Risk factors and preventive interventions for post Covid-19 condition: systematic reviews (preprint)

Background: The Covid-19 outbreak has presented many challenges to governments and healthcare systems, including observations of symptoms that persist beyond acute infection labelled as post Covid-19 condition. Objectives: To systematically identify and synthesize evidence around pre-existing and clinical risk factors for post Covid-19 condition (occurring [≥]12 weeks after positive test/symptom onset) (KQ1), and interventions during the acute and post-acute phases of the illness that could potentially prevent post Covid-19 condition (KQ2). Methods: We searched Medline and Embase (Jan 2021-Aug 12 2021 [KQ1], and Jan 2020-Jul 28, 2021 [KQ2]), Clinicaltrials.gov, organizational websites, and reference lists of included studies and relevant systematic reviews. Two investigators independently reviewed abstracts and full-text articles against a priori inclusion criteria, and disagreements were resolved through discussion or by consulting a third reviewer. One investigator abstracted data and assessed risk of bias using design-specific criteria, and a second investigator checked data abstraction and assessments for completeness and accuracy. Meta-analysis was performed when there was sufficient clinical and methodological similarity in an exposure-outcome comparison, based on prespecified variables. We assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach (GRADE). A relative effect/association of 0.75-1.49 was considered as little-to-no, whereas 0.50-0.74/1.5-1.99 was small-to-moderate and <0.50/[≥]2.00 was large for fewer/benefit or more/harm, respectively Results: From 4,672 (KQ1) and 3,781 (KQ2) citations we included 17 and 18 studies, though 4 studies were included for both KQs. We found small-to-moderate associations between female sex and higher non-recovery, fatigue, and dyspnea (moderate certainty). Severe or critical acute-phase Covid-19 severity (versus not) has probably (moderate certainty) a large association with increased cognitive impairment, a small-to-moderate association with more non-recovery, and a little-to-no association with dyspnea. There may be (low certainty) large associations between hospitalization during the acute illness and increased non-recovery, increased dyspnea, and reduced return to work. There may be small-to-moderate associations between several other risk factors and post Covid-19 condition outcomes, including age [≥]60 versus <60 (functional incapacity), non-White people (lower return to work), children age >6 versus <2 years (non-recovery), having [≥]1 versus no comorbidities (non-recovery), chronic pulmonary disease (fatigue), rheumatologic disorder (depression/anxiety), and chronic obstructive pulmonary disease or hypertension (cognitive impairment). Several other risk factors had low certainty for little-to-no association with one or more outcomes (e.g. diabetes, cardiovascular disease) or very low certainty. Interventions to prevent post Covid-19 condition included medications (standard and traditional/ayurvedic), stem cell therapy, rehabilitation or similar therapies, and screening/referrals at either acute phase (symptom onset to 4 weeks) or early post-acute phase (4-8 week), with short (12-16 weeks) or longer (>16 weeks) follow-up for outcomes. We are very uncertain about the effects of preventive interventions, mainly due to risk of bias, inconsistency/lack of consistency (single studies), and in some cases imprecision. Conclusions: Guidelines in relation to surveillance, screening services, and other services such as access to sickness and disability benefits, might need to focus on females and those with previously severe Covid-19 illness. Interventions targeting fatigue, dyspnea, and cognitive impairment (especially in those who had severe Covid-19) may be good to prioritize for development and evaluation to provide evidence on their effects. Inputs from patients and primary care providers should be taken into account when developing new care pathways and some tailoring to individual needs will likely be paramount. Continuous assessment of the rapidly emerging evidence is important to better shape our understanding as the body of evidence grows. Sufficiently powered prospective trials of preventive interventions are warranted. PROSPERO registration: CRD42021270354

Myocarditis and Pericarditis following COVID-19 Vaccination: Evidence Syntheses on Incidence, Risk Factors, Natural History, and Hypothesized Mechanisms (preprint)

