Powassan Virus Encephalitis after Tick Bite, Manitoba, Canada.

A case of Powassan encephalitis occurred in Manitoba, Canada, after the bite of a black-legged tick. Awareness of this emerging tickborne illness is needed because the number of vector tick species is growing. No specific treatment options exist, and cases with illness and death are high. Prevention is crucial.

Body Louse Pathogen Surveillance among Persons Experiencing Homelessness, Canada, 2020-2021.

We analyzed body lice collected from persons experiencing homelessness in Winnipeg, Manitoba, Canada, during 2020-2021 to confirm vector species and ecotype and to identify louseborne pathogens. Of 556 lice analyzed from 7 persons, 17 louse pools (218 lice) from 1 person were positive for the louseborne bacterium Bartonella quintana.

Exome Sequencing of a Blastomycosis Case-Control Cohort From Manitoba and Northwestern Ontario, Canada.

BACKGROUND: Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada. METHODS: Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. RESULTS: Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). CONCLUSIONS: The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Impact of non-pharmaceutical interventions and vaccination on COVID-19 outbreaks in Nunavut, Canada: a Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Nunavut, the northernmost Arctic territory of Canada, experienced three community outbreaks of the coronavirus disease 2019 (COVID-19) from early November 2020 to mid-June 2021. We sought to investigate how non-pharmaceutical interventions (NPIs) and vaccination affected the course of these outbreaks. METHODS: We used an agent-based model of disease transmission to simulate COVID-19 outbreaks in Nunavut. The model encapsulated demographics and household structure of the population, the effect of NPIs, and daily number of vaccine doses administered. We fitted the model to inferred, back-calculated infections from incidence data reported from October 2020 to June 2021. We then compared the fit of the scenario based on case count data with several counterfactual scenarios without the effect of NPIs, without vaccination, and with a hypothetical accelerated vaccination program whereby 98% of the vaccine supply was administered to eligible individuals. RESULTS: We found that, without a territory-wide lockdown during the first COVID-19 outbreak in November 2020, the peak of infections would have been 4.7 times higher with a total of 5,404 (95% CrI: 5,015-5,798) infections before the start of vaccination on January 6, 2021. Without effective NPIs, we estimated a total of 4,290 (95% CrI: 3,880-4,708) infections during the second outbreak under the pace of vaccination administered in Nunavut. In a hypothetical accelerated vaccine rollout, the total infections during the second Nunavut outbreak would have been 58% lower, to 1,812 (95% CrI: 1,593-2,039) infections. Vaccination was estimated to have the largest impact during the outbreak in April 2021, averting 15,196 (95% CrI: 14,798-15,591) infections if the disease had spread through Nunavut communities. Accelerated vaccination would have further reduced the total infections to 243 (95% CrI: 222-265) even in the absence of NPIs. CONCLUSIONS: NPIs have been essential in mitigating pandemic outbreaks in this large, geographically distanced and remote territory. While vaccination has the greatest impact to prevent infection and severe outcomes, public health implementation of NPIs play an essential role in the short term before attaining high levels of immunity in the population.

Inguinal Ulceroglandular Tularemia Caused by Francisella tularensis Subspecies holarctica, Canada.

Tularemia is a zoonotic disease caused by the gram-negative coccobacillus Francisella tularensis, a Biosafety Level 3 pathogen and potential agent of bioterrorism. We describe 2 cases of perigenital ulcer disease caused by Francisella tularensis subspecies holarctica in Manitoba, Canada. These cases caused inadvertent exposure among laboratory personnel.

Simulating the effect of school closure during COVID-19 outbreaks in Ontario, Canada.

