SARS-CoV-2 Covid-19 Infection During Pregnancy and Differential DNA Methylation in Human Cord Blood Cells From Term Neonates

The effectiveness and safety of mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccines among individuals with chronic kidney diseases

Testing the Asymptomatic Pre-Surgical Population for Severe Acute Respiratory Syndrome Coronavirus 2

Diagnoses of coronavirus disease 2019 (COVID-19) from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were first reported in December 2019. Since its emergence from the Chinese province of Wuhan, the World Health Organization (WHO) has announced 162 million confirmed cases of the SARS-CoV-2 infection worldwide, and reported roughly 3.3 million deaths as of May 16, 2021.1 Stratified by country, the United States leads with nearly 33 million confirmed COVID-19 cases, followed by India, Brazil, France, Turkey, and Russia.2 Structural firefighters perform essential public safety work and have continued that work despite the challenges of COVID-19. Career firefighters typically have long work schedules (24 or 48 hours on duty followed by multiple days off) and eat and sleep at the station as part of a team/shift. Firefighters respond to multiple hazards which include fires and rescues. In many localities, firefighters are dual trained as emergency medical service (EMS) personnel and provide emergency medical care. Because of their close living quarters and contact with the public, including rendering patient care and transporting patients, it is likely that firefighters are at an increased risk of infection with SARS-CoV-2. The fire service is aware of the risk of infection and has quickly adopted the increased use of personal protective equipment (PPE) and modified policies and procedures aimed at reducing the risk to firefighters.3,4 However, very little attention has been paid to occupational risks that may increase the severity of COVID-19 or to the potential long-term consequences of COVID-19 that may pose specific concerns for firefighters. The purpose of this review is to 1) outline the pathogeneses of COVID-19, 2) explore clinical and mechanistic links between COVID-19 and cardiovascular disease, 3) review known risk factors for COVID-19 complications and their prevalence among firefighters, and 4) consider steps that can be taken to better understand the long-term consequences of COVID-19 in the fire service. The review is limited to occupational factors for structural firefighters and does not cover wildland firefighters, although we acknowledge that COVID-19 may also present special concerns for wildland firefighters. PATHOGENESIS OF COVID-19 The SARS-CoV-2 virus enters the body predominantly via the lungs, and often results in pronounced respiratory symptoms. Thus COVID-19 was initially described as a respiratory disease. Indeed, respiratory failure from acute respiratory distress syndrome has been shown to be leading cause of COVID-19 induced mortality.5 A study by Guan et al6 reported that the majority of COVID-19 related consequences feature pneumonia and acute respiratory distress, which is consistent with other analyses suggesting that about 40% of COVID-19 patients develop acute respiratory distress syndrome, and 20% of these syndromes are severe.7 Wang et al8 showed that 61% of the individuals that required intensive care due to COVID-19 developed acute respiratory distress syndrome. COVID-19 not only lead to respiratory symptoms, but also underlying respiratory conditions increase the likelihood of experiencing severe symptoms. Meta-analyses revealed that the odds of severe COVID-19 infection were 5.69 times higher if individuals who have a history of chronic obstructive pulmonary disease.9 The virus requires the cooperation of two key proteins, TMPRSS2, and angiotensinogen converting enzyme 2 (ACE2) to infiltrate the body via the lung pneumocytes. TMPRSS2 is a key cellular regulator of coronavirus spike protein (S protein), with the S1 domain of the S protein responsible for receptor binding and the S2 domain controlling membrane fusion. Thus, coronavirus requires the binding of the S1 region to a cell surface receptor followed by the S2 subunit mediated fusion of the viral and cellular membranes in order to enter its host.10 This process requires S protein priming, or cleavage, by host proteases at the S1and S2 domains of the virus. This process has been described as a principle step for the cellular entry of SARS-CoV-2.11 Following S protein cleavage, Sars-CoV-2 binds to and enters lung cells via the enzyme ACE2, which is highly expressed in alveolar type 2 cells.12 Dissimilar to the original SARS-CoV, it has been suggested that SARS-CoV-2 may have a higher affinity to ACE2 positive cells in the