Hyoscine butylbromide versus acetaminophen for nonspecific colicky abdominal pain in children: a randomized controlled trial

BACKGROUND:Less than two-thirds of children with abdominal pain in the emergency department receive analgesia. We sought to determine whether hyoscine butylbromide was superior to acetaminophen for children with nonspecific colicky abdominal pain.METHODS:We randomly allocated children aged 8–17 years with nonspecific colicky abdominal pain who presented to the pediatric emergency department of London Health Sciences Centre, London, Ontario to receive hyoscine butylbromide, 10 mg given orally, or acetaminophen, 15 mg/kg given orally (maximum 975 mg). We considered the minimal clinically important difference for the primary outcome (self-reported pain at 80 min) to be 13 mm on a 100 mm visual analogue scale. Secondary outcomes included administration of rescue analgesia, adverse effects and pain score less than 30 mm at 80 minutes.RESULTS:A total of 236 participants (120 in the hyoscine butylbromide group and 116 in the acetaminophen group) were included in the trial. The mean visual analogue scale scores at 80 minutes were 29 mm (standard deviation [SD] 26 mm) and 30 mm (SD 29 mm) with hyoscine butylbromide and acetaminophen, respectively (adjusted difference 1, 95% confidence interval −7 to 7). Rescue analgesia was administered to 4 participants (3.3%) in the hyoscine butylbromide group and 1 participant (0.9%) in the acetaminophen groups (p = 0.2). We found no significant differences in rates of adverse effects between hyoscine butylbromide (32/116 [27.6%]) and acetaminophen (28/115 [24.3]) (p = 0.5); no serious adverse effects were observed. The proportion with a pain score less than 30 mm at 80 minutes was 66 (55.0%) with hyoscine butylbromide and 63 (54.3%) with acetaminophen (p = 0.9).INTERPRETATION:Hyoscine butylbromide was not superior to acetaminophen in this setting. Both agents were associated with clinically important pain reduction, and either can be considered for children presenting to the emergency department with nonspecific colicky abdominal pain. Trial registration: Clinicaltrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT02582307","term_id":"NCT02582307"}}NCT02582307

Abdominal pain is reported by a third of school-aged children¹ and accounts for several visits daily in most emergency departments.^2–5 Although the use of analgesia to treat acute abdominal pain is well-supported,^6,7 there is little evidence to guide the management of nonspecific abdominal pain in the emergency department,⁸ which accounts for two-thirds of cases of abdominal pain presenting to the emergency department.^8,9 Acetaminophen is the most commonly used World Health Organization Step 1 analgesic.¹⁰ In children, it is effective for many painful conditions,^11,12 but data supporting its use for abdominal pain are lacking.^13,14 Despite strong advocacy by the American Academy of Pediatrics¹⁵ for adequate pain management, less than two-thirds of children with abdominal pain in the emergency department receive analgesia,^16,17 and roughly half experience ongoing pain after discharge. ¹⁸ Children with nonspecific abdominal pain are less likely than those with a specific cause to receive analgesia.⁵ Available analgesic options for children with nonspecific abdominal pain in the emergency department may result in greater adherence to the American Academy of Pediatrics recommendations.Hyoscine butylbromide is orally administered and available in most Canadian emergency departments. We surmised that it may be effective for colicky abdominal pain owing to its antispasmodic properties.¹⁹ Ten placebo-controlled studies involving 3699 adults with functional abdominal pain showed hyoscine butylbromide to be beneficial, without serious adverse effects.^20–29 In the only pediatric study, hyoscine butylbromide, 10 mg given orally, was found to be beneficial compared to a homeopathic preparation in 204 children, with no serious adverse effects.³⁰ We sought to determine whether hyoscine butylbromide was superior to acetaminophen in relieving pain among children presenting to the emergency department with nonspecific colicky abdominal pain.     

Monitoring,treatment and control of blood glucose and lipids in Ontario First Nations people with diabetes

BACKGROUND:Indigenous people worldwide are disproportionately affected by diabetes and its complications. We aimed to assess the monitoring, treatment and control of blood glucose and lipids in First Nations people in Ontario.METHODS:We conducted a longitudinal population-based study using administrative data for all people in Ontario with diabetes, stratified by First Nations status. We assessed age- and sex-specific rates of completion of recommended monitoring for low-density lipoprotein (LDL) and glycated hemoglobin (A_1c) from 2001/02 to 2014/15. We used data from 2014/15 to conduct a cross-sectional analysis of rates of achievement of A_1c and LDL targets and use of glucose-lowering medications.RESULTS:The study included 22 240 First Nations people and 1 319 503 other people in Ontario with diabetes. Rates of monitoring according to guidelines were 20%–50% for A_1c and 30%–70% for lipids and were lowest for younger First Nations men. The mean age- and sex-adjusted A_1c level was higher among First Nations people than other people (7.59 [95% confidence interval (CI) 7.57 to 7.61] v. 7.03 [95% CI 7.02 to 7.03]). An A_1c level of 8.5% or higher was observed in 24.7% (95% CI 23.6 to 25.0) of First Nations people, compared to 12.8% (95% CI 12.1 to 13.5) of other people in Ontario. An LDL level of 2.0 mmol/L or less was observed in 60.3% (95% CI 59.7 to 61.6) of First Nations people, compared to 52.0% (95% CI 51.1 to 52.9) of other people in Ontario. Among those aged 65 or older, a higher proportion of First Nations people than other Ontarians were using insulin (28.1% v. 15.1%), and fewer were taking no medications (28.3% v. 40.1%).INTERPRETATION:As of 2014/15, monitoring and achievement of glycemic control in both First Nations people and other people in Ontario with diabetes remained suboptimal. Interventions to support First Nations patients to reach their treatment goals and reduce the risk of complications need further development and study.

Diabetes and its related complications are major contributors to morbidity and mortality worldwide.^1–3 Indigenous populations in Canada and around the world are disproportionately affected by diabetes owing to the complex relations among colonization, social disadvantage, stress, trauma and metabolic health.^4–7 In addition to our own work showing persistently higher rates of peripheral vascular disease, stroke, cardiac disease, renal dysfunction and ophthalmologic complications in Ontario First Nations,^8–12 other Canadian and international studies also showed higher complication rates in diverse Indigenous populations.^6,7,13–15Glycemic control is fundamental to the management of diabetes and the prevention of complications.¹⁶ Glycated hemoglobin (A_1c) is a reliable way to estimate the average level of glucose in the blood.¹⁷ Since A_1c levels higher than 7.0% have been associated with an increased risk of microvascular complications,^18–20 treatment guidelines suggest A_1c should be measured every 3–6 months to ensure that glycemic goals are being met or maintained.²¹ Since people with diabetes also have an elevated risk for cardiovascular disease,^22–24 management and control of cardiovascular risk factors, particularly lipids such as low-density lipoprotein (LDL) cholesterol, are also important.^25–27 Guidelines further recommend that a full lipid profile be measured every 1–3 years, depending on cardiovascular risk, and suggest that LDL be consistently less than 2.0 mmol/L.²⁸ Control of A_1c and lipids has been shown to be associated with reduced morbidity and mortality in patients with diabetes.^18,29–32One possible reason for the high burden of complications among Indigenous people with diabetes may be failure to achieve control of these 2 key clinical parameters. We examined differences between Status First Nations people with diabetes in Ontario and all other Ontario residents with diabetes in rates of monitoring of A_1c and lipids, achievement of targets for A_1c and LDL outlined in clinical guidelines, and patterns of medication use to help attain these targets.     