BACKGROUND: The province of Ontario, Canada, has instituted indefinite school closures (SC) as well as other social distancing measures to mitigate the impact of the novel coronavirus disease 2019 (COVID-19) pandemic. We sought to evaluate the effect of SC on reducing attack rate and the need for critical care during COVID-19 outbreaks, while considering scenarios with concurrent implementation of self-isolation (SI) of symptomatic cases. METHODS: We developed an age-structured agent-based simulation model and parameterized it with the demographics of Ontario stratified by age and the latest estimates of COVID-19 epidemiologic characteristics. Disease transmission was simulated within and between different age groups by considering inter- and intra-group contact patterns. The effect of SC of varying durations on the overall attack rate, magnitude and peak time of the outbreak, and requirement for intensive care unit (ICU) admission in the population was estimated. Secondly, the effect of concurrent community-based voluntary SI of symptomatic COVID-19 cases was assessed. RESULTS: SC reduced attack rates in the range of 7.2-12.7% when the duration of SC increased from 3 to 16 weeks, when contacts among school children were restricted by 60-80%, and in the absence of SI by mildly symptomatic persons. Depending on the scenario, the overall reduction in ICU admissions attributed to SC throughout the outbreak ranged from 3.3 to 6.7%. When SI of mildly symptomatic persons was included and practiced by 20%, the reduction of attack rate and ICU admissions exceeded 6.3% and 9.1% (on average), respectively, in the corresponding scenarios. CONCLUSION: Our results indicate that SC may have limited impact on reducing the burden of COVID-19 without measures to interrupt the chain of transmission during both pre-symptomatic and symptomatic stages. While highlighting the importance of SI, our findings indicate the need for better understanding of the epidemiologic characteristics of emerging diseases on the effectiveness of social distancing measures.

Clinical utility of echocardiography for the diagnosis of native valve infective endocarditis in Staphylococcus aureus bacteremia.

BACKGROUND: The incidence of Staphylococcus aureus infective endocarditis (IE) is steadily rising due to advances in health care delivery. Routine echocardiography is essential in the management of Staphylococcus aureus bacteremia (SAB). The aim of this retrospective cohort study was to characterize the real-world use of echocardiography in adult patients with SAB and native valve S aureus IE. METHODS: Using an academic hospital microbiological database, all cases of SAB in adults between 2010 and 2016 were identified. Demographic, echocardiographic, and clinical features were recorded. RESULTS: A total of 738 episodes of SAB were identified, of which 504 (68%) patients underwent transthoracic echocardiography (TTE) within 30 days. Of 73 patients with definite IE, 46 (63%) patients had definite IE diagnosed on the initial TTE. An additional 14 (19%) patients had definite IE diagnosed on repeat TTE, 6 (8%) on transesophageal echocardiography (TEE), and 7 (10%) were diagnosed without fulfilling Duke echocardiographic criteria. The yield of repeat TTE was comparable to that of TEE for identifying new vegetations not identified on the initial TTE (17% vs 21%, P = .78). CONCLUSIONS: Most cases of IE in SAB were identified using TTE alone, with repeat TTE improving the diagnostic yield in the setting of clinical decompensation.

The value of program science to optimize knowledge brokering on infectious diseases for public health.

BACKGROUND: Knowledge translation (KT) and related terms have variously been defined as process and as products. In this paper we contribute to debates on effective KT, specifically knowledge brokering, by describing an adaptation of Program Science that aligns with the real-world of public health activities. We describe an adaptation of the Program Science framework to our knowledge translation and brokering planning and projects at the National Collaborating Centre for Infectious Diseases. The systematic approach allows for layering of knowledge year to year and translating knowledge from one infectious disease content area to another. Using a recent forum on syphilis outbreaks as an example, we also demonstrate the value of using Program Science to shape the design and delivery of the knowledge brokering event. CONCLUSION: The use of scientific knowledge to improve public health program design, implementation and evaluation forms the basis for the program science framework. Providing the right public health information to the right audience at the right time can foster long-term outcomes of networks and new partnerships which can potentially improve delivery of public health services.

Clonal Clusters and Virulence Factors of Group C and G Streptococcus Causing Severe Infections, Manitoba, Canada, 2012-2014.