upper respiratory tract, exacerbating its potent and detrimental effects.11 ACE2 is a membranous protein and importantly, an inactivator of angiotensin II (AngII). The binding of SARS-CoV-2 to ACE2 in lung cells promotes the endocytosis of the ACE2-SARS-CoV-2 complex, resulting in a reduction of membrane ACE2 abundance and an increase in serum AngII.12 Thus, SARS-CoV-2's affinity for ACE2 could explain its downstream effects on vascular parameters, including alterations in systolic and diastolic blood pressures, as elevated plasma AngII can increase blood pressure via aldosterone-mediated vasoconstriction and sodium and water retention on the kidneys.13 Furthermore, increased plasma AngII is associated with increased risks of myocardial infarction and left ventricular hypertrophy.13 In addition, SARS-CoV-2 promotes inflammation via the AT1R.12 The AngII-AT1R axis activates pro-inflammatory transcription factors NF-kB and STAT3, upregulating pro-inflammatory cytokines such as TNFa and IL-6 family cytokines,12,14 possibly leading to vascular inflammation and disease. Furthermore, recent studies suggest that the Sars-CoV-2 protein ORF3a encourages an aggressive inflammatory response via NF-κB activation, chemokine secretion, Golgi fragmentation, ER stress, and cell death.15 ORF3a can also inhibit type I interferon (type I IFN) signaling, downregulate major histocompatibility complex (MHC) class I expression, and reduce CD8+ cytotoxic T cell activity. Specifically, Siu et al15 demonstrated that ORF3a encourages the binding of TRAF3 to cytoplasmic portions of TNF receptors, promoting ubiquitination, and processing of p105 to p50. P50 is generated by TRAF3 ubiquitin-ligase ubiquitination of p150 and 26S proteasome-mediated removal of p105C terminal sequences. P50 then binds to RelA, RelB, or C-Rel subunits to produce functional NF-κB, a transcription factor essential for pro-IL-1β expression. The prevalence of pro-IL-1β transcripts is a requirement for NLRP3 inflammasome activation. Therefore, ORF3a-mediated p105 processing into p50 can help activate the NLRP3 inflammasome and lead to a robust inflammatory response.15 Siu et al further demonstrated ORF3a's ability to induce ASC polyubiquitination via a TRAF3 ubiquitin-ligase.15 ASC is the adapter complex of the NLRP3 inflammasome, and polyubiquitination of ASC provides a nondegradative signal necessary for ASC activation, caspase-1 activation, and mature IL-1β protein formation.15 Ultimately, the studies mentioned above illustrate how COVID-19 can target the cardiovascular system through its mode of entry and lead to vascular inflammation and dysfunction via upregulation of pro-inflammatory signaling. COVID-19 AND CARDIOVASCULAR DISEASE Although SARS-CoV-2 was first described as a respiratory disease, cardiac tissue and blood vessels express ACE2 receptors and appear to be particularly prone to COVID-19 infection.14 The heart, an ACE2 expressing tissue, was studied during the Toronto SARS outbreak (SARS-CoV), and investigators found evidence of SARS-CoV RNA in 35% of autopsied hearts.16 COVID-19 acts in a similar manner to the previous SARS-CoV, indicating that individuals with cardiovascular disease (CVD) are more prone to severe complications of SARS-CoV-2 compared to healthy individuals. Initial research on CVD-induced complications of COVID-19 was conducted in China. Wang et al investigated the association between biomarkers of CVD and the exacerbation of COVID-19 in hospitalized patients and found that cardiac injury, defined as either elevated high-sensitivity cardiac troponin I (hs-cTnI) or ECG/echocardiographic abnormalities, was present in 7.2% of the patients.8,17,19 The study also found that 22% of COVID-19 patients in ICU had biomarkers of cardiac injury.8,17 Zhou et al reported that hs-cTnI levels were at or greater than the 99th percentile upper reference limit in 46% of non-survivors, compared to only 1% of survivors who had levels this high.17,18 Thus, it has become apparent that COVID-19 can have severe cardiovascular consequences. Ultimately, it is also becoming clear that the presence of CVD, or CVD risk factors, can increase the likelihood of severe complications of COVID-19. The observational study by Zhou et al described above, also reported that 8% of patients (13% of non-survivors) had been diagnosed with CVD and 38% (48% of non-survivors) had been diagnosed with hypertension.17,18 Furthermore, Wang et al found that comorbidity of COVID-19 and CVD was prevalent in 15% (25% requiring ICU care) of patients analyzed, and Guan et al reported that 2.5% (9% among those with intubation or death) of COVID-19 patients also suffered from coronary artery disease.10,11,14 Chen et al demonstrated that in a cohort of 99 