Coronavirus disease 2019 (COVID-19) outbreak on an in-patient medical unit associated with unrecognized exposures in common areas-Epidemiological and whole-genome sequencing investigation.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hospital outbreaks have been common and devastating during the coronavirus disease 2019 (COVID-19) pandemic. Understanding SARS-CoV-2 transmission in these environments is critical for preventing and managing outbreaks. DESIGN: Outbreak investigation through epidemiological mapping and whole-genome sequencing phylogeny. SETTING: Hospital in-patient medical unit outbreak in Toronto, Canada, from November 2020 to January 2021. PARTICIPANTS: The outbreak involved 8 patients and 10 staff and was associated with 3 patient deaths. RESULTS: Patients being cared for in geriatric chairs at the nursing station were at high risk for both acquiring and transmitting SARS-CoV-2 to other patients and staff. Furthermore, given the informal nature of these transmissions, they were not initially recognized, which led to further transmission and missing the opportunity for preventative COVID-19 therapies. CONCLUSIONS: During outbreak prevention and management, the risk of informal patient care settings, such as geriatric chairs, should be considered. During high-risk periods or during outbreaks, efforts should be made to care for patients in their rooms when possible.

A Longitudinal, Clinical, and Spatial Epidemiologic Analysis of a Large COVID-19 Long-Term Care Home Outbreak.

OBJECTIVES: COVID-19 has had devastating effects on long-term care homes across much of the world, and especially within Canada, with more than 50% of the mortality from COVID-19 in 2020 in these homes. Understanding the way in which the virus spreads within these homes is critical to preventing further outbreaks. DESIGN: Retrospective chart review. SETTINGS AND PARTICIPANTS: Long-term care home residents and staff in Ontario, Canada. METHODS: We conducted a longitudinal study of a large long-term care home COVID-19 outbreak in Ontario, Canada, using electronic medical records, public health records, staff assignments, and resident room locations to spatially map the outbreak through the facility. RESULTS: By analyzing the outbreak longitudinally, we were able to draw 3 important conclusions: (1) 84.5% had typical COVID-19 symptoms and only 15.5% of residents had asymptomatic infection; (2) there was a high attack rate of 85.8%, which appeared to be explained by a high degree of interconnectedness within the home exacerbated by staffing shortages; and (3) clustering of infections within multibedded rooms was common. CONCLUSION AND IMPLICATIONS: Low rates of asymptomatic infection suggest that symptom-based screening in residents remains very important for detecting outbreaks, a high degree of interconnectedness explains the high attack rate, and there is a need for improved guidance for homes with multibedded rooms on optimizing resident room movement to mitigate spread of COVID-19 in long-term care homes.

Blastomycosis with rapid-onset acute respiratory distress syndrome in an urban setting.

While blastomycosis is endemic to eastern USA and northwestern Ontario, acquisition is an anomaly in urban settings. We present a 54-year-old immunocompetent man from the greater Toronto area with no travel, who presented with a 3-week history of chest pain and dyspnoea. Initial radiographic workup revealed a mass-like opacification in the right apical mediastinum. Extensive investigations including bronchoscopy with bronchoalveolar lavage, mediastinal mass biopsy with fungal and mycobacterial cultures and multiple stains, and CT were unrevealing. The patient progressed to respiratory failure over 4 months. Ultimately, sputum and bone marrow cultures confirmed a diagnosis of disseminated blastomycosis. The patient required prolonged extracorporeal membrane oxygenation and ongoing ventilation postdecannulation. Our case highlights diagnostic challenges with blastomycosis, particularly in immunocompetent individuals with no travel to recreational areas, and emphasises the importance of maintaining a high index of suspicion and sending fungal cultures of appropriate specimens and/or cytopathology in clinically compatible cases.

A Hospital Partnership with a Nursing Home Experiencing a COVID-19 Outbreak: Description of a Multiphase Emergency Response in Toronto, Canada.

Nursing homes have become "ground zero" for the coronavirus disease 2019 (COVID-19) epidemic in North America, with homes experiencing widespread outbreaks, resulting in severe morbidity and mortality among their residents. This article describes a 371-bed acute-care hospital's emergency response to a 126-bed nursing home experiencing a COVID-19 outbreak in Toronto, Canada. Like other healthcare system responses to COVID-19 outbreaks in nursing homes, this hospital-nursing home partnership can be characterized in several phases: (1) engagement, relationship, and trust building; (2) environmental scan, team building, and immediate response; (3) early-phase response; and (4) stabilization and transition period. J Am Geriatr Soc 68:1376-1381, 2020.

