Study protocol: infectious diseases consortium (I3D) for study on integrated and innovative approaches for management of respiratory infections: respiratory infections research and outcome study (RESPIRO).

BACKGROUND: Community-acquired respiratory infections are a leading cause of illness and death globally. The aetiologies of community-acquired pneumonia remain poorly defined. The RESPIRO study is an ongoing prospective observational cohort study aimed at developing pragmatic logistical and analytic platforms to accurately identify the causes of moderate-to-severe community-acquired pneumonia in adults and understand the factors influencing disease caused by individual pathogens. The study is currently underway in Singapore and has plans for expansion into the broader region. METHODS: RESPIRO is being conducted at three major tertiary hospitals in Singapore. Adults hospitalised with acute community-acquired pneumonia or lower respiratory tract infections, based on established clinical, laboratory and radiological criteria, will be recruited. Over the course of the illness, clinical data and biological samples will be collected longitudinally and stored in a biorepository for future analysis. DISCUSSION: The RESPIRO study is designed to be hypothesis generating, complementary to and easily integrated with other research projects and clinical trials. The detailed clinical database and biorepository will yield insights into the epidemiology and outcomes of community-acquired lower respiratory tract infections in Singapore and the surrounding region and offers the opportunity to deeply characterise the microbiology and immunopathology of community-acquired pneumonia.

Antibody Response of Heterologous vs Homologous Messenger RNA Vaccine Boosters Against the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant: Interim Results from the PRIBIVAC Study, a Randomized Clinical Trial.

BACKGROUND: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity have raised the need for booster vaccinations. However, which combination of coronavirus disease 2019 (COVID-19) vaccines offers the strongest immune response against the Omicron variant is unknown. METHODS: This randomized, participant-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. A total of 100 BNT162b2-vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; "BBB") or heterologous messenger RNA (mRNA) (BNT162b2 + BNT162b2 + mRNA-1273; "BBM") booster vaccine. The primary end point was the level of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and VOCs at day 28. RESULTS: A total of 51 participants were allocated to BBB and 49 to BBM; 50 and 48, respectively, were analyzed for safety and immunogenicity outcomes. At day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22 382 IU/mL; 95% confidence interval [CI], 18 210 to 27 517) vs BBM (29 751 IU/mL; 95% CI, 25 281 to 35 011; P = .034) as was the median level of neutralizing antibodies: BBB 99.0% (interquartile range [IQR], 97.9% to 99.3%) vs BBM 99.3% (IQR, 98.8% to 99.5%; P = .021). On subgroup analysis, significant higher mean spike antibody titer, median surrogate neutralizing antibody level against all VOCs, and live Omicron neutralization titer were observed only in older adults receiving BBM. Both vaccines were well tolerated. CONCLUSIONS: Heterologous mRNA-1273 booster vaccination compared with homologous BNT123b2 induced a stronger neutralizing response against the Omicron variant in older individuals. CLINICAL TRIALS REGISTRATION: NCT05142319.

Semiannual Versus Annual Influenza Vaccination in Older Adults in the Tropics: An Observer-blind, Active-comparator-controlled, Randomized Superiority Trial.

BACKGROUND: Antibody titres and vaccine effectiveness decline within 6 months after influenza vaccination in older adults. Biannual vaccination may be necessary to provide year-round protection in the tropics, where influenza circulates throughout the year. METHODS: Tropical Influenza Control Strategies (TROPICS1) was a single-center, 1:1 randomized, observer-blinded, active-comparator-controlled, superiority study in 200 community-resident adults aged ≥65 years. Participants received a standard-dose trivalent inactivated influenza vaccination (IIV3) at enrollment, and either tetanus-diphtheria-pertussis vaccination or IIV3 6 months later. The primary outcome was the proportion of participants with haemagglutination-inhibition (HI) geometric mean titre (GMT) ≥1:40 1 month after the second vaccination (month 7). Secondary outcomes included GMTs to month 12, the incidence of influenza-like illness (ILI), and adverse reactions after vaccination. RESULTS: At month 7, the proportion of participants with an HI tire ≥1:40 against A/H1N1 increased by 21.4% (95% confidence interval [CI] 8.6-33.4) in the semiannual vaccination group. This proportion was not significantly higher for A/H3N2 (4.3, 95% CI -1.1-10.8) or B (2.1, 95% CI -2.0-7.3). Semiannual vaccination significantly increased GMTs against A/H1N1 and A/H3N2, but not B, at month 7. Participants receiving a repeat vaccination of IIV3 reported a significantly lower incidence of ILI in the 6 months after the second vaccination (relative vaccine effectiveness 57.1%, 95% CI 0.6-81.5). The frequency of adverse events was similar after the first and second influenza vaccinations. CONCLUSIONS: Semiannual influenza vaccination in older residents of tropical countries has the potential to improve serological measures of protection against infection. Alternative vaccination strategies should also be studied. CLINICAL TRIALS REGISTRATION: NCT02655874.