Objectives Myocarditis and pericarditis are adverse events of special interest after vaccination for COVID-19. Evidence syntheses were conducted on incidence rates, risk factors for myocarditis and pericarditis after COVID-19 mRNA vaccination, clinical presentation and short- and longer-term outcomes of cases, and proposed mechanisms and their supporting evidence. Design Systematic reviews and evidence reviews. Data sources Medline, Embase and the Cochrane Library were searched from October 2020 to January 10, 2022; reference lists and grey literature (to January 13, 2021). Review methods Large (>10,000) or population-based/multisite observational studies and surveillance data (incidence and risk factors) reporting on confirmed myocarditis or pericarditis after COVID-19 vaccination; case series (n≥5, presentation, short-term clinical course and longer-term outcomes); opinions/letters/reviews/primary studies focused on describing or supporting hypothesized mechanisms. A single reviewer completed screening and another verified 50% of exclusions, using a machine-learning program to prioritize records. A second reviewer verified all exclusions at full text, extracted data, and (for incidence and risk factors) risk of bias assessments using modified Joanna Briggs Institute tools. Team consensus determined certainty of evidence ratings for incidence and risk factors using GRADE. Results 46 studies were included (14 on incidence, 7 on risk factors, 11 on characteristics and short-term course, 3 on longer term outcomes, and 21 on mechanisms). Incidence of myocarditis after mRNA vaccines is highest in male adolescents and young adults (12-17y: range 50-139 cases per million [low certainty] and 18-29y: range 28-147 per million [moderate certainty]). For 5-11 year-old males and females and females 18-29 years of age, incidence of myocarditis after vaccination with Pfizer may be fewer than 20 cases per million (low certainty). There was very low certainty evidence for incidence after a third dose of an mRNA vaccine. For 18-29 year-old males and females, incidence of myocarditis is probably higher after vaccination with Moderna compared to Pfizer (moderate certainty). Among 12-17, 18-29 and 18-39 year-olds, incidence of myocarditis/pericarditis after dose 2 of an mRNA vaccine may be lower when administered ≥31 days compared to ≤30 days after dose 1 (low certainty). Data specific to males aged 18-29 indicated that the dosing interval may need to increase to ≥56 days to substantially drop incidence. For clinical course and short-term outcomes only one small series (n=8) was found for 5-11 year olds. In cases of adolescents and adults, the majority (>90%) of myocarditis cases involved 20-30 year-old males with symptom onset 2 to 4 days after second dose (71-100%). Most cases were hospitalized (≥84%) for a short duration (2-4 d). For pericarditis, data is limited but more variation has been reported in patient age, sex, onset timing and rate of hospitalization. Case series with longer-term (3 mo; n=38) follow-up suggest persistent ECG abnormalities, as well as ongoing symptoms and/or a need for medications or restriction from activities in >50% of patients. 16 hypothesized mechanisms are described, with little direct supporting or refuting evidence. Conclusions Adolescent and young adult males are at the highest risk of myocarditis after mRNA vaccination. Pfizer over Moderna and waiting more than 30 days between doses may be preferred for this population. Incidence of myocarditis in children aged 5-11 may be very rare but certainty was low. Data on clinical risk factors was very limited. Clinical course of mRNA related myocarditis appears to be benign although longer term follow-up data is limited. Prospective studies with appropriate testing (e.g., biopsy, tissue morphology) will enhance understanding of mechanism(s). Funding and Registration no This project was funded in part by the Canadian Institutes of Health Research (CIHR) through the COVID-19 Evidence Network to support Decision-making (COVID-END) at McMaster University. Not registered. Summary box What is already known about this topic? Case reports and surveillance signals of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the two-layered sac surrounding the heart) after COVID-19 vaccination appeared as early as April 2021. These have prompted ongoing surveillance and research of these complications to investigate their incidence, possible attribution to the vaccines, and clinical course. What this study adds This review critically appraises and synthesizes the available evidence to-date on the incidence of and risk factors for myocarditis and pericarditis after COVID-19 vaccination in multiple countries. It summarizes the presentation and clinical course of over 8000 reported cases and describes some initial reports of longer term outcomes. Further, many possible mechanisms are outlined and discussed. Though low, the incidence of myocarditis is probably the highest in young males aged 12-29 years and is probably higher with Moderna than Pfizer mRNA vaccines. Longer dosing intervals may be beneficial. Most cases are mild and self-limiting, though data in 5-11 year-olds is very limited. Continued active surveillance with longer term follow-up is warranted.