The incidence of group C and G Streptococcus (GCGS) bacteremia, which is associated with severe disease and death, is increasing. We characterized clinical features, outcomes, and genetic determinants of GCGS bacteremia for 89 patients in Winnipeg, Manitoba, Canada, who had GCGS bacteremia during 2012-2014. Of the 89 patients, 51% had bacteremia from skin and soft tissue, 70% had severe disease features, and 20% died. Whole-genome sequencing analysis was performed on isolates derived from 89 blood samples and 33 respiratory sample controls: 5 closely related genetic lineages were identified as being more likely to cause invasive disease than non-clade isolates (83% vs. 57%, p = 0.002). Virulence factors cbp, fbp, speG, sicG, gfbA, and bca clustered clonally into these clades. A clonal distribution of virulence factors may account for severe and fatal cases of bacteremia caused by invasive GCGS.

A novel immune biomarker IFI27 discriminates between influenza and bacteria in patients with suspected respiratory infection.

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with in vitro experiments using well-established infection models.We identified a single-gene biomarker, IFI27, which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections.IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection.

Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis.

OBJECTIVES: This study aimed to evaluate the immuno-prophylactic and -therapeutic effect of p110δ-specific pharmacological inhibitors (CAL-101 and IC87114), either alone or in combination with amphotericin B, against experimental cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). METHODS: Female BALB/c mice were infected intravenously with Leishmania donovani or subcutaneously with Leishmania major Prophylactic treatment was initiated 24 h prior to infection, whereas therapeutic treatments with or without amphotericin B were initiated either 1 week or 2 weeks post-infection. At different times post-infection, mice were sacrificed and parasite burden, regulatory T cell (Treg) numbers and cytokine production were assessed in the liver, spleen, draining lymph nodes and footpads. In addition, direct cytolytic effects of the inhibitors on parasite growth in axenic cultures and inside infected and uninfected macrophages were also assessed. RESULTS: Prophylactic and therapeutic administration of p110δ pharmacological inhibitors significantly reduced cutaneous lesion (in CL) and parasite burdens (in VL and CL) in the spleens, livers and footpads of infected mice. The reduction in parasite burden was associated with a concomitant reduction in Treg numbers and cytokine production by liver, spleen and lymph node cells. Combined low-dose CAL-101 and amphotericin B therapy caused complete clearance of parasites in mice infected with L. donovani CONCLUSIONS: Our studies clearly show a novel therapeutic option for leishmaniasis based on CAL-101 monotherapy or CAL-101 and amphotericin B combination therapy. These observations have important and direct implications for antimicrobial immunotherapy and drug/vaccine development against leishmaniasis.

Systemic inflammation before and after antiretroviral therapy initiation as a predictor of immune response among HIV-infected individuals in Manitoba.

INTRODUCTION: Despite the life-prolonging effects of Highly Active Antiretroviral Therapy (HAART), persons with HIV are still prone to higher rates of non-AIDS related morbidity (such as heart, kidney, and liver disease) than the general public. This is likely due to chronic immune activation and inflammation that persists in HIV-positive persons despite virological suppression. What remains undetermined, however, is whether a link exists between chronic inflammation/immune activation and suboptimal immune recovery on HAART. The hypothesis of the present study is that higher levels of systemic subclinical inflammation and immune activation are linked with suboptimal immune recovery on HAART. METHODS: Fifteen eligible patients from the Manitoba HIV program were enrolled and followed for up to two years; blood samples were drawn at 4 timepoints each, and concentrations of 21 proinflammatory markers were measured. Patients were grouped according to CD4:CD8 recovery at viral suppression, and the inflammatory profiles of the two groups were compared. RESULTS AND CONCLUSIONS: APRIL and BAFF are higher in those with poor recovery at the point of viral suppression, but were also higher in this group at the onset of therapy and through the three additional follow-up visits. TNF-R1, CD163, and Osteopontin, were also in higher concentrations at the outset of therapy and beyond. These five molecules could thus see potential use in the future as biomarkers of likely poor immune recovery. Future work should focus on replicating these findings with larger cohorts.

