of cSSTI therapy outcomes, especially in countries like Singapore that has a high disease burden.

OVERVIEW OF DENGUE AND DENGVAXIA®—OPTIMISING THE USE OF DENGVAXIA®

Dengue is the most rapidly spreading mosquito-borneviral disease in the world, associated with high morbidityand mortality. It is caused by the transmission of thedengue virus (DENV) through the bite of the infectedmosquito vector, Aedes aegypti. There are 4 serotypes ofDENV (1–4), and all of them circulate in Singapore.Pre-adolescents and young adults are at the highest riskof dengue in this region. In Singapore, the dengue vaccineis approved for the prevention of dengue caused by DENV1–4 in individuals aged 12–45 years living in endemic areas.The vaccine is effective in reducing symptomatic, severeand hospitalised dengue, with clear benefits inseropositive individuals.

Looking back to move forward: a twenty-year audit of herpes zoster in Asia-Pacific.

BACKGROUND: Herpes zoster (HZ) is a prevalent viral disease that inflicts substantial morbidity and associated healthcare and socioeconomic burdens. Current treatments are not fully effective, especially among the most vulnerable patients. Although widely recommended, vaccination against HZ is not routine; barriers in Asia-Pacific include long-standing neglect of adult immunisation and sparse local data. To address knowledge gaps, raise awareness, and disseminate best practice, we reviewed recent data and guidelines on HZ from the Asia-Pacific region. METHODS: We searched PubMed, Scopus, and World Health Organization databases for articles about HZ published from 1994 to 2014 by authors from Australia, China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. We selected articles about epidemiology, burden, complications, comorbidities, management, prevention, and recommendations/guidelines. Internet searches retrieved additional HZ immunisation guidelines. RESULTS: From 4007 retrieved articles, we screened-out 1501 duplicates and excluded 1264 extraneous articles, leaving 1242 unique articles. We found guidelines on adult immunisation from Australia, India, Indonesia, Malaysia, New Zealand, the Philippines, South Korea, and Thailand. HZ epidemiology in Asia-Pacific is similar to elsewhere; incidence rises with age and peaks at around 70 years - lifetime risk is approximately one-third. Average incidence of 3-10/1000 person-years is rising at around 5% per year. The principal risk factors are immunosenescence and immunosuppression. HZ almost always causes pain, and post-herpetic neuralgia is its most common complication. Half or more of hospitalised HZ patients have post-herpetic neuralgia, secondary infections, or inflammatory sequelae that are occasionally fatal. These disease burdens severely diminish patients' quality of life and incur heavy healthcare utilisation. CONCLUSIONS: Several countries have abundant data on HZ, but others, especially in South-East Asia, very few. However, Asia-Pacific countries generally lack data on HZ vaccine safety, efficacy and cost-effectiveness. Physicians treating HZ and its complications in Asia-Pacific face familiar challenges but, with a vast aged population, Asia bears a unique and growing burden of disease. Given the strong rationale for prevention, most adult immunisation guidelines include HZ vaccine, yet it remains underused. We urge all stakeholders to give higher priority to adult immunisation in general and HZ in particular.

Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection.

Severe acute respiratory syndrome (SARS) is a highly contagious infectious disease which first emerged in late 2002, caused by a then novel human coronavirus, SARS coronavirus (SARS-CoV). The virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats. The re-emergence of SARS-CoV remains a valid concern due to the continual persistence of zoonotic SARS-CoVs and SARS-like CoVs (SL-CoVs) in bat reservoirs. In this study, the screening for the presence of SARS-specific T cells in a cohort of three SARS-recovered individuals at 9 and 11 years post-infection was carried out, and all memory T cell responses detected target the SARS-CoV structural proteins. Two CD8(+) T cell responses targeting the SARS-CoV membrane (M) and nucleocapsid (N) proteins were characterized by determining their HLA restriction and minimal T cell epitope regions. Furthermore, these responses were found to persist up to 11 years post-infection. An absence of cross-reactivity of these CD8(+) T cell responses against the newly-emerged Middle East respiratory syndrome coronavirus (MERS-CoV) was also demonstrated. The knowledge of the persistence of SARS-specific celullar immunity targeting the viral structural proteins in SARS-recovered individuals is important in the design and development of SARS vaccines, which are currently unavailable.