Myocarditis and Pericarditis following COVID-19 Vaccination: Rapid Systematic Review of Incidence, Risk Factors, and Clinical Course (preprint)

Objectives: Myocarditis and pericarditis are adverse events of special interest after vaccination with mRNA vaccines. This rapid systematic review examined incidence rates of myocarditis and pericarditis after COVID-19 vaccination, and the presentation and clinical course of cases. Design: Rapid systematic review Data sources: Medline, Embase and the Cochrane Library were searched from October 2020 to October 6, 2021; reference lists and grey literature (to Oct 21, 2021). Review methods: Randomized controlled trials (RCTs) and large population-based/multisite observational studies and surveillance data reporting on myocarditis or pericarditis in people of any age after receiving any COVID-19 vaccine; systematic reviews of case series. A single reviewer completed screening and another verified 50% of exclusions, using a machine-learning program to prioritize records. A second reviewer verified all exclusions at full text, data extractions, and (for incidence) risk of bias assessments using Cochrane Risk of Bias 2.0 and Joanna Briggs Institute tools. Certainty of evidence ratings for incidence were based on team consensus using GRADE. Patient partners provided key messages from their interpretations of the findings. Results: 3457 titles/abstracts and 159 full texts were screened. For incidence rates we included 7 RCTs (n=3732 to 44,325) and 22 large observational studies/data sources using passive (n=10) and active (n=12) surveillance; for case presentation, we included 11 case series published as articles and three based on publicly available websites (n=12,636 cases). Mainly due to imprecision, the RCTs provided very low certainty evidence for incidence of myocarditis or pericarditis. From observational data, the incidence of myocarditis following mRNA vaccines is low but probably highest in males 12-17 years (55 [7-day risk] to 134 [30-day risk] cases per million; specific to Pfizer) and 18-29 years (40 [7-day risk] to 99 [21-30 day risk]) cases per million) (Moderate certainty evidence). Incidence is lower (<20 per million) or little-to-none in older ages and across all ages of females (Low certainty). Evidence for pericarditis was of very low certainty. Among adult males under 40 years, Moderna compared with Pfizer vaccine may be associated with a small increase (<20 per million) in risk for myocarditis or (one of) myocarditis or pericarditis following vaccination (Low certainty); the evidence for youth under 18 years was very uncertain. No study examined differences in incidence based on pre-existing condition(s) or risk factors apart from age and sex. The majority of myocarditis cases involved males (often >90%) in their 20s, with a short symptom onset of 2 to 4 days after a second dose (71-100%). The majority of cases presented with chest pain/pressure and troponin elevation; a minority (<30%) had left ventricular dysfunction. Most were hospitalized (≥84%), without stays in intensive care units, for a short duration (2-4 d) and treated with anti-inflammatory and/or other supportive therapies. Almost all reports of death are from unverified cases and of unclear cause. Most cases of pericarditis were unconfirmed; for this outcome there appears to be more variation in age, sex, onset timing and rate of hospitalization. Conclusions: Incidence of myocarditis following mRNA vaccines is low but probably highest in males 12-29 years old. Existing evidence does not strongly support preference of one mRNA vaccine, even in young males. Continued active surveillance of myocarditis incidence out to 30 days from dosing is recommended with respect to i) new populations (i.e., children <12y), ii) third and subsequent doses, and iii) affected individuals receiving subsequent mRNA vaccine doses. Future research is needed to examine other risk factors and long-term effects.