COVID-19 infected individuals at the Wuhan Jinyintan Hospital, 40% had some manifestation of cardiovascular or cerebrovascular disease.19 Other researchers have also reported on the higher prevalence of hypertension among COVID-19 patients; one study that although reports 15% of COVID patients had hypertension, 36% of those who needed intubation or suffered death had hypertension. Another study reported 31% of patients with COVID-19 had hypertension; however, 58% of patients requiring ICU care had hypertension.6,8 These findings demonstrate a clinical link between COVID-19 and CVD. EFFECT OF COVID-19 ON CARDIOVASCULAR SYSTEM Following the COVID-19 outbreak, researchers have begun to investigate the mechanisms associating COVID-19 and CVD. Emerging evidence strongly suggests the SARS-CoV-2 infection decreases myocardial functioning. Previous research has demonstrated that SARS-CoV, resembling both the structure and function of SARS-CoV-2, perturbates myocardial functioning.20 Recent research analyzing the cardiac manifestations of the SARS-CoV-2 infection found that the most common cardiac abnormality (39% of patients at baseline) was right ventricular dilation and dysfunction, followed by left ventricular diastolic and systolic dysfunction (16% and 10% of patients at baseline, respectively).21 In this study, 20% of these patients had clinical deterioration, with 60% of them having right ventricle deterioration and 25% having left ventricle systolic and diastolic deterioration.20 Thus, it appears that COVID-19, similar to other severe hypoxic respiratory illnesses, impairs cardiac function mostly by a right ventricular pressure overload state. Myocardial injury involves a pronounced escalation in pro-inflammatory cytokine secretions, which is commonly seen in COVID-19 patients. Specifically, research has found that patients suffering from COVID-19 had an upregulation of the pro-inflammatory cytokines IL1B, IFNγ, IP10, and MCP1. Individuals in ICU admission for COVID-19 had higher concentrations of the cytokines GCSF, IP10, MCP1, MIP1A, and TNFα than those not in ICU.22 An increase in these molecules due to COVID-19 severity can lead to an activation and dysregulation of T helper cells.22 Imbalances in (type 1 and type 2) T helper cells can lead to respiratory dysfunction, hypoxemia, and myocardial injury.20 Interestingly, Huang et al noticed that type 2 T-helper cell cytokines (IL4 and IL10), that suppress inflammation, were upregulated during infection of SARS-CoV-2.20 A study of competitive athletes recovering from COVID-19 found that 15% (4/26) had cardiovascular magnetic resonance findings suggestive of myocarditis despite only 2 of the 4 participants with findings suggestive of myocarditis having had COVID-19 symptoms.23 Acute thrombotic events are another major complication in individuals fighting the SARS-CoV-2 infection. Blood hypercoagulability has been shown to be common among hospitalized COVID-19 patients.24 Elevated D-Dimer levels, associated with thrombus formation and breakdown, are also reported in COVID-19 patients, worsening over the course of the disease.24 A review by Terpos et al elegantly describes how thrombus degradation products including PT and aPT are consistently upregulated in individuals requiring ICU admission.24 COVID-19 has also been shown to induce acute pulmonary embolisms in certain individuals,24–27 and one study found that 30% of COVID-19 patients had acute pulmonary embolus, measured by a CT coronary angiogram.28 This rate of pulmonary embolus is higher than what is usually seen in critically ill patients without COVID-19 (1.3%).28 Ultimately, COVID-19 patients are at higher risk for thromboembolic events, leading to adverse cardiovascular health risks. The endothelium plays key roles in regulating blood flow, maintaining hemostatic balance, and in immune response. Emerging evidence suggests that a vascular disease process contributes to COVID-19 pathogenesis.29 Several studies have begun to elucidate the role of endothelial dysfunction with COVID-19. Epithelial dysfunction, specifically pulmonary endothelial damage, is a common manifestation observed in patients infected with SARS Cov-2 virus and other coronaviruses.26 Endothelium damage due to COVID-19 is thought to occur by multiple mechanisms, including: a dysregulated immune response, enhanced vascular permeability, and exacerbated presence of pulmonary edemas.26,30 Varga et al31 demonstrated endothelial cell dysfunction in vital organs of individuals after becoming infected with COVID-19. These authors presented convincing evidence to indicate that the SARS CoV-2 virus has direct effects on endothelial cells, possibly due to the fact that ACE2 is also widely expressed on endothelial cells