Duration of Influenza Vaccine Effectiveness: A Systematic Review, Meta-analysis, and Meta-regression of Test-Negative Design Case-Control Studies.

Background: Whether influenza vaccination offers protection for the duration of an influenza season was called into question recently after analysis of data from test-negative design (TND) case-control studies. Method: The published literature was systematically reviewed to identify TND studies that estimated the change in vaccine effectiveness (VE) with respect to time since vaccination. Results: Fourteen studies were identified through the literature search as meeting eligibility criteria. Meta-analyses were performed to compare VE 15-90 days after vaccination to VE 91-180 days after vaccination. A significant decline in VE was observed for influenza virus subtype A/H3 (change in VE, -33; 95% confidence interval [CI], -57 to -12) and type B (change in VE, -19; 95% CI, -33 to -6). VE declined for influenza virus subtype A/H1, but this difference was not statistically significant (change in VE -8; 95% CI, -27 to 21). A multivariable mixed-effects meta-regression model indicated that the change VE was associated with the proportion of study participants who were cases and the proportion who were vaccinated controls (P < .05). This could reflect biological effects such as (1) mismatch between the vaccine received and the circulating strains (among cases), (2) herd immunity (among controls), or (3) the reduced power of individual TND studies in the later parts of an influenza outbreak. Conclusions: Exploration of new influenza vaccination strategies must be a priority for influenza control, particularly in tropical countries with year-round influenza virus activity.

Epidemiology and Relative Severity of Influenza Subtypes in Singapore in the Post-Pandemic Period from 2009 to 2010.

BACKGROUND: After 2009, pandemic influenza A(H1N1) [A(H1N1)pdm09] cocirculated with A(H3N2) and B in Singapore. METHODS: A cohort of 760 participants contributed demographic data and up to 4 blood samples each from October 2009 to September 2010. We compared epidemiology of the 3 subtypes and investigated evidence for heterotypic immunity through multivariable logistic regression using a generalized estimating equation. To examine age-related differences in severity between subtypes, we used LOESS (locally weighted smoothing) plots of hospitalization to infection ratios and explored birth cohort effects referencing the pandemic years (1957; 1968). RESULTS: Having more household members aged 5-19 years and frequent public transport use increased risk of infection, while preexisting antibodies against the same subtype (odds ratio [OR], 0.61; P = .002) and previous influenza infection against heterotypic infections (OR, 0.32; P = .045) were protective. A(H1N1)pdm09 severity peaked in those born around 1957, while A(H3N2) severity was least in the youngest individuals and increased until it surpassed A(H1N1)pdm09 in those born in 1952 or earlier. Further analysis showed that severity of A(H1N1)pdm09 was less than that for A(H3N2) in those born in 1956 or earlier (P = .021) and vice versa for those born in 1968 or later (P < .001), with no difference in those born between 1957 and 1967 (P = .632). CONCLUSIONS: Our findings suggest that childhood exposures had long-term impact on immune responses consistent with the theory of antigenic sin. This, plus observations on short-term cross-protection, have implications for vaccination and influenza epidemic and pandemic mitigation strategies.

Metronidazole- and carbapenem-resistant bacteroides thetaiotaomicron isolated in Rochester, Minnesota, in 2014.