South-East Asia study alliance guidelines on the management of acne vulgaris in South-East Asian patients.

The management of acne in South-East Asia is unique, as Asian skin and local variables require a clinical approach unlike that utilized in other parts of the world. There are different treatment guidelines per country in the region, and a group of leading dermatologists from these countries convened to review these guidelines, discuss current practices and recent advances, and formulate consensus guidelines to harmonize the management of acne vulgaris in the region. Emphasis has been placed on formulating recommendations to impede the development of antibiotic resistance in Propionibacterium acnes. The group adopted the Acne Consensus Conference system for grading acne severity. The group recommends that patients may be treated with topical medications including retinoids, benzoyl peroxide (BPO), salicylic acid, a combination of retinoid and BPO, or a combination of retinoids and BPO with or without antibiotics for mild acne; topical retinoid with topical BPO and a oral antibiotic for moderate acne; and oral isotretinoin if the patient fails first-line treatment (a 6- or 8-week trial of combined oral antibiotics and topical retinoids with BPO) for severe acne. Maintenance acne treatment using topical retinoids with or without BPO is recommended. To prevent the development of antibiotic resistance, topical antibiotics should not be used as monotherapy or used simultaneously with oral antibiotics. Skin care, comprised of cleansing, moisturizing and sun protection, is likewise recommended. Patient education and good communication is recommended to improve adherence, and advice should be given about the characteristics of the skin care products patients should use.

Acute free-floating carotid artery thrombus causing stroke in a young patient: unique etiology and management using endovascular approach.

Atherosclerotic disease accounts for 20%-30% of strokes in the general population. In young adults, it is an unexpected event and its causes involve diverse pathologies. Herein, we describe a unique case of acute embolic stroke in a young adult patient due to the presence of a large clot in the right common and internal carotid arteries, as a result of an extrinsic cause. Surgical clot retrieval was considered unsafe at that point in time in view of the active inflammatory changes surrounding the affected vessels. This was eventually treated with a novel endovascular technique, a unique alternative to open surgery, with excellent clinical outcome. To our knowledge, the penumbra system has never been used for thrombus removal in a nonacute setting.

Echinocandins in invasive candidiasis.

We summarise a recent meeting, sponsored by Pfizer Inc., where experts in Asia shared their clinical experience in managing IC. The echinocandins have demonstrated good activity against non-albicans infections and also azole-resistant strains, both preclinically and in recent clinical trials. As well as proving efficacious, echinocandins have a favourable safety profile and are well tolerated, including among inpatient subpopulations, such as transplant recipients and those with renal or hepatic dysfunction. In addition the echinocandins generally have minimal drug-drug interactions, unlike the oral azoles, which have multiple effects on cytochrome P450-mediated drug metabolism. Echinocandins are characterised by a good safety profile, few drug-drug interactions and good susceptibilities. With the increase in potentially azole-resistant non-albicans infections, echinocandins may become the first-line treatment of choice for many patients.

Conditional ligands for Asian HLA variants facilitate the definition of CD8+ T-cell responses in acute and chronic viral diseases.

Conditional ligands have enabled the high-throughput production of human leukocyte antigen (HLA) libraries that present defined peptides. Immunomonitoring platforms typically concentrate on restriction elements associated with European ancestry, and such tools are scarce for Asian HLA variants. We report 30 novel irradiation-sensitive ligands, specifically targeting South East Asian populations, which provide 93, 63, and 79% coverage for HLA-A, -B, and -C, respectively. Unique ligands for all 16 HLA types were constructed to provide the desired soluble HLA product in sufficient yield. Peptide exchange was accomplished for all variants as demonstrated by an ELISA-based MHC stability assay. HLA tetramers with redirected specificity could detect antigen-specific CD8(+) T-cell responses against human cytomegalovirus, hepatitis B (HBV), dengue virus (DENV), and Epstein-Barr virus (EBV) infections. The potential of this population-centric HLA library was demonstrated with the characterization of seven novel T-cell epitopes from severe acute respiratory syndrome coronavirus, HBV, and DENV. Posthoc analysis revealed that the majority of responses would be more readily identified by our unbiased discovery approach than through the application of state-of-the-art epitope prediction. This flow cytometry-based technology therefore holds considerable promise for monitoring clinically relevant antigen-specific T-cell responses in populations of distinct ethnicity.