Mortality among patients with frequent emergency department use for alcohol-related reasons in Ontario: a population-based cohort study

BACKGROUND:Little is known about the risk of death among people who visit emergency departments frequently for alcohol-related reasons, including whether mortality risk increases with increasing frequency of visits. Our primary objective was to describe the sociodemographic and clinical characteristics of this high-risk population and examine their 1-year overall mortality, premature mortality and cause of death as a function of emergency department visit frequency in Ontario, Canada.METHODS:We conducted a population-based retrospective cohort study using linked health administrative data (Jan. 1, 2010, to Dec. 31, 2016) in Ontario for people aged 16–105 years who made at least 2 emergency department visits for mental or behavioural disorders due to alcohol within 1 year. We subdivided the cohort based on visit frequency (2, 3 or 4, or ≥ 5). The primary outcome was 1-year mortality, adjusted for age, sex, income, rural residence and presence of comorbidities. We examined premature mortality using years of potential life lost (YPLL).RESULTS:Of the 25 813 people included in the cohort, 17 020 (65.9%) had 2 emergency department visits within 1 year, 5704 (22.1%) had 3 or 4 visits, and 3089 (12.0%) had 5 or more visits. Males, people aged 45–64 years, and those living in urban centres and lower-income neighbourhoods were more likely to have 3 or 4 visits, or 5 or more visits. The all-cause 1-year mortality rate was 5.4% overall, ranging from 4.7% among patients with 2 visits to 8.8% among those with 5 or more visits. Death due to external causes (e.g., suicide, accidents) was most common. The adjusted mortality rate was 38% higher for patients with 5 or more visits than for those with 2 visits (adjusted hazard ratio 1.38, 95% confidence interval 1.19–1.59). Among 25 298 people aged 16–74 years, this represented 30 607 YPLL.INTERPRETATION:We observed a high mortality rate among relatively young, mostly urban, lower-income people with frequent emergency department visits for alcohol-related reasons. These visits are opportunities for intervention in a high-risk population to reduce a substantial mortality burden.

Alcohol is a leading driver of morbidity and mortality worldwide.¹ An estimated 3 million deaths in 2016 — 5% of all global deaths — were attributable to alcohol consumption.² The 2016 Global Burden of Disease Study showed that alcohol was the single greatest risk factor for ill health worldwide among people aged 15–49 years.³ In Canada, hospital admissions for alcohol-attributable conditions out-number those for myocardial infarction.⁴ Alcohol-related harms cost Canadians about $14.6 billion annually, with $3.3 billion in health care costs.⁵In addition to the societal impact of mental and behavioural disorders due to alcohol (henceforth referred to as alcohol-related) — mainly acute intoxication and withdrawal — these disorders are common reasons for emergency department visits.^6,7 Data from the United States and Canada, furthermore, suggest that alcohol-related emergency department visits have increased in recent years.^8,9 For example, a study in Ontario showed that, between 2003 and 2016, the age-standardized rates of alcohol-attributable emergency department visits increased by 86.5% in women and 53.2% in men.⁸ People who visit emergency departments frequently for alcohol-related reasons have high levels of comorbidity and social disadvantage,^10,11 and represent a readily identifiable patient population for whom interventions to address unmet social and health care needs could be developed.^12–14 A systematic review suggested that screening and brief intervention for alcohol-related problems in the emergency department is a promising approach for reducing problematic alcohol consumption.¹³Despite this, little is known about the risk of death, a key outcome for health system performance, among people who use emergency departments frequently for alcohol-related reasons, including whether mortality risk increases with increasing frequency of visits. To address this gap, our primary objective was to describe the sociodemographic and clinical characteristics of this high-risk population and examine their 1-year overall mortality, premature mortality and cause of death as a function of emergency department visit frequency in Ontario, the most populous Canadian province.¹⁵     

Characteristics of patients with mental illness and persistent high-cost status: a population-based analysis

BACKGROUND:Most of the literature on high-cost users of health care has evaluated this population as a whole, but few studies have focused on high-cost patients with mental illness and whether they persist in the high-cost state. We sought to analyze this patient population in depth and determine predictors of persistency in the high-cost state.METHODS:We used 8 years of longitudinal patient-level population data (2010–2017) from Ontario to follow high-cost patients (those in and above the 90th percentile of the cost distribution) with mental illness. We classified high-cost status, based on the proportion of the study period that patients spent in the high-cost state, as persistent (6–8 yr), sporadic (1–2 yr) or moderate (3–5 yr). We compared characteristics between groups and determined predictors of being a patient with mental illness and persistent high-cost status.RESULTS:Among 52 638 patients with mental illness and high-cost status, 18 149 (34.5%) were considered persistent high cost. These patients had higher mean annual costs of care ($44 714, 95% confidence interval [CI] $43 724–$45 703) than patients with sporadic ($23 205, 95% CI $22 741–$23 668) and moderate ($31 055, 95% CI $30 359–31 751) status, largely owing to psychiatric hospital admissions. Patients with mental illness and persistent high-cost status were more likely to be female, older, long-term residents of Ontario (information ascertained from the Immigrants, Refugees and Citizenship Canada Database), living in low-income or urban areas, or to have comorbidities. The strongest predictors of persistent (v. sporadic) high-cost status were HIV (relative risk ratio [RRR] 4.32, 95% CI 3.08–6.06), psychosis (RRR 3.41, 95% CI 3.25–3.58) and dementia (RRR 3.21, 95% CI 2.81–3.68).INTERPRETATION:Among patients with mental illness and high-cost status, persistence in the high-cost state was determined mainly by psychosis and other comorbidities. Quality-of-care interventions directed at managing psychosis and multimorbidity, as well as preventive interventions to target patients with mental illness before they enter the persistent high-cost state, are needed.

To address rising health care costs, it is important to understand the composition of the population of patients with high-cost status. Most work on high-cost patients has considered this population as a whole.^1–3 However, previous work has shown that policies and interventions designed to address quality of care and high health care spending in general will likely not apply to all subgroups of high-cost patients.^4,5 Moreover, research has shown that high-cost patients are a heterogeneous population.⁶ For example, high-cost patients who use mainly mental health services are quite different from other high-cost patients — they are younger, live in poorer neighbourhoods and have different patterns of health care use.^4,6 They also have high levels of comorbidity and incur over 30% more costs than other high-cost patients, suggesting they may be a more complex population with higher needs.^4,6It is also important to understand whether high-cost patients remain in the high-cost state for long periods of time or whether this is a one-time occurrence. The few studies that have examined persistency in the high-cost state evaluated such patients as a whole and followed them for only 3 years.^7,8 Although previous studies have found that individuals with mental illness are more likely to be patients with persistent high-cost status,^9,10 no studies have specifically examined persistency in the high-cost state among patients with mental illness⁴ or followed these patients for long periods of time.¹¹ The goal of this study was to provide an in-depth analysis of patients with mental illness and persistent high-cost status, using administrative health care data from Ontario, Canada’s most populous province.     

Total knee replacement after high tibial osteotomy: time-to-event analysis and predictors

BACKGROUND:An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it.METHODS:We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery.RESULTS:Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m², 95% CI 1.12–1.53).INTERPRETATION:We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO.