in multiple organs.14 Thus, it appears that recruitment of immune cells and pro-inflammatory cytokines due to ubiquitous expression of ACE2 can result in extensive endothelial dysfunction and cellular apoptosis. THE EFFECTS OF OBESITY ON CARDIOVASCULAR HEALTH AND COVID-19 Obesity has been recognized as an important predictor of CVD risk and adverse cardiorespiratory outcomes. Genetic and clinical experiments have found that that obesity is causally related to many disease states including hypertension, diabetes mellitus type 2, coronary heart disease, stroke, atrial fibrillation, renal disease, and heart failure.32 Others have reported that around 75% of hypertension can be attributed to obesity.33 It is clear that this obesity-induced hypertension leads to renal dysfunction due to an increased sympathetic nervous state and upregulated renin–angiotensin system.33 Obesity has effects on the infection and exacerbation of the SARS-CoV-2 infection. Sattar et al propose that obesity and ectopic fat deposition might reduce both optimal cardiorespiratory and immune response mechanisms, two major factors that can lead to severe manifestations of COVID-19.32 Several studies have reported on an association between obesity and COVID-19. Hamer et al reported a two-fold risk ratio of being infected with COVID-19 for obese individuals compared to normal weight individuals.34 These risk ratios were adjusted for age, sex, and mutually for each lifestyle, and physical inactivity. Furthermore, obesity was identified as the risk factor that contributed greatly to the prediction of COVID-19 infection risk. Finally, Hamer et al calculated a Population Attributable Fraction (PAF), which corresponds to the prevalence of risk factors in a population and the strength of its association with an outcome (COVID-19).34 The PAF used adjusted effect estimates on lifestyle factors (smoking, physical inactivity, overweight, and obesity) and COVID-19 and found that the total PAF for the three unhealthy lifestyle factors was 51.4%.34 Specifically, overweight and obesity had a PAF of 29.5%, smoking had a PAF of 13.3%, and physical inactivity had a PAF of 8.6%. Overall, it has become quite clear through both mechanistic and clinical research that there is a powerful effect of obesity on COVID-19 infection and severity. POTENTIAL RELATIONSHIPS BETWEEN FIREFIGHTERS AND COVID-19 As discussed through this paper, there is a strong relationship between both pulmonary disease, CVD and COVID-19. While initial research has focused on risk factors that place individuals at increased risk for COVID-19 complications, this section details ways that occupational exposures and cardiovascular risk factors that are known to be prevalent among firefighters, might make firefighters an occupational group that is at high risk of developing COVID-19 complications and for whom the long-term effects of COVID-19 infection might be particularly problematic. As summarized in Tables 1 and 2 and discussed in the following section, there are multiple factors that are known to exacerbate the rate of infection or severity of infection with SARS-CoV-2 and that are occupationally associated with firefighting. TABLE 1 - Association Between Medical Conditions of COVID-19 and Firefighting Medical Conditions COVID-19 Research Fire Service Research 1. Pulmonary disease • Significantly associated with a severe COVID-19 infection (OR 5.69, 95% CI: 2.49–13.00)9• 30% of studied COVID-19 patients developed acute respiratory distress syndrome,28 61% of studied COVID-19 patients developed acute respiratory distress syndrome,7,8,28 with approximately 20% of these cases being severe8 • Decrements in respiratory function were two-to-four-times greater in firefighters than general population35• Pulmonary function is associated with frequency of fire exposure36• Those who transitioned to less active assignments might not be protected from pulmonary disease88 2. Cardiovascular disease • 15–40% of patients had some manifestation of cardiovascular or cerebrovascular disease7,8,19 • Firefighters with other comorbidities demonstrated unfavorable CVD and cardiorespiratory fitness profiles70 COVID-19, coronavirus disease 2019; CVD, cardiovascular disease. TABLE 2 - Association Between Risk Factors of COVID-19 and Firefighting Risk Factors COVID-19 Research Fire Service Research 1. Age • Significant association of older age (≥65 years) and risk of COVID-19 mortality• Ranging from an OR of 3.76 (95% CI: 1.15–17.39; P = 0.023) to 4.59 (95% CI: 2.61–8.04; P < 0.001)57,58 • 9% of the entire US firefighting cohort is 60 years of age or older55 2. Sex • Males have made up as much as 60.3–70% of patients hospitalized with the SARS-CoV-2 infection• Prostatic diseases are associated