Emerging antimicrobial resistance in members of the Bacteroides fragilis group is a concern in clinical medicine. Although metronidazole and carbapenem resistance have been reported in Bacteroides thetaiotaomicron, a member of the B. fragilis group, they have not, to the best of our knowledge, been reported together in the same B. thetaiotaomicron isolate. Herein, we report isolation of piperacillin-tazobactam-, metronidazole-, clindamycin-, ertapenem-, and meropenem-resistant B. thetaiotaomicron from a patient with postoperative intra-abdominal abscess and empyema. Whole-genome sequencing demonstrated the presence of nimD with at least a portion of IS1169 upstream, a second putative nim gene, two ß-lactamase genes (one of which has not been previously reported), two tetX genes, tetQ, ermF, two cat genes, and a number of efflux pumps. This report highlights emerging antimicrobial resistance in B. thetaiotaomicron and the importance of identification and antimicrobial susceptibility testing of selected anaerobic bacteria.

Climate change and its impact on infectious diseases in Asia.

ABSTRACT: Climate change, particularly increasing temperature, changes in rainfall, extreme weather events and changes in vector ecology, impacts the transmission of many climate-sensitive infectious diseases. Asia is the world's most populous, rapidly evolving and diverse continent, and it is already experiencing the effects of climate change. Climate change intersects with population, sociodemographic and geographical factors, amplifying the public health impact of infectious diseases and potentially widening existing disparities. In this narrative review, we outline the evidence of the impact of climate change on infectious diseases of importance in Asia, including vector-borne diseases, food- and water-borne diseases, antimicrobial resistance and other infectious diseases. We also highlight the imperative need for strategic intersectoral collaboration at the national and global levels and for the health sector to implement adaptation and mitigation measures, including responsibility for its own greenhouse gas emissions.

Association of systemic vitamin D on the course of dengue virus infection in adults: a single-centre dengue cohort study at a large institution in Singapore.

INTRODUCTION: Host immune responses may impact dengue severity in adults. Vitamin D has multiple immunomodulatory effects on innate and adaptive immunity. METHODS: We evaluated the association between systemic 25-hydroxyvitamin D [25-(OH) D] and dengue disease severity in adults. We measured plasma for total 25-(OH) D levels with an electrochemiluminescence immunoassay using stored samples from participants with laboratory confirmed dengue who were prospectively enrolled in 2012-2016 at our institution. RESULTS: 80 participants (median age 43 years) were enrolled. Six participants had severe dengue based on the World Health Organisation (WHO) 1997 criteria (i.e. dengue haemorrhagic fever/dengue shock syndrome) and another six had severe dengue based on the WHO 2009 criteria. Median 25-(OH) D at acute phase of dengue was 6.175 µg/L (interquartile range 3.82-8.21; range 3.00-15.29) in all participants. 25-(OH) D showed inverse linear trend with severe dengue manifestations based on the WHO 2009 criteria (aRR 0.72; 95% confidence interval 0.57-0.91; p < 0.01) after adjustment for age, gender and ethnicity. CONCLUSION: Limited studies have evaluated the role of systemic 25-(OH) D on dengue severity. Our study found low systemic 25-(OH) D was associated with increased dengue disease severity, particularly for severe bleeding that was not explained by thrombocytopenia. Further studies investigating the underlying immune mechanisms and effects on the vascular endothelium are needed.

Why Climate Action Is Global Health Action.

The impacts of climate change on global health and populations are far-reaching, yet they disproportionately affect vulnerable groups, thereby exacerbating disparities. As humanity reckons with the emergency of climate change, our global health community needs to contend with our own contributions to greenhouse gas emissions. We know that transformation is possible and that climate action is the antidote to the existential challenge. As a global health community, we have an immense opportunity, responsibility, and commitment to lead, support, inspire, and empower climate action, research, and innovation that align deeply with our mission and core values.

DYNAMIC cohort study evaluating metabolic predictors of influenza vaccine immune response in older adults.