The burden of knee osteoarthritis (OA) on patients and health care systems is substantial and growing.¹ The current treatment strategy that relies largely on total knee replacement (TKR) for end-stage disease may not be sustainable.^2–5 Reduced quality of life and loss of productivity due to knee OA in middle-aged people in the workforce is particularly problematic.^5–8 The global prevalence of knee OA peaks at about 50 years of age.⁹ Worldwide, the estimated years lived with disability is 2.4 million for people younger than 50 years of age, the approximate age of peak prevalence for knee OA.^9,10 Accordingly, the number of middle-aged patients seeking treatment for knee OA, including TKR, is increasing. ¹¹ Joint replacement may not be the most appropriate treatment for these patients.¹² Earlier TKR is associated with prosthesis infection, ¹³ lower patient satisfaction¹⁴ and revision surgery;^15–18 about 25% of all TKRs are considered “likely inappropriate.”¹⁹ Clinicians have identified a clear treatment gap between exhausting nonoperative management and appropriateness for TKR, resulting in years of pain, decreased function, productivity losses and associated costs.^5–9,20,21 It is therefore imperative to identify additional effective treatments for the large group of patients with knee OA.Medial opening wedge high tibial osteotomy (HTO) is a limb realignment surgery intended for patients with medial compartment knee OA who are not suitable candidates for TKR because of less severe disease, younger age and greater physical demands. The purpose of HTO is to correct malalignment, thereby shifting load away from the more involved knee compartment and limit OA progression.^22,23 Substantial shifts in knee loading^24,25 have resulted in clinically important improvements in pain and function after HTO^26,27 and the procedure is cost-effective,^28,29 yet the surgery is uncommon in Canada.³⁰ Unlike the high and increasing rates of other knee surgical procedures including arthroscopy³¹ and TKR,³² rates of HTO remain low.^33,34High tibial osteotomy may help fill the treatment gap between nonsurgical treatments and definitive TKR. At the London Health Sciences Centre in London, Ontario, HTO is performed frequently with a goal of preventing or delaying the need for TKR. Thus, it is appropriate to investigate the duration of benefit of HTO, and the preoperative characteristics associated with it. When quantified as conversion from HTO to TKR, registries using administrative data enable large sample sizes (> 2500 patients) to estimate cumulative incidence of TKR.^30,35,36 However, there can be limitations in using only administrative data, including confirming the correct procedure, limb and diagnosis. Administrative data often lack detailed information assessed preoperatively, such as radiographic features (e.g., disease severity and lower limb alignment) and patient-reported outcome measures. Previously reported predictors of conversion to TKR such as female sex and greater age^30,35–39 may be influenced (perhaps confounded) by other clinical characteristics not typically included in administrative data. Therefore, our objective was to investigate the cumulative incidence of TKR after medial opening wedge HTO and potential predictors using data collected prospectively from a single Canadian centre that focuses on HTO. Specifically, we evaluated the time to conversion from HTO to TKR and investigated the association of HTO preoperative characteristics with subsequent TKR.     

Preoperative levels of natriuretic peptides and the incidence of postoperative atrial fibrillation after noncardiac surgery: a prospective cohort study

BACKGROUND:Postoperative atrial fibrillation (POAF) is associated with clinically significant short- and long-term complications after noncardiac surgery. Our aim was to describe the incidence of clinically important POAF after noncardiac surgery and establish the prognostic value of N-terminal pro–brain-type natriuretic peptide (NT-proBNP) in this context.METHODS:The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Study was a prospective cohort study involving patients aged 45 years and older who had inpatient noncardiac surgery that was performed between August 2007 and November 2013. We determined 30-day incidence of clinically important POAF (i.e., resulting in angina, congestive heart failure, symptomatic hypotension or requiring treatment) using logistic regression models to analyze the association between preoperative NT-proBNP and POAF.RESULTS:In 37 664 patients with no history of atrial fibrillation, we found that the incidence of POAF was 1.0% (95% confidence interval [CI] 0.9%–1.1%; 369 events); 3.2% (95% CI 2.3%–4.4%) in patients undergoing major thoracic surgery, 1.3% (95% CI 1.2%–1.5%) in patients undergoing major nonthoracic surgery and 0.2% (95% CI 0.1%–0.3%) in patients undergoing low-risk surgery. In a subgroup of 9789 patients with preoperative NT-proBNP measurements, the biomarker improved the prediction of POAF risk over conventional prognostic factors (likelihood ratio test p < 0.001; fraction of new information from NT-proBNP was 16%). Compared with a reference NT-proBNP measurement set at 100 ng/L, adjusted odds ratios for the occurrence of POAF were 1.31 (95% CI 1.15–1.49) at 200 ng/L, 2.07 (95% CI 1.27–3.36) at 1500 ng/L and 2.39 (95% CI 1.26–4.51) at 3000 ng/L.INTERPRETATION:We determined that the incidence of clinically important POAF after noncardiac surgery was 1.0%. We also found that preoperative NT-proBNP levels were associated with POAF independent of established prognostic factors. Trial registration: ClinicalTrials.gov, no. {"type":"clinical-trial","attrs":{"text":"NCT00512109","term_id":"NCT00512109"}}NCT00512109

Postoperative atrial fibrillation (POAF) is the most common arrhythmia that occurs after noncardiac surgery¹ and is associated with prolonged hospital stays and an increased risk of stroke and death,^2–8 both of which raise societal costs.⁹ The reported incidence of POAF ranges from 3.7% to 21.0% in patients undergoing thoracic surgery^3,10 and from less than 0.5% to 10.0% in patients undergoing noncardiac, nonthoracic surgery (Appendix 1, Supplementary Table 1, available at www.cmaj.ca/lookup/doi/10.1503/cmaj.200840/tab-related-content).^6,11Brain-type natriuretic peptide (BNP) is a neurohormone released by cardiomyocytes in response to volume and pressure overload.¹² This biomarker has an established role in the diagnosis and management of heart failure and in predicting cardiovascular morbidity and mortality.¹³ Although natriuretic peptides have been shown to predict new-onset atrial fibrillation (AF) in the nonsurgical setting reliably,^14–18 their value in predicting POAF after noncardiac surgery is unclear.^19–21The Vascular events In non-cardiac Surgery patIents cOhort evaluatioN (VISION) Study was a prospective international cohort study involving a representative sample of adults who underwent noncardiac surgery that required an overnight hospital stay. One of the predefined objectives in VISION was to determine the incidence of new-onset, clinically important POAF. We aimed to describe the overall and surgery-specific incidence of POAF after noncardiac surgery and to investigate the association between preoperative N-terminal pro–brain-type natriuretic peptide (NT-proBNP) and POAF. We hypothesized that measurement of NT-proBNP would improve POAF risk prediction beyond conventional prognostic factors.     

