Recent Developments in the Evaluation and Management of Cardiorenal Syndrome: A Comprehensive Review.

Cardiorenal syndrome (CRS) is increasingly recognized diagnostic entity associated with high morbidity and mortality among acutely ill heart failure (HF) patients with acute and/ or chronic kidney diseases (CKD). While traditionally viewed as a state of decline in glomerular filtration rate (GFR) due to decreased renal perfusion, mainly due to therapeutic interventions to relieve congestive in HF, Recent insights into the underlying pathophysiologic mechanisms of CRS led to a broader definition and further classification of CRS into five distinct types. In this comprehensive review, we discuss the classification of CRS, highlighting the underlying common pathogenetic pathways of heart failure and kidney injury, including increased congestion, neurohormonal dysregulation, oxidative stress as well as inflammation, and cytokine storm that are particularly evident in COVID-19 patients with multiorgan failure and also in those with other disorders including sepsis, systemic lupus erythematosus and amyloidosis. In this review we also present the recent advances in the diagnostic strategies of CRS including cardiac and renal biomarkers as well as advanced cardiac and renal imaging techniques that are available to aid in the diagnosis as well as in the prognostication of this disorder. Finally, we discuss the various therapeutic options available to-date, including fluid optimization, hemofiltration, renal replacement therapy as well as the role of SGLT2 inhibitors in light of recent data from RCTs. It is important to note that, CRS population are either excluded or underrepresented, at best, in major RCTs and therefore, therapeutic recommendations are largely extrapolated from FH and CKD clinical trials.

Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices.

The coronavirus disease 2019 (COVID-19) pandemic is associated with significant morbidity and mortality throughout the world, predominantly due to lung and cardiovascular injury. The virus responsible for COVID-19-severe acute respiratory syndrome coronavirus 2-gains entry into host cells via ACE2 (angiotensin-converting enzyme 2). ACE2 is a primary enzyme within the key counter-regulatory pathway of the renin-angiotensin system (RAS), which acts to oppose the actions of Ang (angiotensin) II by generating Ang-(1-7) to reduce inflammation and fibrosis and mitigate end organ damage. As COVID-19 spans multiple organ systems linked to the cardiovascular system, it is imperative to understand clearly how severe acute respiratory syndrome coronavirus 2 may affect the multifaceted RAS. In addition, recognition of the role of ACE2 and the RAS in COVID-19 has renewed interest in its role in the pathophysiology of cardiovascular disease in general. We provide researchers with a framework of best practices in basic and clinical research to interrogate the RAS using appropriate methodology, especially those who are relatively new to the field. This is crucial, as there are many limitations inherent in investigating the RAS in experimental models and in humans. We discuss sound methodological approaches to quantifying enzyme content and activity (ACE, ACE2), peptides (Ang II, Ang-[1-7]), and receptors (types 1 and 2 Ang II receptors, Mas receptor). Our goal is to ensure appropriate research methodology for investigations of the RAS in patients with severe acute respiratory syndrome coronavirus 2 and COVID-19 to ensure optimal rigor and reproducibility and appropriate interpretation of results from these investigations.

Factors associated with hospital readmissions among patients with COVID-19: A single-center experience.

Identify factors associated with readmission after an index hospital admission for coronavirus disease 2019 (COVID-19) infection in a single center serving an underserved and predominantly minority population. This retrospective descriptive study included 275 patients who tested COVID-19 positive via reverse transcriptase-polymerase chain reaction assay at our institution and who survived the index hospitalization. The main outcomes were 1- and 6-month readmission rates after an index hospitalization for COVID-19. The mortality rate among the readmitted patients was also determined. Factors independently associated with readmission were investigated using multivariable logistic regression. A final sample of 275 patients was included. The mean age was 64.69 ± 14.64 (SD), 133 (48%) were female and 194 (70%) were African American. Their chronic medical conditions included hypertension 203 (74%) and diabetes mellitus 121 (44%). After the hospitalization, 1-month readmission rate was 7.6%, while 6-month readmission rate was 24%. Nine percent of patients who were readmitted subsequently died. Coronary artery disease (CAD) was significantly associated with 6-month readmission odds ratio (OR), 2.15 (95% confidence interval [CI]: 1.04-4.44; p = 0.039) after adjustment for age, gender, ethnicity, and comorbidities. Readmissions were due to cardiac, respiratory, and musculoskeletal symptoms. Hispanic ethnicity was associated with increased readmission OR, 3.16 (95% CI: 1.01-9.88; p = 0.048). No significant difference was found between inflammatory markers or clinical outcomes during the index hospitalization among patients who were readmitted compared to those who were not. A significant number of patients hospitalized for COVID-19 may be readmitted. The presence of CAD is independently associated with high rates of 6-month readmission.