Immunosenescence (age-related immune dysfunction) and inflamm-aging contribute to suboptimal immune responses in older adults to standard-dose influenza vaccines, which may be exacerbated in those with metabolic co-morbidities. We sought to investigate metabolic factors/predictors of influenza vaccine immune response in an older adult (age ≥65 years) cohort in Singapore, where influenza typically circulates year-round. The primary outcome for the DYNAMIC prospective cohort study was haemagglutination-inhibition titer (HAI) response to each of the trivalent inactivated influenza vaccine strains at day 28 (D28) compared to baseline (D0), as assessed by seroconversion and D28/D0 log2 HAI fold rise. Baseline blood samples were tested for total Vitamin D (25-(OH) D) levels. We enrolled 234 participants in June-Dec 2017. Two hundred twenty completed all study visits. The median age was 71 [IQR 68-75] years, 67 (30.5%) had diabetes mellitus (DM), and the median BMI was 24.9 [IQR 22.2-27.8] kg/m2. Median baseline totals 25-(OH) D was 29 [IQR: 21-29] ng/ml. Age, DM, obesity, and baseline 25-(OH) D were not associated with HAI fold rise in multivariable analysis. More recent prior influenza vaccination and higher baseline HAI titers were associated with lower HAI fold rise for influenza A/HK/H3N2. Physical activity was associated with a higher HAI fold rise for influenza A/HK/H3N2 in a dose-response relationship (p-test for trend = 0.015). Older adults with well-controlled metabolic co-morbidities retain HAI response to the influenza vaccine, and physical activity had a beneficial effect on immune response, particularly for influenza A/HK/H3N2.

Vaccine-associated Rubella - a report of two cases and a review of the literature.

We report the clinical characteristics of two adult patients, presenting with a typical erythematous rash consistent with rubella disease after MMR vaccination. Both patients had an uncomplicated clinical course and recovered uneventfully. One patient was confirmed to have vaccine-associated rubella via sequencing of virus isolated in viral culture. The other patient had a pharyngeal swab positive for rubella virus PCR, with sequencing matching the vaccine strain. There are few reports of clinical disease from rubella vaccine-strains in the literature. Previous authors have reported severe disseminated vaccine-associated rubella in both immunodeficient and immunocompetent patients. Further study is required to ascertain the incidence, risk factors, and clinical characteristics of this condition; as well as investigate the extent of horizontal transmission to guide infection control recommendations.

Psychological impact of repeated epidemic exposure on healthcare workers: findings from an online survey of a healthcare workforce exposed to both SARS (severe acute respiratory syndrome) and COVID-19.

OBJECTIVE: To measure the psychological well-being of healthcare workers (HCWs) during this COVID-19 pandemic and examine the experiences of the subgroup of participants who were also HCWs during the 2003 SARS epidemic. DESIGN: Anonymous online survey adapted from a similar study conducted during the SARS epidemic, disseminated from July 2020 to August 2020. SETTING: Nine healthcare institutions across Singapore ranging from primary care, community care, tertiary care and specialised referral centres. PARTICIPANTS: Employees working in the participating healthcare institutions. RESULTS: Of 3828 survey returns, 3616 had at least one completed item on the questionnaire. Majority were female (74.7%), nurses (51.7%), foreign-born (53.2%) and not working in the tertiary care setting (52.1%). The median score on the Impact of Events Scale (IES) was 15 (IQR 23) and 28.2% of the sample scored in the moderate/severe range. 22.7% of the participants were also HCWs during SARS and more than half of them felt safer and better equipped in the current pandemic. 25.2% of SARS HCWs and 25.9% of non-SARS HCWs had moderate/severe IES scores (p=0.904). After adjusting for age, marital status, parity and length of work experience, racial minority groups and living apart from family were independent predictors of high IES regardless of prior SARS epidemic experience. Daily exposure to confirmed or suspect COVID-19 cases increased the odds of high IES for non-SARS HCWs only. CONCLUSIONS AND RELEVANCE: Overall, while 28% of HCWs in our study suffered from significant trauma-related psychological symptoms regardless of prior experience with the SARS epidemic, those with prior experience reported feeling safer and better equipped, finding the workload easier to manage, as well as having more confidence in their healthcare leaders. We recommend for more trauma-informed support strategies for our HCWs especially those from racial minority groups, who are foreign-born and isolated from their families.