Prepregnancy renal function and risk of preterm birth and related outcomes

BACKGROUND:Prepregnancy kidney dysfunction has been associated with preterm birth, which is the leading cause of neonatal morbidity and mortality; however, the relation is not well understood. We determined the risk of preterm birth in women with prepregnancy kidney dysfunction, defined using pregnancy-specific serum creatinine cut points.METHODS:This population-based cohort study in the province of Ontario, Canada, involved women aged 16 to 50 years who had a singleton birth between 2006 and 2016 and measurement of serum creatinine within 10 weeks preceding their estimated conception date. The exposure was abnormally elevated prepregnancy serum creatinine, defined as greater than the 95th percentile (> 77 μmol/L), a value derived from a population-based sample of women without known kidney disease who became pregnant soon after the measurement was obtained. The main outcome was any preterm birth from 23 to 36 weeks’ gestation. Secondary outcomes included provider-initiated preterm birth before 37 weeks’ gestation and spontaneous preterm birth before 37 weeks.RESULTS:Among 55 946 pregnancies, preterm birth before 37 weeks’ gestation occurred in 3956 women (7.1%). The risk of preterm birth before 37 weeks was higher among women with prepregnancy creatinine above the 95th percentile, relative to those with prepregnancy creatinine at or below the 95th percentile (9.1% v. 7.0%; adjusted relative risk [RR] 1.23, 95% confidence interval [CI] 1.09 to 1.38). The effect was significant for provider-initiated preterm birth (adjusted RR 1.30, 95% CI 1.11 to 1.52) but not for spontaneous preterm birth (adjusted RR 1.12, 95% CI 0.91 to 1.37).INTERPRETATION:Given that prepregnancy kidney dysfunction conferred an increased risk of preterm birth, measurement of serum creatinine (a relatively inexpensive blood test) may form part of the assessment of risk for preterm birth among those planning pregnancy.

Prepregnancy kidney dysfunction may perturb the normal physiologic adaptations of pregnancy, predisposing a woman and her fetus to adversity, at least partly mediated by placental and endothelial dysfunction.¹ Complications such as preeclampsia² and poor fetal growth³ may necessitate provider-initiated preterm birth. Preterm birth of any form before 37 weeks’ gestation occurs in 6% to 11% of viable pregnancies and is the leading cause of infant death.⁴Prepregnancy kidney dysfunction has been associated with preterm birth.^5–7 Prior studies of the relation between prepregnancy kidney dysfunction and preterm birth were primarily case series and thus had inadequate statistical power to differentiate between the outcomes of spontaneous versus provider-initiated preterm birth. In addition, arbitrary cut points were used in these studies to define prepregnancy kidney dysfunction, and there was no accounting for important confounders.^5,8–14In an effort to overcome the aforementioned limitations, we completed a large cohort study in a setting where prenatal and obstetric care is covered under a provincial health insurance plan. Using population-derived cut points for prepregnancy serum creatinine to define kidney dysfunction, we examined the risk of preterm birth and other related outcomes.     

Burden of noninfluenza respiratory viral infections in adults admitted to hospital: analysis of a multiyear Canadian surveillance cohort from 2 centres

BACKGROUND:Data on the outcomes of noninfluenza respiratory virus (NIRV) infections among hospitalized adults are lacking. We aimed to study the burden, severity and outcomes of NIRV infections in this population.METHODS:We analyzed pooled patient data from 2 hospital-based respiratory virus surveillance cohorts in 2 regions of Canada during 3 consecutive seasons (2015/16, 2016/17, 2017/18; n = 2119). We included patients aged ≥ 18 years who developed influenza-like illness or pneumonia and were hospitalized for management. We included patients confirmed positive for ≥ 1 virus by multiplex polymerase chain reaction assays (respiratory syncytial virus [RSV], human rhinovirus/enterovirus (hRV), human coronavirus (hCoV), metapneumovirus, parainfluenza virus, adenovirus, influenza viruses). We compared patient characteristics, clinical severity conventional outcomes (e.g., hospital length-of stay, 30-day mortality) and ordinal outcomes (5 levels: discharged, receiving convalescent care, acute ward or intensive care unit [ICU] care and death) for patients with NIRV infections and those with influenza.RESULTS:Among 2119 adults who were admitted to hospital, 1156 patients (54.6%) had NIRV infections (hRV 14.9%, RSV 12.9%, hCoV 8.2%) and 963 patients (45.4%) had influenza (n = 963). Patients with NIRVs were younger (mean 66.4 [standard deviation 20.4] yr), and more commonly had immunocompromising conditions (30.3%) and delay in diagnosis (median 4.0 [interquartile range (IQR) 2.0–7.0] days). Overall, 14.6% (12.4%–19.5%) of NIRV infections were acquired in hospital. Admission to ICU (18.2%, median 6.0 [IQR 3.0–13.0] d), hospital length-of-stay (median 5.0 [IQR 2.0–10.0] d) and 30-day mortality (8.4%; RSV 9.5%, hRV 6.6%, hCoV 9.2%) and the ordinal outcomes were similar for patients with NIRV infection and those with influenza. Age > 60 years, immunocompromised state and hospital-acquired viral infection were associated with worse outcomes. The estimated median cost per acute care admission was $6000 (IQR $2000–$16 000).INTERPRETATION:The burden of NIRV infection is substantial in adults admitted to hospital and associated outcomes may be as severe as for influenza, suggesting a need to prioritize therapeutics and vaccines for at-risk people.

The global burden of lower respiratory tract infections is substantial, leading to many hospital admissions and deaths, especially among young children and older adults.¹ Respiratory viruses are responsible for almost half of such infections in adults that require in-hospital management; previous studies estimate that 28%–62% are caused by noninfluenza respiratory viruses (NIRVs).^2–4 With some geographical and seasonal variations, respiratory syncytial virus (RSV), human rhinovirus (hRV) and human coronavirus (hCoV) are among the most frequently identified NIRV infections.^1–7 Most infected adults develop mild, self-limiting illnesses, but increasing evidence suggest that NIRVs, either alone or with coinfecting bacteria, can result in severe pneumonia and death.^8,9 For instance, RSV has been shown to cause severe respiratory failure, with fatality rates comparable to or exceeding those observed among adults admitted to hospital with influenza.^10–12 Data on hRV, hCoV and other NIRVs are more limited, owing to the lack of accurate diagnostics and systematic case-finding approaches.^7–9 However, with the increasing availability of multiplex polymerase chain reaction (PCR) assays that can simultaneously detect influenza and NIRVs, these infections are now readily diagnosed as part of a syndromic approach in patients who present with acute respiratory illnesses.^2–5,13,14 The burden, clinical significance and impacts of NIRVs on the health care system remain inadequately characterized.To address this gap, we analyzed the relative frequencies, patient characteristics, location of acquisition (community or hospital), severity and clinical outcomes of patients with NIRV and influenza infections diagnosed by multiplex PCR in a cohort of adults admitted to hospital in 2 large Canadian health care centres during a 3-year surveillance period. The associated health care resource use was also estimated.     

Individual and social determinants of SARS-CoV-2 testing and positivity in Ontario,Canada: a population-wide study

BACKGROUND:Optimizing the public health response to reduce the burden of COVID-19 necessitates characterizing population-level heterogeneity of risks for the disease. However, heterogeneity in SARS-CoV-2 testing may introduce biased estimates depending on analytic design. We aimed to explore the potential for collider bias in a large study of disease determinants, and evaluate individual, environmental and social determinants associated with SARS-CoV-2 testing and diagnosis among residents of Ontario, Canada.METHODS:We explored the potential for collider bias and characterized individual, environmental and social determinants of being tested and testing positive for SARS-CoV-2 infection using cross-sectional analyses among 14.7 million community-dwelling people in Ontario, Canada. Among those with a diagnosis, we used separate analytic designs to compare predictors of people testing positive versus negative; symptomatic people testing positive versus testing negative; and people testing positive versus people not testing positive (i.e., testing negative or not being tested). Our analyses included tests conducted between Mar. 1 and June 20, 2020.RESULTS:Of 14 695 579 people, we found that 758 691 were tested for SARS-CoV-2, of whom 25 030 (3.3%) had a positive test result. The further the odds of testing from the null, the more variability we generally observed in the odds of diagnosis across analytic design, particularly among individual factors. We found that there was less variability in testing by social determinants across analytic designs. Residing in areas with the highest household density (adjusted odds ratio [OR] 1.86, 95% confidence interval [CI] 1.75–1.98), highest proportion of essential workers (adjusted OR 1.58, 95% CI 1.48–1.69), lowest educational attainment (adjusted OR 1.33, 95% CI 1.26–1.41) and highest proportion of recent immigrants (adjusted OR 1.10, 95% CI 1.05–1.15) were consistently related to increased odds of SARS-CoV-2 diagnosis regardless of analytic design.INTERPRETATION:Where testing is limited, our results suggest that risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment in and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding, occupation and structural racism.