Characteristics and clinical outcomes of COVID-19 patients in an underserved-inner city population: A single tertiary center cohort.

There is limited information describing the characteristics and clinical outcomes of patients infected with coronavirus disease 2019 (COVID-19) especially those in underserved urban area with minority population in the United States. This is a retrospective single-center study for patients who were admitted with COVID-19 infection. Data collection was from 1 March through 24 April 2020. Demographic, clinical, laboratory, and treatment data were presented using descriptive statistics and frequencies. The χ2 test and multivariate logistic regression were used to determine association of risk factors and clinical outcomes. A total of 242 inpatients were included with a mean age of 66 ± 14.75 (±standard deviation). A total of 50% were female and 70% were African American. Comorbidities included hypertension (74%), diabetes mellitus (49%), and 19% had either COPD or asthma. Older age was associated with higher risk of inpatient death odds ratio (OR): 1.056 (95% confidence interval [CI]: 1.023-1.090; P = .001). Inpatient mortality occurred in 70% who needed mechanical ventilation (OR: 29.51; 95% CI: 13.28-65.60; P < .0001), 58% who required continuous renal replacement therapy/hemodialysis (CRRT/HD) (OR: 6.63; 95% CI: 2.74-16.05; P < .0001), and 69% who needed vasopressors (OR: 30.64; 95% CI: 13.56-69.20; P < .0001). Amongst biomarkers of disease severity, only baseline CRP levels (145 ± 116 mg/L) were associated with mortality OR: 1.008 (95% CI: 1.003-1.012; P = .002). Majority of hospitalized patients had hypertension and diabetes. Older age was an independent risk factor for inpatient mortality. Requirement of mechanical ventilation, vasopressor use, and CRRT/HD was associated significantly with inpatient mortality. Higher baseline CRP was significantly associated with inpatient death.

Bacterial infections and patterns of antibiotic use in patients with COVID-19.

Bacterial coinfection is associated with poor outcomes in patients with viral pneumonia, but data on its role in the mortality of patients with coronavirus disease 2019 (COVID-19) is limited. This is a single-center retrospective analysis of 242 patients with confirmed COVID-19 admitted to both intensive care and non-intensive care settings. Bacterial coinfection was determined by the presence of characteristic clinical features and positive culture results. Multivariable logistic regression was used to analyze the association of concomitant bacterial infection with inpatient death after adjusting for demographic factors and comorbidities. Antibiotic use pattern was also determined. Bacterial coinfection was detected in 46 (19%) patients. Genitourinary source was the most frequent, representing 57% of all coinfections. The overall mortality rate was 21%. Concomitant bacterial infections were independently associated with increased inpatient mortality (OR, 5.838; 95% CI, 2.647-12.876). Patients with bacterial coinfection were relatively older (71.35 ± 11.20 vs 64.78 ± 15.23; P = .006). A total of 67% of patients received antibiotic therapy, yet 72% did not have an obvious source of bacterial infection. There was a significantly higher rate of inpatient mortality in patients who received antibiotics compared to those who did not (30% vs 5%; P < .0001). Bacterial coinfection in COVID-19 is associated with increased mortality.

Predictors of venous thromboembolism in patients with COVID-19 in an underserved urban population: A single tertiary center experience.