Prior history of testing for syphilis, hepatitis B and hepatitis C among a population-based cohort of HIV-positive individuals and their HIV-negative controls.

Understanding patterns of serological testing for hepatitis B & C, and syphilis among HIV-positive individuals, prior to HIV diagnosis, can inform HIV diagnosis, engagement and prevention strategies. This was a population-based, retrospective analysis of prior serological testing among HIV-positive individuals in Manitoba, Canada. HIV cases were age-, sex- and region-matched to HIV-negative controls at a 1:5 ratio. Conditional logistic regression was used to examine previous serological tests and HIV status. Odds ratios (ORs) and their 95% confidence intervals (95% CI) were reported. A total of 193 cases and 965 controls were included. In the 5 years prior to diagnosis, 50% of cases had at least one test, compared to 26% of controls. Compared to those who did not have serological testing in the 5 years prior to HIV infection, those who had one serological test were at twice the odds of being HIV positive (OR: 1.9, 95% CI: 1.2-2.9), while those with 2 or more tests were at even higher odds (OR: 5.5, 95%CI: 3.7-8.4). HIV cases had higher serological testing rates. Interactions between public health and other healthcare providers should be strengthened.

Evaluation of the Utility of Point-of-Care HIV Testing on a Canadian Internal Medicine Inpatient Unit.

Point-of-care (POC) HIV testing has been shown to be an acceptable method for increasing HIV testing uptake. To date, no studies have examined the use of POC testing for routine HIV screening on the medicine inpatient unit. A prospective cross-sectional study was conducted over a three-month period in July, August, and October 2016 to evaluate the prevalence of undiagnosed HIV and the attitudes towards routine POC HIV testing. Patients admitted directly to medicine inpatient teaching units at a tertiary hospital in Winnipeg, Canada, were approached for participation. The POC HIV test was administered at the bedside. Reactive and indeterminate tests were confirmed with standard serological HIV testing. Participants were given a questionnaire regarding their attitudes towards POC testing on the unit. Although no cases of previously undiagnosed HIV were identified during the study period, only 35% of participants were found to have ever had HIV testing previously. The majority of participants were satisfied with the POC testing experience and would choose to have the POC testing again. Overall, the low rate of outpatient testing highlights the need for routine HIV testing on an inpatient basis.

Unique cytokine and chemokine patterns in bronchoalveolar lavage are associated with specific causative pathogen among HIV infected patients with pneumonia, in Medellin, Colombia.

We wanted to investigate the pro-inflammatory cytokine/chemokine profile associated with the etiological agents identified in HIV patients. Immunosuppressed patients admitted to two hospitals in Medellin, Colombia, with clinical and radiographic diagnosis of pneumonia were enrolled in the study. After consent, bronchoalveolar lavage (BAL) was collected for bacterial, mycobacterial and fungal diagnosis. All patients were followed for a year. A stored BAL sample was used for cytokine/chemokine detection and measurement using commercial, magnetic human cytokine bead-based 19-plex assays. Statistical analysis was performed by assigning cytokine/chemokine concentrations levels into <25 percentile (lower), 25-75 percentile (normal) and >75 percentile (higher). Principal component analysis (PCA) and Kruskal-Wallis analysis were conducted to identify the clustering of cytokines with the various infectious etiologies (fungi, Mycobacterium tuberculosis - MTB, and bacteria). Average age of patients was 35, of whom 77% were male, and the median CD4 count of 33cells/µl. Of the 57 HIV infected patients, in-hospital mortality was 12.3% and 33% died within a year of follow up. The PCA revealed increased IL-10, IL-12, IL-13, IL-17, Eotaxin, GCSF, MIP-1α, and MIP-1ß concentrations to be associated with MTB infection. In patients with proven fungal infection, low concentrations of IL-1RA, IL-8, TNF-α and VEGF were identified. Bacterial infections displayed a distinct cytokine pattern and were not misclassified using the MTB or fungi cytokine patterns (p-value<0.0001). Our results indicate a unique pattern of pro-inflammatory cytokine/chemokine, allowing differentiation between bacterial and non-bacterial pathogens. Moreover, we found distinct, if imperfectly discriminatory, cytokine/chemokine patterns associated with MTB and fungal infections.