with elevations in COVID-19 induced cardiac injury (OR 1.505, 95% CI; P = 0.046)60• In males, each standard deviation increase in free androgen escalates risk of severe COVID-19 manifestations (OR 1.22, 95% CI: 1.03–1.45; P = 0.024)60 • 96% of the US fire service is comprised of men, and more than half of US metropolitan departments have no women firefighters55,62 3. Hypertension • 56.6% of New York City area COVID-19 patients had hypertension59• Significant associate of COVID-19 mortality (pooled OR 2.70, 95% CI: 1.40–5.24; P = 0.003)57 • Up to 30% of the entire fire service have hypertension63,72• 46% of males and 29% of females firefighters had blood pressure the of 1 or 2 58% of firefighters and of firefighters have Obesity • been as the one of COVID-19 obese individuals are at greater risk for severe COVID-19 • of firefighters = were as either overweight or of overweight and obese firefighters may the US Cardiovascular • troponin is associated with COVID-19 mortality risk (OR 95% CI: P < cardiac injury in 7.2% of patients, and in 22% of ICU of patients had right ventricular dilation and dysfunction, had left ventricular diastolic dysfunction, 10% had systolic • Acute of decreases can induce ventricular and of myocardial and blood and • increased ACE2 and TMPRSS2 in alveolar type 2 cells and • Decrements in were more than the rate in were related to frequency of fire but not to age, smoking or Firefighters who a during fire a times greater rate of compared to COVID-19, coronavirus disease 2019; vital Pulmonary from recent study indicate that in the respiratory function of firefighters years) was two-to-four-times greater than the in the general reports with findings and also that the of pulmonary function in firefighters is associated with the frequency of fire of fires are more potent of than previous on their occupational firefighters appear to be at an increased risk of pulmonary is less evidence that firefighting leads to increased pulmonary disease, but this is a pulmonary disease is associated with increased risk for developing a severe COVID-19 infection. Pulmonary Risk and the acute and long-term effects of and is a in the fire service. have that and can reduce firefighters in 1 by lung function often to Furthermore, et demonstrated an of in firefighters following a of with 30% of the cohort having a in of Other studies have shown that the in which firefighters for and of can cause decreases in and vital as as in serum cell protein and serum studies the effects of long-term and on health have been the results are A study conducted on firefighters from the fire showed that in the and were not associated with of firefighting in active and that the protective respiratory equipment used by the fire service to be the detrimental effects of enhanced and In addition, a review of studies from to that the of and on health is and limited by of and that firefighters in pulmonary However, a study by et found that the in were more than the rate and was related to frequency of fire but not to age, smoking or et further showed that active firefighters a greater in compared to those who had or firefighters who a during fire a times greater rate of compared to Other studies have shown that with respiratory use in et showed that after years of there was a 10% in the of firefighters who to the World Thus, there is but not evidence that to and can both and pulmonary function in firefighters, use of respiratory protective equipment in the fire service. As pulmonary function is a robust to COVID-19 infection and severe COVID-19 Recent evidence also demonstrated that to can increase both ACE2 and TMPRSS2 in alveolar type 2 cells and due to firefighting might have a direct effect on COVID-19 but further research is Cardiovascular Risk Age cardiovascular health is by the prevalence of cardiovascular risk factors which can include age, sex, hypertension, and from that 9% of US firefighters are 60 years of age or Although a this of the fire service might have a more pronounced risk of COVID-19 infection than the general A recent observational study reported that age is one of the leading risk factors for infection and death due to Other studies have confirmed this that older individuals (≥65 years) have from to times higher risk of COVID-19 Cardiovascular Risk Sex suggests that males are more to a COVID-19 infection than with one study from the New York City area that males made up of the patients hospitalized with the SARS-CoV-2 A study in found that males made up of the patients on in the males were more in COVID-19 patients than in The in and COVID-19 infection is thought to be due to levels of between males and Specifically, TMPRSS2 expression has been shown to be by and androgen receptor