INTRODUCTION: Venous thromboembolism (VTE) is reported in up to 27% of patients with COVID-19 due to SARS-CoV-2 infection. Dysregulated systemic inflammation and various patient traits are presumed to underlie this anomaly. Optimal VTE prophylaxis in COVID-19 patients has not been established due to a lack of validated models for predicting VTE in this population. Our study aims to address this deficiency by identifying demographic and clinical characteristics of COVID-19 patients associated with increased VTE risk. METHODS: This study is a retrospective analysis of all adult patients (final sample, n = 355) hospitalized with confirmed COVID-19 at Einstein Medical Center Philadelphia between March 1 and April 24, 2020. Demographic and clinical patient data were collected and factors associated with VTE were identified and analyzed using t-tests, multivariable logistic regression, and receiver operating characteristic (ROC) curves. RESULTS: Thirty patients (8.5%) developed VTE. Patients with VTE had significantly higher D-dimer levels on admission (P = 0.045) and peak D-dimer levels (P < 0.0001), in addition to higher rates of vasopressor requirements (P = 0.038), intubation (P = 0.003), and death (P = 0.023). Age (OR 1.042), obstructive sleep apnea (OR 5.107), and need for intubation (OR 3.796) were associated with significantly increased odds of VTE. Peak D-dimer level was a good predictor of VTE (AUC 0.806, P < 0.0001) and a D-dimer cutoff of >6640 ng/mL had high (>70%) sensitivity and specificity for VTE. CONCLUSION: Peak D-dimer level may be the most reliable clinical marker in COVID-19 patients for predicting VTE and future prospective studies should attempt to further validate this.

Insulin Use and Poor COVID-19 Outcomes among Diabetes Patients: Association Not Necessarily Causation.

Our study looked at the relationship between insulin use and clinical outcomes in COVID-19. A response to our article, written by Dr. Chia Sing Kow and Dr. Syed Shahzad Hasan raised a few questions. They mentioned our use of hemoglobin A1c may be inaccurate as the patients in our study had high rates of CKD or ESRD which could alter the hemoglobin A1c levels. However due to the limitations of our patient population and perhaps in a lot of other sample populations in the real-world setting, it was the most feasible way to represent glucose control.The writers also suggested that the use of metformin, a potential confounder, was also not adjusted for. This should be considered in future research but addition of too many variables in a regression model may lead to less reliability of results for our study.The letter writers also suggested that the results of our paper may lead to misinterpretation by readers and may influence providers to not use insulin therapy for their patients when necessary due to fear of worse outcomes in the setting of COVID-19. We reiterated that it is very important that the data not be misinterpreted, and that nowhere in our paper did we imply or suggest that patients who need insulin therapy to treat their diabetes should not receive proper therapy due to the association we delineated in our paper. Instead, more careful surveillance of patients with advanced diabetes is needed especially when admitted with COVID-19.

Association of Pre-Admission Statin Use With Reduced In-Hospital Mortality in COVID-19.

BACKGROUND: Coronavirus disease-19 (COVID-19) infection is associated with an uncontrolled systemic inflammatory response. Statins, given their anti-inflammatory properties, may reduce the associated morbidity and mortality. This study aimed to determine the association between statin use prior to hospitalization and in-hospital mortality in COVID-19 patients. METHODS: In this retrospective study, clinical data were collected from the electronic medical records of patients admitted to the hospital with confirmed COVID-19 infection from March 1, 2020 to April 24, 2020. A multivariate regression analysis was performed to study the association of pre-admission statin use with in-hospital mortality. RESULTS: Of 255 patients, 116 (45.5%) patients were on statins prior to admission and 139 (54.5%) were not. The statin group had a higher proportion of end stage renal disease (ESRD) (13.8% vs. 2.9%, p = 0.001), diabetes mellitus (63.8% vs. 35.2%, p<0.001), hypertension (87.9% vs. 61.1%, p < 0.001) and coronary artery disease (CAD) (33.6% vs. 5%, p < 0.001). On multivariate analysis, we found a statistically significant decrease in the odds of in-hospital mortality in patients on statins before admission (OR 0.14, 95% CI 0.03- 0.61, p = 0.008). In the subgroup analysis, statins were associated with a decrease in mortality in those with CAD (OR 0.02, 95% CI 0.0003-0.92 p = 0.045) and those without CAD (OR 0.05, 95% CI 0.005-0.43, p = 0.007). CONCLUSIONS: Our study suggests that statins are associated with reduced in-hospital mortality among patients with COVID-19, regardless of CAD status. More comprehensive epidemiological and molecular studies are needed to establish the role of statins in COVID-19.

Insulin Use, Diabetes Control, and Outcomes in Patients with COVID-19.