Factors Affecting Pre-Travel Health Seeking Behaviour and Adherence to Pre-Travel Health Advice: A Systematic Review.

BACKGROUND: Recent years have seen unprecedented growth in international travel. Travellers are at high risk for acquiring infections while abroad and potentially bringing these infections back to their home country. There are many ways to mitigate this risk by seeking pre-travel advice (PTA), including receiving recommended vaccinations and chemoprophylaxis, however many travellers do not seek or adhere to PTA. We conducted a systematic review to further understand PTA-seeking behaviour with an ultimate aim to implement interventions that improve adherence to PTA and reduce morbidity and mortality in travellers. METHODS: We conducted a systematic review of published medical literature selecting studies that examined reasons for not seeking PTA and non-adherence to PTA over the last ten years. 4484 articles were screened of which 56 studies met our search criteria after full text review. RESULTS: The major reason for not seeking or non-adherence to PTA was perceived low risk of infection while travelling. Side effects played a significant role for lack of adherence specific to malaria prophylaxis. CONCLUSIONS: These data may help clinicians and public health providers to better understand reasons for non-adherence to PTA and target interventions to improve travellers understanding of potential and modifiable risks. Additionally, we discuss specific recommendations to increase public health education that may enable travellers to seek PTA.

The use of air travel data for predicting dengue importation to China: A modelling study.

BACKGROUND: Dengue virus importation from abroad is still the main driver of dengue incidence in China. Using global flight data to model importation may improve our understanding and prediction of dengue virus importation and onward transmission. METHODS: A retrospective analysis was performed of surveillance cases of dengue infections imported to China and volume of air traffic to China for the years 2005 through 2014, inclusive. The data were aggregated by year, destination province, and source country. Descriptive statistics were calculated, and a random effects negative binomial model was created to predict the number of imported cases based on the volume of travelers from dengue-endemic countries. RESULTS: There were 1,822 cases of imported dengue infections over the study period. Most imported cases are from a small number of high-incidence countries with a large volume of travel to China, most notably Myanmar (22% of cases). The number of imported cases of dengue infections increased by 5.9% for every 10% increase in travel volume from dengue-endemic countries. CONCLUSION: Patterns of air travel have a measurable impact on the importation of dengue to China. Modelling dengue importation risk may be a useful strategy to direct public health surveillance and interventions.

An Update on Malaria Rapid Diagnostic Tests.

PURPOSE OF REVIEW: Modern advances in malaria rapid diagnostic test (RDT) technology have increased demand for low-cost, easy-to-use assays in areas endemic for malaria. Substantial developments in diagnostic sensitivity and specificity, improvements in non-falciparum RDTs, and novel biotechnological innovations are gradually aligning the performance of RDTs with reference-level diagnostics including PCR and expert microscopy gold standards. RECENT FINDINGS: Trends have emerged in recent malaria RDT literature: (1) improvements in the sensitivity and specificity of RDTs for Plasmodium falciparum diagnosis, making them comparable to expert microscopic examination; (2) reduced false-positive and false-negative reactions with novel antibody development; (3) improved sensitivity and specificity capabilities of Plasmodium vivax-specific RDTs; (4) developing RDTs for co-endemic mixed infection differentiation; (5) significant improvements of RDTs for Plasmodium knowlesi; (6) a global push towards assessing and confronting the growing concerns of widespread pfhrp2 gene deletions; and (7) original innovation in loop-mediated isothermal amplification (LAMP) biotechnological RDT-like platforms that demonstrate promising performance characteristics for P. falciparum, P. vivax, and P. knowlesi infections. The past 5 years have been characterized by increasing demand for malaria RDTs, translating into meaningful improvements in performance and novel biotechnological innovation. Future work should facilitate the development of improved RDT platforms for Plasmodium ovale, P. knowlesi, and Plasmodium malariae, and surmount the issue of pfhrp2 gene deletions, while maintaining comparable performance to both PCR and expert microscopy reference standards.

Prolonged antibiotic use leading to Clostridium difficile colitis in an ill returned traveller with acute fascioliasis.

We report a case of a 29-year-old woman who presented to hospital with fever, right upper quadrant pain, marked eosinophilia, and liver abscesses after returning to Canada from Bali, Indonesia. Diagnostic delay and prolonged antibiotic use led to morbidity before the eventual diagnosis and treatment of fascioliasis.