The spread of SARS-CoV-2, the virus causing COVID-19, has resulted in a pandemic with heterogeneity in exposure and risk of transmission.^1–4Heterogeneity in social determinants of COVID-19 may exist at the individual and community (e.g., by housing density^5–7) levels. In addition, social determinants of health, including barriers to health care, occupation, structural racism and xenophobia, have been implicated in COVID-19 risk.^8,9 Environmental determinants such as ambient air pollution may also play a role, as evidence indicates that higher ambient air pollution increases risk for infection with other respiratory viruses^10,11 and the development of severe COVID-19.^12,13 Environmental factors are linked with structural racism (e.g., in the context of low-quality housing).^12,14Using observational data to identify risk factors for COVID-19 relies on SARS-CoV-2 testing, a service that is not equally distributed.¹⁵ Differential testing introduces the potential for selection biases,^16,17 including collider bias.¹⁷ Collider bias may be introduced into epidemiologic studies of COVID-19 risk factors if the factors under investigation are related both to developing an infection and to the likelihood of being tested.^17–19 For example, data suggest that people with diabetes are more likely to develop severe COVID-19 if infected with SARS-CoV-2.^20,21 Thus, if infected, people with diabetes may be more likely to be tested, and consequently, diabetes may appear to be associated with a diagnosis of COVID-19 in studies of those tested for SARS-CoV-2, even if diabetes is not a risk factor for infection.¹⁷ The opposite may occur with underlying respiratory diseases (e.g., asthma) that have symptoms similar to those caused by SARS-CoV-2, leading to the appearance of potentially “protective” associations with COVID-19.²²Our objectives were to explore the potential for collider bias in a large study of COVID-19 determinants and examine individual, environmental and social determinants associated with testing and diagnosis among 14.7 million people in Ontario, Canada.¹⁷     

Birth outcomes following cesarean delivery on maternal request: a population-based cohort study

BACKGROUND:Data on the effect of cesarean delivery on maternal request (CDMR) on maternal and neonatal outcomes are inconsistent and often limited by inadequate case definitions and other methodological issues. Our objective was to evaluate the trends, determinants and outcomes of CDMR using an intent-to-treat approach.METHODS:We designed a population-based retrospective cohort study using data on low-risk pregnancies in Ontario, Canada (April 2012–March 2018). We assessed temporal trends and determinants of CDMR. We estimated the relative risks for component and composite outcomes used in the Adverse Outcome Index (AOI) related to planned CDMR compared with planned vaginal delivery using generalized estimating equation models. We compared the Weighted Adverse Outcome Score (WAOS) and the Severity Index (SI) across planned modes of delivery using analysis of variance.RESULTS:Of 422 210 women, 0.4% (n = 1827) had a planned CDMR and 99.6% (n = 420 383) had a planned vaginal delivery. The prevalence of CDMR remained stable over time at 3.9% of all cesarean deliveries. Factors associated with CDMR included late maternal age, higher education, conception via in vitro fertilization, anxiety, nulliparity, being White, delivery at a hospital providing higher levels of maternal care and obstetrician-based antenatal care. Women who planned CDMR had a lower risk of adverse outcomes than women who planned vaginal delivery (adjusted relative risk 0.42, 95% confidence interval [CI] 0.33 to 0.53). The WAOS was lower for planned CDMR than planned vaginal delivery (mean difference −1.28, 95% CI −2.02 to −0.55). The SI was not statistically different between groups (mean difference 3.6, 95% CI −7.4 to 14.5).Interpretation:Rates of CDMR have not increased in Ontario. Planned CDMR is associated with a decreased risk of short-term adverse outcomes compared with planned vaginal delivery. Investigation into the long-term implications of CDMR is warranted.

Cesarean delivery is the most common inpatient surgical procedure in North America,^1,2 where rates often exceed World Health Organization recommendations (10%–15% of deliveries).³ Given the financial and resource implications of cesarean deliveries on health care systems, the contribution of cesarean deliveries on maternal request (CDMR) to rising cesarean section rates is of ongoing interest. Women may prefer CDMR for many reasons, including scheduling convenience, anxiety regarding labour pain, perceptions that the quality of obstetrical care is better for women who have cesarean deliveries, and concerns about possible urinary incontinence and sexual dysfunction after vaginal delivery.^4–7 Challenges in characterizing the epidemiology of CDMR include the lack of internationally accepted case definitions and inconsistencies in documentation that hinder meaningful comparisons across jurisdictions.^8–11 In Canada, the prevalence of CDMR has been estimated at 2% of cesarean deliveries,¹² but robust contemporary data are lacking.The benefits of vaginal delivery are well known and include a lower risk of transient tachypnea of the newborn, newborn exposure to the vaginal microbiome, shorter maternal hospital stays and lower risk of complications associated with abdominal surgeries. The findings of 1 Canadian study suggest that midpelvic operative vaginal delivery is associated with a greater risk of severe birth and obstetric trauma than cesarean delivery.¹³ Evidence on the risks and benefits of CDMR is sparse, and existing data are inconsistent.^14–19 Analyses are frequently limited by inadequate case definitions and unaddressed confounding from baseline maternal and neonatal factors.^4,11 Professional organizations in the United States, Canada and Europe do not recommend CDMR over vaginal delivery.^11,20–22 Patient counselling is suggested to inform patients of pain management options, and of potential benefits and harms related to cesarean deliveries. However, obstetrical care providers often accede to patient preferences, given the ethical imperative of patient autonomy. ^23–27 Contemporary, high-quality observational studies leveraging robust population-based data are required. Our objective was to evaluate the trends, determinants and outcomes of CDMR compared with planned vaginal delivery using an intent-to-treat approach.     

Physician choices in pulmonary embolism testing

BACKGROUND:Evidence-based guidelines advise excluding pulmonary embolism (PE) diagnosis using d-dimer in patients with a lower probability of PE. Emergency physicians frequently order computed tomography (CT) pulmonary angiography without d-dimer testing or when d-dimer is negative, which exposes patients to more risk than benefit. Our objective was to develop a conceptual framework explaining emergency physicians’ test choices for PE.METHODS:We conducted a qualitative study using in-depth interviews of emergency physicians in Canada. A nonmedical researcher conducted in-person interviews. Participants described how they would test simulated patients with symptoms of possible PE, answered a knowledge test and were interviewed on barriers to using evidence-based PE tests.RESULTS:We interviewed 63 emergency physicians from 9 hospitals in 5 cities, across 3 provinces. We identified 8 domains: anxiety with PE, barriers to using the evidence (time, knowledge and patient), divergent views on evidence-based PE testing, inherent Wells score problems, the drive to obtain CT rather than to diagnose PE, gestalt estimation artificially inflating PE probability, subjective reasoning and cognitive biases supporting deviation from evidence-based tests and use of evidence-based testing to rule out PE in patients who are very unlikely to have PE. Choices for PE testing were influenced by the disease, environment, test qualities, physician and probability of PE.INTERPRETATION:Analysis of structured interviews with emergency physicians provided a conceptual framework to explain how these physicians use tests for suspected PE. The data suggest 8 domains to address when implementing an evidence-based protocol to investigate PE.