Risk factors associated with severe outcomes of COVID-19: An updated rapid review to inform national guidance on vaccine prioritization in Canada (preprint)

Background: To inform vaccine prioritization guidance by the National Advisory Committee on Immunization (NACI), we reviewed evidence on the magnitude of association between risk factors and severe outcomes of COVID-19. Methods: We updated our existing review by searching online databases and websites for cohort studies providing multivariate adjusted associations. One author screened studies and extracted data. Two authors estimated the magnitude of association between exposures and outcomes as little-to-no (odds, risk, or hazard ratio <2.0, or >0.50 for reduction), large (2.0-3.9, or 0.50-0.26 for reduction), or very large (>=4.0, or <=0.25 for reduction), and rated the evidence certainty using GRADE. Results: Of 7,819 unique records we included 111 reports. There is probably (moderate certainty) at least a large increase in mortality from COVID-19 among people aged 60-69 vs. <60 years (11 studies, n=517,217), with 2+ vs. no comorbidities (4 studies, n=189,608), and for people with (vs. without): Down syndrome (1 study, n>8 million), type 1 and 2 diabetes (1 study, n>8 million), end-stage kidney disease (1 study, n>8 million), epilepsy (1 study, n>8 million), motor neuron disease, multiple sclerosis, myasthenia gravis, or Huntingtons disease (as a grouping; 1 study, n>8 million). The magnitude of association with mortality is probably very large for Down syndrome and may (low certainty) be very large for age 60-69 years, and diabetes. There is probably little-to-no increase in severe outcomes with several cardiovascular and respiratory conditions, and for adult males vs. females. Interpretation: Future research should focus on risk factors where evidence is low quality (e.g., social factors) or non-existent (e.g., rare conditions), the pediatric population, combinations of comorbidities that may increase risk, and long-term outcomes. Systematic review registration: PROSPERO #CRD42021230185.

Risk factors for severe outcomes of COVID-19: a rapid review (preprint)

Background: Identification of high-risk groups is needed to inform COVID-19 vaccine prioritization strategies in Canada. A rapid review was conducted to determine the magnitude of association between potential risk factors and risk of severe outcomes of COVID-19. Methods: Methods, inclusion criteria, and outcomes were prespecified in a protocol that is publicly available. Ovid MEDLINE(R) ALL, Epistemonikos COVID-19 in LOVE Platform, and McMaster COVID-19 Evidence Alerts, and select websites were searched to 15 June 2020. Studies needed to be conducted in Organisation for Economic Co-operation and Development countries and have used multivariate analyses to adjust for potential confounders. After piloting, screening, data extraction, and quality appraisal were all performed by a single reviewer. Authors collaborated to synthesize the findings narratively and appraise the certainty of the evidence for each risk factor-outcome association. Results: Of 3,740 unique records identified, 34 were included in the review. The studies included median 596 (range 44 to 418,794) participants with a mean age between 42 and 84 years. Half of the studies (17/34) were conducted in the United States and 19/34 (56%) were rated as good quality. There was low or moderate certainty evidence for a large ([≥]2-fold) association with increased risk of hospitalization in people having confirmed COVID-19, for the following risk factors: obesity class III, heart failure, diabetes, chronic kidney disease, dementia, age over 45 years (vs. younger), male gender, Black race/ethnicity (vs. non-Hispanic white), homelessness, and low income (vs. above average). Age over 60 and 70 years may be associated with large increases in the rate of mechanical ventilation and severe disease, respectively. For mortality, a large association with increased risk may exist for liver disease, Bangladeshi ethnicity (vs. British white), age over 45 years (vs. <45 years), age over 80 years (vs. 65-69 years), and male gender in those 20-64 years (but not older). Associations with hospitalization and mortality may be very large ([≥]5-fold increased risk) for those aged over 60 years. Conclusion: Among other factors, increasing age (especially >60 years) appears to be the most important risk factor for severe outcomes among those with COVID-19. There is a need for high quality primary research (accounting for multiple confounders) to better understand the level of risk that might be associated with immigration or refugee status, religion or belief system, social capital, substance use disorders, pregnancy, Indigenous identity, living with a disability, and differing levels of risk among children. PROSPERO registration: CRD42020198001