Substance use and its impact on care outcomes among HIV-infected individuals in Manitoba.

The high prevalence of substance use among HIV-infected individuals creates numerous challenges to patient care. This study was undertaken in order to understand the impact of substance use on care outcomes for HIV-infected individuals in Manitoba. Clinical records of 564 HIV-infected individuals in care at Health Sciences Centre in Winnipeg, Manitoba were reviewed. Clinical data were extracted from patient charts for substance users (illicit substance users, alcohol abusers and chronic users of opioids or benzodiazepines) and non-users. Substance users and non-users were analysed using chi-square analysis and logistic regression models to compare basic socio-demographic and clinic variables. Chi-square and analysis of variance were used to compare a subset of substance users based on similar socio-demographic and clinical characteristics. Among HIV-infected individuals in Manitoba, 38% were substance users with over-representation by Aboriginals, females, young adults and residents of Winnipeg's core areas. Opioids and benzodiazepines were the most commonly used substances with the majority of substance users having used multiple classes of substances in their lifetime. Substance users were more likely than non-users to have missed clinic appointments. Among substance users, missed appointments were more common among those who self-identified as Aboriginal, female, young adults, residents of Winnipeg's core areas, heterosexuals and those who had abused alcohol or cocaine/crack. Aboriginal substance users were also less likely to achieve viral load suppression compared to non-Aboriginal substance users. With the high prevalence of substance use among HIV-infected individuals in Manitoba, it is important to identify at-risk individuals in order to implement appropriate care strategies and improve treatment adherence and health outcomes.

Relapse of visceral leishmaniasis in an HIV-infected patient successfully treated with a combination of miltefosine and amphotericin B.

The present report documents a 49-year-old HIV-infected man receiving antiretroviral therapy with a suboptimal immune response and a CD4 count of 95 cells/mm(3), despite virological suppression. Investigation of bone marrow was conducted and yielded a diagnosis of visceral leishmaniasis. The clinical course was complicated by gastrointestinal involvment and relapse occurred after amphotericin B therapy. With the addition of miltefosine, the patient no longer presented with bone marrow amastigotes, and displayed an increased CD4 count and negative Leishmania polymerase chain reaction results. The present case highlights atypical presentation of visceral leishmaniasis, including poor immune reconstitution and gastrointestinal involvement. The high likelihood of relapse and response to combination therapy are illustrated.

Le présent rapport rend compte du cas d'un homme de 49 ans atteint du VIH sous antirétroviraux dont la réponse immunitaire était sous-optimale et dont la numération de CD4 était de 95 cellules/mm3, malgré une suppression virologique. L'examen de la moelle osseuse a confirmé un diagnostic de leishmaniose viscérale. L'évolution clinique de la maladie a été compliquée par une atteinte gastro-intestinale, et le patient a fait une rechute après un traitement à l'amphotéricine B. Après l'ajout de miltéfosine, le patient n'avait plus d'amastigotes de la moelle osseuse, présentait une augmentation de la numération de CD4 et des résultats négatifs de Leishmania à la réaction en chaîne par polymérase. Le présent cas fait ressortir la présentation atypique de cette leishmaniose viscérale, y compris la mauvaise reconstitution immunitaire et l'atteinte gastro-intestinale. La forte probabilité de rechute et de réponse à une thérapie combinée est exposée.