Murine Plasmodium chabaudi malaria increases mucosal immune activation and the expression of putative HIV susceptibility markers in the gut and genital mucosae.

OBJECTIVE: To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure. BACKGROUND: Malaria and HIV have a high degree of geographical overlap and interact substantially within coinfected individuals. We used a murine model to test the hypothesis that malaria might also enhance HIV susceptibility at mucosal sites of HIV sexual exposure. METHODS: Female C57/BL6 mice were infected with Plasmodium chabaudi malaria using a standardized protocol. Blood, gastrointestinal tissues, upper and lower genital tract tissues, and iliac lymph nodes were sampled 10 days postinfection, and the expression of putative HIV susceptibility and immune activation markers on T cells was assessed by flow cytometry. RESULTS: P. chabaudi malaria increased expression of mucosal homing integrin α4ß7 on blood CD4 and CD8 T cells, and these α4ß7 T cells had significantly increased co-expression of both CCR5 and CD38. In addition, malaria increased expression of the HIV co-receptor CCR5 on CD4 T cells from the genital tract and gut mucosa as well as mucosal T-cell expression of the immune activation markers CD38, Major Histocompatibility Complex -II (MHC-II) and CD69. CONCLUSIONS: Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin α4ß7 in blood as well as gut and genital mucosal T-cell immune activation and HIV co-receptor expression. Human studies are required to confirm these murine findings and to examine whether malarial infection enhances the sexual acquisition of HIV.

Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria.

BACKGROUND: Severe falciparum malaria (SM) pathogenesis has been attributed, in part, to deleterious systemic host inflammatory responses to infection. High mobility group box 1 (HMGB1) protein is an important mediator of inflammation implicated in sepsis pathophysiology. METHODS: Plasma levels of HMGB1 were quantified in a cohort of febrile Ugandan children with Plasmodium falciparum infection, enrolled in a prospective observational case-controlled study, using a commercial enzyme-linked immunosorbent assay. The utility of HMGB1 to distinguish severe malaria (SM; n = 70) from uncomplicated malaria (UM; n = 33) patients and fatal (n = 21) versus non-fatal (n = 82) malaria, at presentation, was examined. Receiver operating characteristic curve analysis was used to assess the prognostic accuracy of HMGB1. The ability of P. falciparum-parasitized erythrocytes to induce HMGB1 from peripheral blood mononuclear cells was assessed in vitro. The effect of an anti-HMGB1 neutralizing antibody on disease outcome was assessed in the experimental Plasmodium berghei ANKA rodent parasite model of SM. Mortality and parasitaemia was assessed daily and compared to isotype antibody-treated controls. RESULTS: Elevated plasma HMGB1 levels at presentation were significantly associated with SM and a subsequent fatal outcome in paediatric patients with P. falciparum infection. In vitro, parasitized erythrocytes induced HMGB1 release from human peripheral blood mononuclear cells. Antibody-mediated neutralization of HMGB1 in the experimental murine model of severe malaria failed to reduce mortality. CONCLUSION: These data suggest that elevated HMGB1 is an informative prognostic marker of disease severity in human SM, but do not support HMGB1 as a viable target for therapeutic intervention in experimental murine SM.

Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria.

The host immune response contributes to the onset and progression of severe malaria syndromes, such as cerebral malaria. Adjunctive immunomodulatory strategies for severe malaria may improve clinical outcome beyond that achievable with artemisinin-based therapy alone. Here, we report that prophylaxis with inhaled nitric oxide significantly reduced systemic inflammation (lower TNF, IFNγ and MCP-1 in peripheral blood) and endothelial activation (decreased sICAM-1 and vWF, and increased angiopoeitin-1 levels in peripheral blood) in an experimental cerebral malaria model. Mice that received inhaled nitric oxide starting prior to infection had reduced parasitized erythrocyte accumulation in the brain, decreased brain expression of ICAM-1, and preserved vascular integrity compared to control mice.Inhaled nitric oxide administered in combination with artesunate, starting as late as 5.5 days post-infection, improved survival over treatment with artesunate alone (70% survival in the artesunate only vs. 100% survival in the artesunate plus iNO group, p = 0.03). These data support the clinical investigation of inhaled nitric oxide as a novel adjunctive therapy in patients with severe malaria.

S1P is associated with protection in human and experimental cerebral malaria.

Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL)(-/-) mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4(+) and CD8(+) T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.