Immunogenicity and safety of recombinant tetravalent dengue vaccine (CYD-TDV) in individuals aged 2-45 y: Phase II randomized controlled trial in Singapore.

This was a multicenter, blinded, Phase II study (NCT00880893) conducted in Singapore. The primary objectives were to evaluate the safety of a tetravalent dengue vaccine (TDV) comprising four recombinant, live, attenuated viruses (CYD-TDV) and the dengue virus serotype-specific antibody responses before and 28 d after each vaccination. Participants were randomized 3:1 to receive three doses of CYD-TDV or a control vaccine at 0, 6 and 12 mo. Control vaccine was placebo for the first dose (all ages) and for subsequent doses, licensed hepatitis-A for children (aged 2-11 y) or influenza vaccine for adolescents (12-17 y) and adults (18-45 y). Between April and October 2009, 317 children, 187 adolescents and 696 adults were enrolled. In all age groups, reactogenicity was higher after the first injection of CYD-TDV than after placebo control. Reactogenicity after subsequent CYD-TDV doses was no higher than after the first dose, and tended to be lower or similar to that seen after active control vaccination. Seropositivity rates and geometric mean neutralizing antibody titers (GMTs; 1/dil) against all four dengue virus serotypes increased in all age groups after each of the three CYD-TDV doses. Post-dose 3, 66.5% of all participants were seropositive to all four serotypes, and 87.2% were seropositive to ≥ 3 serotypes; GMTs for all participants ranged from 43.0 against dengue virus serotype 1 to 100 against dengue virus serotype 4. GMTs were higher in children than in adolescents. These results support the continued development of CYD-TDV for the prevention of dengue disease.

Polyarthritis in four patients with chikungunya arthritis.

The incidence of chikungunya infection in Singapore has been on the rise since the first reported case in 2006. Acute polyarthritis, a common manifestation among affected patients, may precede fever and present with debilitating arthritis to rheumatologists, orthopaedists, internists and primary care physicians. The diagnosis of chikungunya infection requires careful history taking and a high index of suspicion, with supporting evidence from the reverse transcription-polymerase chain reaction or the chikungunya IgM serology test. Treatment of chikungunya arthritis usually involves non-steroidal anti-inflammatory drugs. Rarely, polyarthritis in chikungunya may persist even after resolution of the acute infection, necessitating treatment with disease-modifying anti-rheumatic drugs. In this article, we present the different manifestations of chikungunya arthritis in our local setting and review the literature.

Engineering T cells specific for a dominant severe acute respiratory syndrome coronavirus CD8 T cell epitope.

Severe acute respiratory syndrome (SARS) is a highly contagious and life threatening disease, with a fatality rate of almost 10%. The etiologic agent is a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), with animal reservoirs found in bats and other wild animals and thus the possibility of reemergence. In this study, we first investigated at 6 years postinfection whether SARS-specific memory T cells persist in SARS-recovered individuals, demonstrating that these subjects still possess polyfunctional SARS-specific memory CD4+ and CD8+ T cells. A dominant memory CD8+ T cell response against SARS-CoV nucleocaspid protein (NP; amino acids 216 to 225) was then defined in SARS-recovered individuals carrying HLA-B*40:01, a HLA-B molecule present in approximately one-quarter of subjects of Asian ethnicities. To reconstitute such a CD8+ T cell response, we isolated the alpha and beta T cell receptors of the HLA-B*40:01-restricted SARS-specific CD8+ T cells. Using T cell receptor gene transfer, we generated SARS-specific redirected T cells from the lymphocytes of normal individuals. These engineered CD8+ T cells displayed avidity and functionality similar to that of natural SARS-specific memory CD8+ T cells. They were able to degranulate and produce gamma interferon, tumor necrosis factor alpha, and macrophage inflammatory proteins 1α and 1ß after antigenic stimulation. Since there is no effective treatment against SARS, these transduced T cells specific for an immunodominant SARS epitope may provide a new avenue for treatment during a SARS outbreak.

