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

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