which is a requirement for the transcription of et reported that related to androgen increased the odds of having troponin T levels induced cardiac by the et also found that free androgen associated with COVID-19 and severity in males, but not in among males who were for COVID-19, each standard deviation increase in free androgen increased the odds of a positive COVID-19 as as severe COVID-19 by The fire service is et reported that to of the US fire service is comprised of and more than half of US metropolitan departments have no women firefighters. Other that of firefighters and of firefighters are an occupational group by is most likely to be by the SARS-CoV-2, as higher androgen levels are found in Cardiovascular Risk Hypertension Hypertension is a risk factor of COVID-19 and CVD that is known to have a high prevalence the US fire service. Hypertension is reported to be one of the most common comorbidities related to COVID-19 infection. In et al found that hypertension was present in 56.6% of hospitalized COVID-19 patients the New York City A these that chronic hypertension, with other cardiovascular were more among patients than survivors (48% also suggests that hypertension is associated with COVID-19 and that individuals as have higher odds of from COVID-19 than a Research that approximately 20% to 30% of the entire fire service have recent study found that 46% of firefighters and 29% of females had blood pressure the of 1 or 2 Cardiovascular Risk Obesity As discussed obesity has been found to increase the risk of a COVID-19 infection. there is a high prevalence of obesity in the US fire service. have shown that obesity was present in of COVID-19 hospitalized Interestingly, work by et al a between age and body Thus, with pronounced obesity are at an increased risk of being infected with SARS-CoV-2. This is for the US fire as obesity is a major CVD risk factor found in firefighters. Obesity has also been found to increase the risk of coronary heart disease and links the mechanisms of vascular alterations to cardiac suggests that firefighters with high have vascular function and are at a greater risk for

AGA Rapid Recommendations for Gastrointestinal Procedures During the COVID-19 Pandemic

To evaluate the rate of coronavirus disease 2019 (COVID-19) infection with the use of universal testing in our obstetric population presenting for scheduled deliveries, as well as the concordance or discordance rate among their support persons during the initial 2-week period of testing. Additionally, we assessed the utility of a screening tool in predicting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing results in our cohort. This was an observational study in which all women who were scheduled for a planned delivery within the Mount Sinai Health system from April 4 to April 15, 2020, were contacted and provided with an appointment for themselves as well as their support persons to undergo COVID-19 testing 1 day before their scheduled delivery. Both the patients and the support persons were administered a standardized screen specific for COVID-19 infection by telephone interview. Those support persons who screened positive were not permitted to attend the birth. All patients and screen-negative support persons underwent SARS-CoV-2 testing. During the study period, 155 patients and 146 support persons underwent SARS-CoV-2 testing. The prevalence of asymptomatic COVID-19 infection was 15.5% (CI 9.8-21.2%) and 9.6% (CI 4.8-14.4%) among patients and support persons, respectively. The rate of discordance among tested pairs was 7.5%. Among patients with COVID-19 infection, 58% of their support persons also had infection; in patients without infection, fewer than 3.0% of their support persons had infection. We found that more than 15% of asymptomatic maternity patients tested positive for SARS-CoV-2 infection despite having screened negative with the use of a telephone screening tool. Additionally, 58% of their asymptomatic, screen-negative support persons also tested positive for SARS-CoV-2 infection. Alternatively, testing of the support persons of women who had tested negative for COVID-19 infection had a low yield for positive results. This has important implications for obstetric and newborn care practices as well as for health care professionals.

COVID-19 infection in patients with mast cell disorders including mastocytosis does not impact mast cell activation symptoms

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients.

Electrocardiographic features of patients with COVID-19: One year of unexpected manifestations

The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Utilization of deceased donors during a pandemic: argument against using SARS-CoV-2-positive donors.