SARS--my personal battle.

It isn't every day that a doctor becomes a patient. It is more peculiar when it occurs with an unknown mysterious epidemic respiratory illness that kills. Severe acute respiratory syndrome (SARS) gripped the world in 2003, spreading via air-links and throwing the global economy into disarray. As a practicing physician in Singapore, one of the first countries affected, I describe my first-hand account of my battle with this illness, how I acquired this illness in Singapore, and eventually quarantine in Frankfurt am Main, Germany.

Chronic hepatitis e infection resulting in graft failure in a liver transplant tourist.

Hepatitis E, usually an acute hepatitis in the immunocompetent, has a chronic form described in immunocompromised hosts. We report the clinical course and outcome of an adult liver transplant recipient whose posttransplant period was complicated by chronic hepatitis E, Epstein-Barr virus infection, and cellular rejection of the graft.

Severe infection with H1N1 requiring intensive care--lessons for preparedness programmes.

INTRODUCTION: The influenza pandemic has generated much interest in the press and the medical world. We report our experience with 15 cases of severe novel influenza A H1N1 (2009) infections requiring intensive care. The aim of this review is to improve our preparedness for epidemics and pandemics by studying the most severely affected patients. CLINICAL PICTURE: During the epidemic, hospitals were required to provide data on all confirmed H1N1 cases admitted to an intensive care unit (ICU) to the Ministry of Health. We abstracted information from this dataset for this report. To highlight learning points, we reviewed the case notes of, and report, the fi ve most instructive cases. TREATMENT: There were 15 cases admitted to an ICU from July 4, 2009 to August 30, 2009. Two patients died. CONCLUSIONS: The lessons we wish to share include the following: preparedness should include having intermediate-care facilities that also provide single room isolation and skilled nursing abilities, stringent visitor screening should be implemented and influenza may trigger an acute myocardial infarction in persons with risk factors.

Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal sites.

Fluorescent in situ hybridization (FISH) was used to investigate the chromosomal integration sites of human herpesvirus 6 (HHV-6) in phytohemagglutinin-stimulated leukocytes and B lymphocytes from Epstein-Barr virus transformed lymphoblastoid cell lines (LCLs). Five different chromosomal integration sites were found in nine individuals. Only one site was identified in each individual, each site was in the vicinity of the telomeric region and was on either the p or q arm of only one of the two chromosome homologues. The sites were 9q34.3, 10q26.3, 11p15.5, 17p13.3, and 19q 13.4, of which three have not been previously identified. For 9q34.3 the site of integration was further mapped using a locus-specific probe for 9q34.3 together with a pan-telomeric probe and both co-localized with the HHV-6 signal. Similarly an arm-specific telomeric probe for 19q co-localized with the HHV-6 signal. It was therefore concluded that the site of integration is actually within the telomere. The number of viral DNA copies/cell was calculated in blood, LCL cells and hair follicles and was one or more in every case for each of the nine individuals. This result was confirmed by FISH where 100% of cells gave an HHV-6 signal. These findings add to previous reports suggesting that integrated HHV-6 DNA is found in every cell in the body and transmitted vertically. Finally, including our data, worldwide seven different chromosomal sites of HHV-6 integration have now been identified. Large epidemiological studies of chromosomal integration are required to identify further telomeric sites, geographical or racial variation and possible clinical consequences.

Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis.