Pulmonary embolism (PE) occurs when a blood clot lodges in the pulmonary arteries. If left untreated, the disorder can progress, causing worsening morbidity and may become fatal.¹ Because of the acute nature of this condition, many patients with PE present to the emergency department.Diagnosing and excluding PE using computed tomography pulmonary angiography (CTPA) alone can be problematic because of radiation exposure, anaphylaxis to contrast, misdiagnosis and “overdiagnosis” of inconsequential PE² (leading to unnecessary anticoagulation therapy and psychological distress³). Choosing Wisely^4,5 and the guideline from the American College of Physicians⁶ recommend the use of risk stratification tools, including the Pulmonary Embolism Rule-out Criteria (PERC) clinical decision rule,⁷ the Wells score⁸ and blood concentration of d-dimer. These tools use different predetermined diagnostic algorithms to indicate the need for CTPA.^8–11 Evidence-based guidelines discourage further testing in patients at lower risk who have normal d-dimer levels, where imaging can cause more harm than benefit.^12,13 However, many emergency physicians opt for CTPA as a stand-alone test for PE.^14–17It remains unclear why emergency physicians sometimes do not use validated diagnostic PE tools. Furthermore, implementation of computerized decision support systems has had little success in modifying this behaviour.^18,19 We sought to develop a conceptual framework to describe how Canadian emergency physicians test for PE, and to document the cognitive and contextual barriers to using existing evidence-based diagnostic PE pathways.     

COVID-19 in patients undergoing long-term dialysis in Ontario

BACKGROUND:Patients undergoing long-term dialysis may be at higher risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of associated disease and mortality. We aimed to describe the incidence, risk factors and outcomes for infection in these patients in Ontario, Canada.METHODS:We used linked data sets to compare disease characteristics and mortality between patients receiving long-term dialysis in Ontario who were diagnosed SARS-CoV-2 positive and those who did not acquire SARS-CoV-2 infection, between Mar. 12 and Aug. 20, 2020. We collected data on SARS-CoV-2 infection prospectively. We evaluated risk factors for infection and death using multivariable logistic regression analyses.RESULTS:During the study period, 187 (1.5%) of 12 501 patients undergoing dialysis were diagnosed with SARS-CoV-2 infection. Of those with SARS-CoV-2 infection, 117 (62.6%) were admitted to hospital and the case fatality rate was 28.3%. Significant predictors of infection included in-centre hemodialysis versus home dialysis (odds ratio [OR] 2.54, 95% confidence interval [CI] 1.59–4.05), living in a long-term care residence (OR 7.67, 95% CI 5.30–11.11), living in the Greater Toronto Area (OR 3.27, 95% CI 2.21–4.80), Black ethnicity (OR 3.05, 95% CI 1.95–4.77), Indian subcontinent ethnicity (OR 1.70, 95% CI 1.02–2.81), other non-White ethnicities (OR 2.03, 95% CI 1.38–2.97) and lower income quintiles (OR 1.82, 95% CI 1.15–2.89).INTERPRETATION:Patients undergoing long-term dialysis are at increased risk of SARS-CoV-2 infection and death from coronavirus disease 2019. Special attention should be paid to addressing risk factors for infection, and these patients should be prioritized for vaccination.

As of Aug. 20, 2020, in Ontario, Canada’s most populous province, almost 41 000 people had tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19),¹ which represented 0.3% of the provincial population. Close to 2800 people had died, a case fatality rate of 6.8%.²Patients undergoing dialysis have high rates of comorbid conditions, are often older adults, have varying degrees of immunosuppression and are more likely to reside in long-term care, which puts them at risk of both acquiring SARS-CoV-2 and developing complicated disease.^3,4 Furthermore, in Ontario, those who receive in-centre hemodialysis typically have 3 treatments per week in outpatient units located in or affiliated with hospitals, and the consequent inability to fully self-isolate means that patients undergoing hemodialysis likely have an even higher risk of SARS-CoV-2 infection.^3,4 Recent studies support this but do not compare infection rates with those in the local population of patients not undergoing dialysis.^5–10 Several studies have reported SARS-CoV-2 infection in single or multicentre cohorts of patients undergoing dialysis,^5–10 but we are unaware of any that have identified risk factors for infection at the level of a large region. Some studies have found that patients with SARS-CoV-2 infection who are undergoing dialysis are at high risk of severe illness and death.^6–10     

Changes over time in means of suicide in Canada: an analysis of mortality data from 1981 to 2018

BACKGROUND:Ongoing surveillance of the means of suicide is necessary for effective prevention. We examined how mortality rates owing to different means of suicide changed in Canada from 1981 to 2018.METHODS:We obtained data from 1981 to 2018 on suicide deaths of individuals aged 10 years and older, from the Canadian Vital Statistics Death Database. We used joinpoint regression analysis to examine changes over time in the suicide mortality rate for the 3 most common means of suicide.RESULTS:The age-standardized suicide mortality rate declined in earlier decades for both sexes, but did not significantly change in recent decades for either sex. The age-standardized rate of suicide by suffocation increased from 1993 for females (2.1% per year) and from 1996 for males (0.4% per year). The age-standardized rate of suicide by poisoning decreased for females (2.2% per year) and males (2.1% per year) from 1981 to 2018. The age-standardized rate of suicide by firearm decreased from 1981 to 2008 (7.4% per year) but did not significantly change there-after for females; for males, it decreased 2.1% per year from 1981 to 1993 and 5.7% per year from 1993 to 2007, but did not significantly change thereafter.INTERPRETATION:For both sexes, the rate of suicide by poisoning is decreasing, the rate of suicide by suffocation is increasing, and the rate of suicide by firearm has not significantly changed in the last decade. Given the high proportion of suicide deaths by suffocation, its increasing rate and the difficulty of restricting the means of suffocation, other approaches to suicide prevention are needed.

The overall suicide mortality rate in Canada is lower than it was a few decades ago, but continued declines have been absent in recent years and the impact of suicide remains high.^1,2 Suicide was the ninth leading cause of death in 2018.³ More than three-quarters of suicide deaths in Canada are a result of suffocation, poisoning and firearms.^4–6 Suffocation is the predominant suicide method in most countries.⁴ However, the prevalence of different means of suicide can vary over time because of changes in the accessibility of certain means.⁷ Evidence suggests that the relative frequency of different means of suicide has changed in Canada, but those studies have not included data from more recent years.^8,9 Ongoing surveillance of the means of suicide and understanding changes over time are essential for designing and implementing prevention programs.¹⁰It is especially important to consider sex and age in suicide surveillance, because of differences across these sociodemographic characteristics. For instance, females are more likely to self-report thoughts of suicide and to be admitted to hospital owing to self-inflicted injuries,^5,11 while suicide mortality rates are about 3 times higher among males than females in Canada.^2,3,6 Higher suicide mortality rates for males have been observed in almost all countries,¹ and have been attributed, in part, to more lethal means of suicide (e.g., firearms).^5,6,12 Suicide-related behaviour also varies across the lifespan, with the suicide mortality rate tending to be high in middle-aged adults and males older than 80 years, but hospital admissions owing to self-inflicted injuries tending to occur during adolescence (particularly among females).^2,3,5,6,13Canadian data from 2000 to 2009 indicated that suicide by suffocation was more prevalent among individuals aged 15–39 years, while suicide by firearm was more prevalent among individuals aged 60 years and older.⁶ Canadian data for 2001 to 2011 suggested that rates of suicide by firearm and poisoning declined for males aged 15 years and older, but were unchanged among females during this period.⁹ Less is known about whether the means used by age and sex groups have fluctuated over longer periods and in more recent years. We sought to document the means of suicide deaths in Canada in 2018 (the most recent data available at the time of writing) and investigate how the use of different means has changed for males and females and across age groups since 1981.     