SARS-CoV-2 seroprevalence and transmission risk factors among high-risk close contacts: a retrospective cohort study.

BACKGROUND: The proportion of asymptomatic carriers and transmission risk factors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among household and non-household contacts remains unclear. In Singapore, extensive contact tracing by the Ministry of Health for every diagnosed COVID-19 case, and legally enforced quarantine and intensive health surveillance of close contacts provided a rare opportunity to determine asymptomatic attack rates and SARS-CoV-2 transmission risk factors among community close contacts of patients with COVID-19. METHODS: This retrospective cohort study involved all close contacts of confirmed COVID-19 cases in Singapore, identified between Jan 23 and April 3, 2020. Household contacts were defined as individuals who shared a residence with the index COVID-19 case. Non-household close contacts were defined as those who had contact for at least 30 min within 2 m of the index case. All patients with COVID-19 in Singapore received inpatient treatment, with access restricted to health-care staff. All close contacts were quarantined for 14 days with thrice-daily symptom monitoring via telephone. Symptomatic contacts underwent PCR testing for SARS-CoV-2. Secondary clinical attack rates were derived from the prevalence of PCR-confirmed SARS-CoV-2 among close contacts. Consenting contacts underwent serology testing and detailed exposure risk assessment. Bayesian modelling was used to estimate the prevalence of missed diagnoses and asymptomatic SARS-CoV-2-positive cases. Univariable and multivariable logistic regression models were used to determine SARS-CoV-2 transmission risk factors. FINDINGS: Between Jan 23 and April 3, 2020, 7770 close contacts (1863 household contacts, 2319 work contacts, and 3588 social contacts) linked to 1114 PCR-confirmed index cases were identified. Symptom-based PCR testing detected 188 COVID-19 cases, and 7582 close contacts completed quarantine without a positive SARS-CoV-2 PCR test. Among 7518 (96·8%) of the 7770 close contacts with complete data, the secondary clinical attack rate was 5·9% (95% CI 4·9-7·1) for 1779 household contacts, 1·3% (0·9-1·9) for 2231 work contacts, and 1·3% (1·0-1·7) for 3508 social contacts. Bayesian analysis of serology and symptom data obtained from 1150 close contacts (524 household contacts, 207 work contacts, and 419 social contacts) estimated that a symptom-based PCR-testing strategy missed 62% (95% credible interval 55-69) of COVID-19 diagnoses, and 36% (27-45) of individuals with SARS-CoV-2 infection were asymptomatic. Sharing a bedroom (multivariable odds ratio [OR] 5·38 [95% CI 1·82-15·84]; p=0·0023) and being spoken to by an index case for 30 min or longer (7·86 [3·86-16·02]; p<0·0001) were associated with SARS-CoV-2 transmission among household contacts. Among non-household contacts, exposure to more than one case (multivariable OR 3·92 [95% CI 2·07-7·40], p<0·0001), being spoken to by an index case for 30 min or longer (2·67 [1·21-5·88]; p=0·015), and sharing a vehicle with an index case (3·07 [1·55-6·08]; p=0·0013) were associated with SARS-CoV-2 transmission. Among both household and non-household contacts, indirect contact, meal sharing, and lavatory co-usage were not independently associated with SARS-CoV-2 transmission. INTERPRETATION: Targeted community measures should include physical distancing and minimising verbal interactions. Testing of all household contacts, including asymptomatic individuals, is warranted. FUNDING: Ministry of Health of Singapore, National Research Foundation of Singapore, and National Natural Science Foundation of China.

Pyomyositis in the United States 2002-2014.