The prevalence and concentration of human herpesvirus 6 (HHV-6) DNA in the cerebrospinal fluid (CSF) of the immunocompetent in primary infection was compared with that in viral chromosomal integration. Samples from 510 individuals with suspected encephalitis, 200 young children and 310 older children and/or adults, and 12 other patients were tested. HHV-6 DNA concentration (log(10) copies/ml) was measured in CSF, serum, and whole blood using PCR. Serum HHV-6 immunoglobulin G antibody was measured by indirect immunofluorescence. Primary infection was defined by antibody seroconversion and/or a low concentration of HHV-6 DNA (<3.0 log(10) copies/ml) in a seronegative serum. Chromosomal integration was defined by a high concentration of viral DNA in serum (>/=3.5 log(10) copies/ml) or whole blood (>/=6.0 log(10) copies/ml). The prevalences of CSF HHV-6 DNA in primary infection and chromosomal integration were 2.5% and 2.0%, respectively, in the young children (<2 years) and 0% and 1.3%, respectively, in the older children and/or adults. The mean concentration of CSF HHV-6 DNA in 9 children with primary infection (2.4 log(10) copies/ml) was significantly lower than that of 21 patients with viral chromosomal integration (4.0 log(10) copies/ml). Only HHV-6B DNA was found in primary infection, whereas in viral integration, 4 patients had HHV-6A and 17 patients HHV-6B. Apart from primary infection, chromosomal integration is the most likely cause of HHV-6 DNA in the CSF of the immunocompetent. Our results show that any diagnosis of HHV-6 encephalitis or other type of active central nervous system infection should not be made without first excluding chromosomal HHV-6 integration by measuring DNA load in CSF, serum, and/or whole blood.

The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors.

A lesser-recognized form of human herpesvirus 6 (HHV-6) persistence is integration of the viral genome in a host chromosome and high viral copy numbers in blood or sera are characteristic of this phenomenon. A cross-sectional study was performed to determine the frequency of high HHV-6 viral loads in whole blood (>6 log(10) copies/ml) in a population of blood donors in London, UK. Blood samples from 500 anonymized blood donors were collected from one donation center, DNA extracted, and quantitative realtime PCR used to measure viral load. Four samples (0.8%) were found to have high viral copy numbers of HHV-6 (median 6.7 log(10) copies/ml; range 6.5- 6.9 log(10) copies/ml). Cellular DNA was also quantitated using qRT-PCR for beta-globin. By comparing these two results, we calculated that there were between two and five copies of HHV-6 present per cell in these four donors. The median viral load detected in plasma from the four individuals was 3.8 log(10) copies/ml (range 3.5-4.0 log(10) copies/ml). All samples were HHV-6 variant B. In addition, a retrospective analysis of all diagnostic blood samples performed for HHV-6 in our center showed a prevalence of 2.9% of high viral loads characteristic of integration. In conclusion, high viral copy numbers of HHV-6, representing a population of viral integration, is detected in 0.8% of UK blood donors. The presence of high HHV-6 viral loads in healthy normal individuals reiterates the need to consider the confounding effect of HHV-6 viral integration in any laboratory diagnosis of HHV-6 infection.

Clinical and epidemiological predictors of transmission in Severe Acute Respiratory Syndrome (SARS).

BACKGROUND: Only a minority of probable SARS cases caused transmission. We assess if any epidemiological or clinical factors in SARS index patients were associated with increased probability of transmission. METHODS: We used epidemiological and clinical data on probable SARS patients admitted to Tan Tock Seng Hospital. Using a case-control approach, index patients who had probable SARS who subsequently transmitted the disease to at least one other patient were analysed as "cases" against patients with no transmission as "controls", using multivariate logistic regression analysis. RESULTS: 98 index patients were available for analysis (22 with transmission, 76 with no transmission). Covariates positively associated with transmission in univariate analysis at p < 0.05 included delay to isolation (Day 7 of illness or later), admission to a non-isolation facility, pre-existing chronic respiratory disease and immunosuppressive disease, need for oxygen, shortness of breath, vomiting, and higher lactate dehydrogenase levels and higher neutrophil counts. In the multivariate analysis, only three factors were significant: delay to isolation, admission to a non-isolation facility and higher lactate dehydrogenase levels of >650 IU/L (OR 6.4, 23.8 and 4.7 respectively). CONCLUSION: Clinical and epidemiological factors can help us to explain why transmission was observed in some instances but not in others.