Temporal estimates of case-fatality rate for COVID-19 outbreaks in Canada and the United States

BACKGROUND:Estimates of the case-fatality rate (CFR) associated with coronavirus disease 2019 (COVID-19) vary widely in different population settings. We sought to estimate and compare the COVID-19 CFR in Canada and the United States while adjusting for 2 potential biases in crude CFR.METHODS:We used the daily incidence of confirmed COVID-19 cases and deaths in Canada and the US from Jan. 31 to Apr. 22, 2020. We applied a statistical method to minimize bias in the crude CFR by accounting for the survival interval as the lag time between disease onset and death, while considering reporting rates of COVID-19 cases less than 50% (95% confidence interval 10%–50%).RESULTS:Using data for confirmed cases in Canada, we estimated the crude CFR to be 4.9% on Apr. 22, 2020, and the adjusted CFR to be 5.5% (credible interval [CrI] 4.9%–6.4%). After we accounted for various reporting rates less than 50%, the adjusted CFR was estimated at 1.6% (CrI 0.7%–3.1%). The US crude CFR was estimated to be 5.4% on Apr. 20, 2020, with an adjusted CFR of 6.1% (CrI 5.4%–6.9%). With reporting rates of less than 50%, the adjusted CFR for the US was 1.78 (CrI 0.8%–3.6%).INTERPRETATION:Our estimates suggest that, if the reporting rate is less than 50%, the adjusted CFR of COVID-19 in Canada is likely to be less than 2%. The CFR estimates for the US were higher than those for Canada, but the adjusted CFR still remained below 2%. Quantification of case reporting can provide a more accurate measure of the virulence and disease burden of severe acute respiratory syndrome coronavirus 2.

The risk of death associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to the disease burden imposed by the coronavirus disease 2019 (COVID-19) pandemic. Quantification of this risk can provide critical information on the health and socioeconomic impact of the pandemic and identify population subgroups at highest risk for severe outcomes. The risk of death from a diagnosed infection, often referred to as the case-fatality rate (CFR), is the proportion of people who die from a disease among all those diagnosed with the disease over a certain period.Estimates of the COVID-19 CFR vary in different populations and at different stages of the outbreak, ranging from 0.4% in China¹ to 31.4% in the northwest region of Italy.² From individual-level data for patients in Hubei Province, Mainland China,³ an adjusted CFR of 3.6% (95% confidence interval [CI] 3.6%–3.8%) was estimated. For the outbreak on the Diamond Princess cruise ship, the age-adjusted CFR was estimated at 2.6% (95% CI 0.9%–6.7%) in all age groups but was substantially higher (13.0%, 95% CI 5.2%–26.0%) among those aged 70 years or older.⁴For ongoing outbreaks and especially during the exponential growth phase, the delay between onset of disease and knowledge of the final outcome may result in biased estimates of the CFR.⁵ Furthermore, underestimation of the number of COVID-19 cases will inflate the CFR. Limited ability to test or recognize mildly or moderately symptomatic people in both the United States and Canada has likely led to substantial underestimation of the rate of infection in affected communities.^6,7Given the importance of the CFR in public health planning, we sought to estimate the CFR for ongoing COVID-19 outbreaks in the US and Canada while accounting for preferential ascertainment of severe cases (leading to underestimation) and the lag time between disease onset and death.     

Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis

BACKGROUND:The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID-19) remain uncertain. To support a guideline on COVID-19 management, we conducted a systematic review and meta-analysis of convalescent plasma in COVID-19 and other severe respiratory viral infections.METHODS:In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta-analysis using random-effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.RESULTS:Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID-19. One nonrandomized study (n = 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS-CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70). Pooled estimates from 4 RCTs on influenza (n = 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81), complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference −1.62, 95% CI −3.82 to 0.58, d). The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low-quality evidence).INTERPRETATION:Studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events.

Coronavirus disease 2019 (COVID-19) has been diagnosed in nearly 3 million individuals around the globe, of whom around 0.2 million have died.¹ Many patients with COVID-19 develop severe acute respiratory illness requiring admission to intensive care units (ICU) and often mechanical ventilation.² The case fatality rate in COVID-19 may be as high as 2.3% overall² and from 10% to 40% among severely affected individuals. ^3,4 There is an urgent need for effective therapies.Emerging epidemiologic and clinical data show both similarities and differences between severe COVID-19 and severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).⁵ Similarly, treatment strategies for severe influenza infections tested during the H1N1 pandemic and H5N1 and H7N9 outbreaks could inform the care of patients with severe COVID-19.⁶Of the treatment options proposed for COVID-19,⁷ convalescent plasma has evidence suggesting a mortality benefit for Ebola virus infection.⁸ This intervention has also been tested in other severe acute viral respiratory infections.^6,9,10 “Convalescent plasma” refers to plasma obtained from individuals recently recovered from a viral illness, which is expected to contain the highest levels of polyclonal antibodies directed against the virus.¹¹ Similarly, “hyperimmune plasma” is collected from donors exhibiting high titres of neutralizing antibodies, independent of time elapsed since viral illness. Authors have used the terms interchangeably, and because viral neutralization is only one of the postulated mechanisms by which antibodies exert their antiviral effect, the importance of the distinction between the 2 products remains unclear (Figure 1).Open in a separate windowFigure 1:Potential mechanisms of action of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in coronavirus disease 2019 (COVID-19). This figure illustrates the normal entry of SARS-CoV-2 in a host cell, in which membrane fusion is mediated by the interaction between the SARS-CoV-2 spike glycoprotein (red) and the angiotensin-converting enzyme 2 (ACE2) receptor (green) on the host cell, either through the cytoplasmic or endosomal route. Antibodies directed against the receptor-binding domain (RBD) of the spike protein can interfere with its interaction with the ACE2 receptor and prevent viral entry in the host cell (panel A). Antibodies directed against epitopes outside the RBD can also exert antiviral functions through other mechanisms (panels B, C and D). The relative importance of these various functions in rescuing patients from an active SARS-CoV-2 infection is unknown. Importantly, neutralization assays generally used to qualify hyperimmune products measure only 1 of the 4 mechanisms depicted here and do not necessarily correlate with the others.Clinicians have typically administered convalescent plasma to patients with viral infections whose condition deteriorated despite supportive care.⁶ Although the primary postulated mechanism of action of convalescent plasma is reduction in viremia (passive immunity),¹² an increase in host immune response (active immunity) has also been proposed.¹³ We describe in Figure 1 the possible mechanisms by which convalescent plasma inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Systematic summaries of the available evidence regarding safety and effectiveness can inform the use of convalescent plasma in patients with COVID-19. We therefore conducted a systematic review to summarize the evidence for convalescent plasma to support a guideline on COVID-19 management.¹⁴ Because we anticipated a paucity of direct evidence addressing the use of convalescent plasma in COVID-19, we summarized the available evidence addressing convalescent plasma in the treatment of SARS, MERS and influenza, including H1N1, H7N9 and H5N1, as well as addressing possible adverse effects in patients with Ebola disease.     