In-center hemodialysis (HD) patients face greater communicable disease risks, including drug-resistant bacterial colonization and viral hepatitis, compared with home dialysis patients, who limit these risks, avoiding three-times weekly travel to dialysis clinics for treatments (1,2). Minimizing the high coronavirus disease 2019 (COVID-19) morbidity in dialysis patients is essential (3). We explored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive rates, COVID-19–related hospitalization, mortality, and intensive care unit (ICU) admission by dialysis modality in Ontario, Canada. Data collection was in accordance with Ontario Health's legislative authority under the Ontario Personal Health Information Protection Act of 2004. We linked seven administrative health databases including the Ontario Renal Reporting System, which captures the modality and treatment changes of all adult (>18 years) home dialysis (peritoneal dialysis or home HD) or center-based HD patients across Ontario. Our observation period was between March 1, 2020 and November 20, 2020. For individuals, demographic data, neighborhood income quintile, location, residence in long-term care, comorbidity, hospitalization, ICU admission, deaths, and SARS-CoV-2 provincial RT-PCR testing and results information was obtained. Assuming a 14-day SARS-CoV-2 incubation period, COVID-19 infection was ascribed to the dialysis modality after 14 consecutive days of a home or in-center modality. Patients were followed until death, kidney transplantation, or study end. Follow-up SARS-CoV-2 tests after initial positive results were excluded in ascertaining testing rates. Long-term care residents and regional programs with no COVID-19 infections during the study period were excluded. Event rates for the following were defined as: (1) SARS-CoV-2 tests; (2) positive SARS-CoV-2 tests; (3) initial COVID-19 hospitalization (hospitalization within 1 week of SARS-CoV-2 positivity and/or hospitalization with an international classification of diseases-10 diagnosis of COVID-19); (4) COVID-19 mortality or ICU admission (admission to an ICU with COVID-19 during the initial COVID-19 hospitalization or death within 30 days of COVID-19 admission or SARS-CoV-2 positivity); (5) non–COVID-19 mortality (deaths during the study period not occurring within 30 days of SARS-CoV-2 positivity or COVID-19 admission; and (6) all-cause mortality. Unadjusted and adjusted rate ratios (ARR) for these events were calculated by dialysis modality using a log-binomial model. Logistic regression was used to calculate the adjusted odds ratio (AOR) of hospitalization and ICU admission and/or 30-day mortality by dialysis modality among those with COVID-19 infection. All models were adjusted for factors as indicated in Table 1. Marginal generalized estimating equations and a working dependence correlation structure were used to account for patients contributing patient-times to both modalities. Analyses were performed using SAS Version 9.4 SAS Institute, Cary, NC). Table 1. - Adjusted rate ratios for SARS-CoV-2 and COVID-19 outcomes by dialysis modality Outcome Number with Outcome/ Person Days Rate (per 100,000 person-days) Unadjusted Rate Ratio(95% CI) Adjusted Rate Ratio(95% CI) SARS-CoV-2 tests In-center HD 20804/2,084,665 998 1.0 (Ref) 1.0 (Ref) Home dialysis 2317/761,059 304 0.35 (0.34 to 0.38) 0.37 (0.35 to 0.38) SARS-CoV-2 positive In-center HD 182/2,084,665 8.7 1.0 (Ref) 1.0 (Ref) Home dialysis 34/761,059 4.5 0.59 (0.41 to 0.86) 0.57 (0.39 to 0.83) COVID-19 Hospitalization In-center HD 177/2,084,665 8.5 1.0 (Ref) 1.0 (Ref) Home dialysis 29/761,059 3.8 0.53 (0.38 to 0.75) 0.57 (0.40 to 0.81) COVID-19 ICU admission 30-day mortality In-center HD 45/2,084,665 2.2 1.0 (Ref) 1.0 (Ref) Home dialysis 6/761,059 0.8 0.37 (0.16 to 0.85) 0.44 (0.18 to 1.09) Overall Mortality In-center HD 1030/2,084,665 49.4 1.0 (Ref) 1.0 (Ref) Home dialysis 283/761,059 37.2 0.75 (0.66 to 0.86) 0.94 (0.82 to 1.08) Non-COVID-19 mortality In-center HD 996/2,084,665 47.8 1.0 (Ref) 1.0 (Ref) Home dialysis 278/761,059 36.5 0.76 (0.67 to 0.87) 0.96 (0.83 to 1.09) Mortality reported over the study period. All models adjusted for age, gender, diabetes, length of time on dialysis, race, neighborhood income quintile, geographic location, and prior kidney transplantation. A total of 587 patients contributed to both modalities during the study period. Linked databases included: The Ontario Renal Reporting System, The Registered Persons Database, The Ontario Laboratory Information System COVID-19 database, The Ontario Renal Network COVID-19 data collection tool, The Canadian Institute for Health Information Discharge Abstract Database, The Ontario Health Insurance Plan (was used to determined residency in long-term care), and the Postal Code Conversion File (Statistics Canada; was linked via postal codes to determine neighborhood income quintiles and geographic location). 