OBJECTIVES: Primary pyomyositis is a bacterial infection of skeletal muscle first recognized in tropical regions of the world but needing characterization in temperate climates. METHODS: This population-based study used the Healthcare Utilization Project/Nationwide Inpatient Sample database to characterize the trends of pyomyositis admissions in the United States from 2002-2014 using ICD-9 diagnostic codes. RESULTS: We found a concerning more than three-fold increase in the incident pyomyositis admissions over our study period. The median length of stay was over twice as long compared to other hospitalized patients. Patients with pyomyositis were younger and more likely to be male and Black. There were more cases in the West and South compared to Midwest and Northeast. Age-adjusted odds ratios revealed significant association of pyomyositis with HIV, types 1 and 2 diabetes mellitus, hematologic malignancy, organ transplant, malnutrition, chronic kidney disease, obesity, and rheumatoid arthritis. The most commonly identified bacterial diagnosis was Staphylococcus aureus. Pseudomonas species were the most commonly identified gram-negative bacteria. CONCLUSION: This nationwide review of pyomyositis in the United States suggests a concerning increase in incidence and provides information on the trends, demographics, risk factors, and causative organisms for pyomyositis in the United States.

Pregnancy Outcomes in COVID-19: A Prospective Cohort Study in Singapore.

INTRODUCTION: Pregnant women are reported to be at increased risk of severe coronavirus disease 2019 (COVID-19) due to underlying immunosuppression during pregnancy. However, the clinical course of COVID-19 in pregnancy and risk of vertical and horizontal transmission remain relatively unknown. We aim to describe and evaluate outcomes in pregnant women with COVID-19 in Singapore. METHODS: Prospective observational study of 16 pregnant patients admitted for COVID-19 to 4 tertiary hospitals in Singapore. Outcomes included severe disease, pregnancy loss, and vertical and horizontal transmission. RESULTS: Of the 16 patients, 37.5%, 43.8% and 18.7% were infected in the first, second and third trimesters, respectively. Two gravidas aged ≥35 years (12.5%) developed severe pneumonia; one patient (body mass index 32.9kg/m2) required transfer to intensive care. The median duration of acute infection was 19 days; one patient remained reverse transcription polymerase chain reaction (RT-PCR) positive >11 weeks from diagnosis. There were no maternal mortalities. Five pregnancies produced term live-births while 2 spontaneous miscarriages occurred at 11 and 23 weeks. RT-PCR of breast milk and maternal and neonatal samples taken at birth were negative; placenta and cord histology showed non-specific inflammation; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulins were elevated in paired maternal and umbilical cord blood (n=5). CONCLUSION: The majority of COVID-19 infected pregnant women had mild disease and only 2 women with risk factors (obesity, older age) had severe infection; this represents a slightly higher incidence than observed in age-matched non-pregnant women. Among the women who delivered, there was no definitive evidence of mother-to-child transmission via breast milk or placenta.

Aggressive subcutaneous panniculitis-like T-cell lymphoma with hemophagocytosis in two children (subcutaneous panniculitis-like T-cell lymphoma).

Subcutaneous panniculitis-like T-cell lymphoma is an uncommon form of cutaneous lymphoma in the pediatric population. It is characterized histologically by subcutaneous infiltration of pleomorphic cytotoxic T cells, mimicking a lobular panniculitis. Although usually described as having an indolent clinical course, the condition may be complicated by systemic involvement and hemophagocytic syndrome, resulting in a poorer prognosis. We present two pediatric patients with aggressive forms of subcutaneous panniculitis-like T-cell lymphoma complicated by hemophagocytic syndrome, and discuss the current literature.

Spontaneous pneumomediastinum and epidural pneumatosis in an adolescent precipitated by weight lifting: a case report and review.

Spontaneous pneumomediastinum is an uncommon condition in athletes. The most common cause of spontaneous pneumomediastinum is alveolar rupture into the bronchovascular sheath as a result of increased intrathoracic pressure. Epidural pneumatosis (pneumorrhachis) has been rarely associated with spontaneous pneumomediastinum. In this article, we describe a case of a 17-year-old male who presented with neck and chest pain that started 14 hours after a weight lifting session. He developed both a pneumomediastinum and epidural pneumatosis--an association that is rarely reported in a setting without trauma. To our knowledge, there have been only 5 case reports of pneumomediastinum precipitated by weight lifting. Improper breathing technique during weight lifting can increase the intrathoracic pressure and the risk of pneumomediastinum; hence, it is important that physicians and trainers who work with athletes provide instructions regarding proper breathing techniques during weight lifting. In addition to the case discussion, this article reviews spontaneous pneumomediastinum and epidural pneumatosis.