A population-based analysis of the impact of the COVID-19 pandemic on common abdominal and gynecological emergency department visits

BACKGROUND:Reduced use of the emergency department during the COVID-19 pandemic may result in increased disease acuity when patients do seek health care services. We sought to evaluate emergency department visits for common abdominal and gynecologic conditions before and at the beginning of the pandemic to determine whether changes in emergency department attendance had serious consequences for patients.METHODS:We conducted a population-based analysis using administrative data to evaluate the weekly rate of emergency department visits pre-COVID-19 (Jan. 1–Mar. 10, 2020) and during the beginning of the COVID-19 pandemic (Mar. 11–June 30, 2020), compared with a historical control period (Jan. 1–July 1, 2019). All residents of Ontario, Canada, presenting to the emergency department with appendicitis, cholecystitis, ectopic pregnancy or miscarriage were included. We evaluated weekly incidence rate ratios (IRRs) of emergency department visits, management strategies and clinical outcomes.RESULTS:Across all study periods, 39 691 emergency department visits met inclusion criteria (40.2 % appendicitis, 32.1% miscarriage, 21.3% cholecystitis, 6.4% ectopic pregnancy). Baseline characteristics of patients presenting to the emergency department did not vary across study periods. After an initial reduction in emergency department visits, presentations for cholecystitis and ectopic pregnancy quickly returned to expected levels. However, presentations for appendicitis and miscarriage showed sustained reductions (IRR 0.61–0.80), with 1087 and 984 fewer visits, respectively, after the start of the pandemic, relative to 2019. Management strategies, complications and mortality rates were similar across study periods for all conditions.INTERPRETATION:Although our study showed evidence of emergency department avoidance in Ontario during the first wave of the COVID-19 pandemic, no adverse consequences were evident. Emergency care and outcomes for patients were similar before and during the pandemic.

Avoidance of the emergency department for conditions that may require urgent surgery has been a global concern during the COVID-19 pandemic, and could result in higher case severity and morbidity.^1–3 Resource constraints and provider concerns around the safety of surgery^4–6 may influence rates of nonoperative management for abdominal and gynecological emergencies,⁷ even when existing nonoperative options are not optimal. Limited data suggest that patients with appendicitis and cholecystitis, the 2 most common abdominal emergencies that routinely require operative management,^8,9 may be more likely to avoid the hospital,¹⁰ present with more severe illness^9,10 and be managed nonoperatively during the pandemic, with uncertain consequences for patient outcomes.^10–13 Similarly, the management of early pregnancy complications (i.e., miscarriage and ectopic pregnancy) may be medical or surgical, depending on patient preference and pregnancy characteristics (e.g., stability, gestational age).¹⁴ Up to 80% of women experiencing miscarriage routinely access emergency services; however, there are concerns that women requiring emergency care for miscarriages are avoiding the emergency department.¹⁵ Reduced access to emergency care for early pregnancy complications may result in more adverse outcomes; a study in Italy found an increased rate of ruptured ectopic pregnancy in the early months of the pandemic.¹⁶We sought to characterize the impact of COVID-19 on emergency department visits for and management of appendicitis, cholecystitis, miscarriage and ectopic pregnancy. We aimed to determine if there was a difference in the rate of patients presenting to the emergency department before and during the pandemic, whether a reduction in emergency department visits for these conditions resulted in adverse patient outcomes and whether the proportion of patients undergoing operative management differed before and during the pandemic.     

Risk factors for outbreaks of SARS-CoV-2 infection at retirement homes in Ontario,Canada: a population-level cohort study

BACKGROUND:The epidemiology of SARS-CoV-2 infection in retirement homes (also known as assisted living facilities) is largely unknown. We examined the association between home-and community-level characteristics and the risk of outbreaks of SARS-CoV-2 infection in retirement homes since the beginning of the first wave of the COVID-19 pandemic.METHODS:We conducted a population-based, retrospective cohort study of licensed retirement homes in Ontario, Canada, from Mar. 1 to Dec. 18, 2020. Our primary outcome was an outbreak of SARS-CoV-2 infection (≥ 1 resident or staff case confirmed by validated nucleic acid amplification assay). We used time-dependent proportional hazards methods to model the associations between retirement home– and community-level characteristics and outbreaks of SARS-CoV-2 infection.RESULTS:Our cohort included all 770 licensed retirement homes in Ontario, which housed 56 491 residents. There were 273 (35.5%) retirement homes with 1 or more outbreaks of SARS-CoV-2 infection, involving 1944 (3.5%) residents and 1101 staff (3.0%). Cases of SARS-CoV-2 infection were distributed unevenly across retirement homes, with 2487 (81.7%) resident and staff cases occurring in 77 (10%) homes. The adjusted hazard of an outbreak of SARS-CoV-2 infection in a retirement home was positively associated with homes that had a large resident capacity, were co-located with a long-term care facility, were part of larger chains, offered many services onsite, saw increases in regional incidence of SARS-CoV-2 infection, and were located in a region with a higher community-level ethnic concentration.INTERPRETATION:Readily identifiable characteristics of retirement homes are independently associated with outbreaks of SARS-CoV-2 infection and can support risk identification and priority for vaccination.

Frail older adults living in congregate care settings have been at the centre of the COVID-19 pandemic in Canada and internationally.^1,2 Long-term care facilities — whose residents are the congregate living population most affected by COVID-19 — have been the subject of immense scientific and public interest during the pandemic.³ Retirement homes (often known as assisted living facilities) have received far less examination despite also housing many vulnerable older adults.^4–7 In contrast to long-term care facilities, retirement homes are private residential complexes that provide a range of supportive care and lifestyle services that are purchased out of pocket by residents or their families.⁸ Although residents of retirement homes access supportive care services, they are substantially less frail and dependent than residents of long-term care homes.⁵ Inconsistent regulation of these facilities throughout Canada and the United States has limited research into the epidemiology of SARS-CoV-2 infection in retirement homes.⁹There are 770 licensed retirement homes in Ontario, Canada’s most populous province, that house more than 50 000 older adults, a population size that approaches the number of Ontario residents of long-term care homes.¹⁰ Since the onset of the COVID-19 pandemic in Ontario, the number of positive cases and deaths in retirement homes has continued to grow. As of Apr. 11, 2021, retirement home residents accounted for about 8% of deaths from COVID-19 in Ontario (596/7552).¹¹ Outbreaks of SARS-CoV-2 infection surged in retirement homes during the first and second waves in Canada and the US,^11,12 and there has been limited examination in the literature beyond early reports of case surveillance.¹³We examined the association between home- and community-level characteristics and the risk of outbreaks of SARS-CoV-2 infection during the first wave of the COVID-19 epidemic in Ontario’s retirement homes. Consistent with our previous population-level work in Ontario long-term care homes,^2,14 we hypothesized that home size and regional incidence of SARS-CoV-2 infection would be associated with the risk of an outbreak.