95% CI, 95% confidence interval; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease; HD-hemodialysis; ICU, intensive care unit. We identified 3622 home dialysis (n=2853 peritoneal dialysis, n=769 home HD) and 9890 center-based HD patients (761,059 and 2,084,665 person-days, respectively). In-center patients were older (66.0±15 versus 63±15 years) and of longer dialysis vintage (median interquartile range, 2 [1–4] versus 2 [1–3] years), and a greater proportion had diabetes (53% versus 41%) compared with home dialysis patients. Fifty-three percent and 49% of home dialysis and in-center patients were in the greater Toronto area, respectively. SARS-CoV-2 testing rates were lower in home versus in-center dialysis patients (ARR, 0.37; 95% confidence interval [95% CI], 0.35 to 0.38). Six positive SARS-COV-2 episodes occurring within 14 days of dialysis initiation/modality transition were excluded. Positive SARS-CoV-2 tests and COVID-19 hospitalization rates were lower in home compared with in-center dialysis patients. COVID-19–related ICU admission and mortality (ARR, 0.44; 95% CI, 0.18 to 1.09) was lower in home versus in-center patients but did not reach statistical significance (Table 1). Among COVID-19–infected individuals, hospitalization occurred in 85% (29 of 34) and 86% (177 of 205) of home and in-center patients, respectively. Median length of hospitalization (interquartile range; days) was 13 (3–25) for in-center dialysis patients compared with 12 (11–27) for home dialysis patients. Mortality and/or ICU admission occurred in 18% (6 of 34) and 21% (45 of 205) of infected home and in-center patients, respectively. There were no differences in hospitalization (AOR, 1.3; 95% CI, 0.38 to 4.8) or death and/or ICU admission risks (AOR, 1.3; 95% CI, 0.37 to 4.8) in home compared with in-center COVID-19–infected patients. Non-COVID-19–related and overall mortality rates were similar in home versus center-based patients over the study period. We found a lower burden of COVID-19 infection, hospitalization, mortality, and ICU admission in community-dwelling home dialysis versus in-center patients. Our findings may relate to greater case finding in the in-center population, more frequent health care encounters, and routine screening/outbreak surveillance, which was at the program's discretion. If increased testing among in-center HD patients was the only explanation for the higher rates of COVID-19, one would have expected a disproportionate excess of milder cases (i.e., SARS-CoV-2 positivity not requiring hospital admission) among in-center compared with home dialysis patients. However, among in-center HD patients, we also observed higher rates of COVID-19 hospitalization, mortality, and ICU admission that may have been due to a higher infection rate rather than greater case-associated morbidity. Among COVID-19–infected individuals, we found no differences in the adjusted odds of hospitalization and ICU admission or 30-day mortality by home versus in-center treatment (albeit with limited power owing to low event rates). Our study captured over 90% of SARS-CoV-2 provincial tests. A limitation of this study is residual confounding based on unmeasured differences between in-center and home dialysis patients. One cannot exclude case-mix differences in the in-center versus home patients that may have accounted for the differences in COVID-19–related adverse event risks. We also could not distinguish between asymptomatic and symptomatic outpatient cases. Asymptomatic cases may have not been identified in the absence of mass screening. As community transmission of SARS-CoV-2 increased, and as HD facilities intensified infection prevention and control measures, differences in COVID-19 infection rates by dialysis modality may be attenuated compared with our observed findings over the early pandemic period. In the United States, rates of home dialysis continue to increase following the introduction of favorable reimbursement and policy reform (4,5). In addition to other purported benefits, a major shift to home-based dialysis care could render the ESKD population more resilient to the effects of COVID-19, reducing exposure episodes and total exposure time to SARS-CoV-2 while conferring lower future exposure risks to highly transmissible infections. Disclosures P.G. Blake is a contracted Medical Lead and Medical Director at Ontario Renal Network, Ontario Health, has received honoraria from Baxter Global for speaking engagements, and is on the Editorial Board of American Journal of Nephrology. J. Ip, Y. Tang, D. Thomas, and A. Yeung are salaried employees of Ontario Renal Network, Ontario Health. M. Oliver is a contracted Medical Lead at Ontario Renal Network, Ontario Health and is owner of Oliver Medical Management Inc., which licenses Dialysis Management Analysis and Reporting System software. He has received honoraria for speaking from Baxter Healthcare and participated on Advisory Boards for Janssen and Amgen. J. Perl reports grants from the Agency for Healthcare Research and Quality during the conduct of the study; personal fees from AstraZeneca Canada, Baxter Healthcare, DaVita Healthcare Partners, DCI, Fresenius Medical Care, LiberDi, Otsuka, and US Renal Care; research funding and salary support from Arbor Research Collaborative For Health and Agency for Healthcare Research and Quality; speakers bureau for Baxter Healthcare and Fresenius Medical Care; and is on the advisory board for Liberdi, outside of the submitted work. Funding None.

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