Background: The novel coronavirus (SARS CoV-2) has caused significant morbidity and mortality in patients with diabetes. However, the effects of diabetes control including insulin use remain uncertain in terms of clinical outcomes of patients with COVID-19.Methods: In this single-center, retrospective observational study, all adult patients admitted to Einstein Medical Center, Philadelphia, from March 1 through April 24, 2020 with a diagnosis of COVID-19 and diabetes were included. Demographic, clinical and laboratory data, insulin dose at home and at the hospital, other anti-hyperglycemic agents use, and outcomes were obtained. Multivariate logistic regression was used to evaluate the factors associated with diabetes control and mortality.Results: Patients who used insulin at home had higher mortality compared to those who did not (35% vs 18% p = .015), this was true even after adjustment for demographics, comorbidities and a1c OR 2.65 95% CI (1.23-5.71) p = .013. However, the mean a1c and the median home requirements of insulin did not significantly differ among patients who died compared to the ones that survived. Patients who died had significantly higher inpatient insulin requirements (highest day insulin requirement recorded in units during hospitalization) 36 (11-86) vs 21 (8-52) p = .043 despite similar baseline a1c and steroid doses received. After adjusting for demographics, comorbidities and a1c, peak insulin requirements remained significantly associated with inpatient mortality OR 1.022 95% CI (1.00-1.04) p = .044.Conclusion: Among diabetic patients infected with COVID-19, insulin therapy at home was significantly independently associated with increased mortality. Peak daily inpatient insulin requirements was also independently associated with increased inpatient mortality.

Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: The use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in patients with coronavirus disease 2019 (COVID-19) given their interaction with the angiotensin-converting enzyme-2 (ACE-2) receptor remains controversial. . OBJECTIVE: To investigate the impact of ACEI/ARB on COVID-19 disease severity and mortality through a systematic review and meta-analysis. METHODS: We searched PubMed and CINAHL databases as well as pre-print servers for studies investigating usage of ACEIs/ARBs in patients with COVID-19 compared to a control group of COVID-19 patients without ACEI/ARB use. COVID-19 related severity of disease, and death were identified as end points. Pooled odds ratios (OR) and their 95% confidence intervals (CI) were calculated using random-effects model. RESULTS: 21 studies were included in the meta-analysis. For mortality with ACEI/ARB use, the pooled odds ratio was 1.29 [0.89-1.87] p = 0.18 with heterogeneity of 91%, while the pooled OR for COVID-19 severity was 0.94 [0.59-1.50] p = 0.81 with heterogeneity of 89% (Figure 2). In combining both mortality and severe disease outcomes, the pooled odds ratio was 1.09 [0.80-1.48] p = 0.58 but with heterogeneity of 92%. EXPERT OPINION: Even on pooled analysis of both un-adjusted data, adjusted data(studies with matched controls) and taking into account factors such as risk of bias of studies via meta regression and sensitivity analyses, the results hold true that ACEI/ARB use is not associated with COVID-19 disease severity or mortality. To look for any potential beneficial effects, randomized controlled trials are needed. CONCLUSION: use of ACEI/ARB was not associated with increased mortality or severe COVID-19.

Anticoagulation and bleeding risk in patients with COVID-19.

BACKGROUND: There is no current standardized approach to anticoagulation in patients with Coronavirus Disease 2019 (COVID-19) while potential bleeding risks remain. Our study characterizes the patterns of anticoagulation use in COVID-19 patients and the risk of related bleeding. METHODS: This is a single center retrospective analysis of 355 adult patients with confirmed diagnosis of COVID-19 from March 1 to May 31, 2020. Chi-square was used to analyze the relationship between degree of anticoagulant dose and bleeding events by site. Multivariable logistic regression was used to look at factors associated with inpatient death. RESULTS: 61% of patients were being treated with prophylactic doses of anticoagulation, while 7% and 29% were being treated with sub-therapeutic and therapeutic anticoagulation (TA) doses respectively. In 44% of patients, we found that the decision to escalate the dose of anticoagulation was based on laboratory values characterizing the severity of COVID-19 such as rising D-dimer levels. There were significantly higher rates of bleeding from non-CNS/non-GI sites (p = 0.039) and from any bleeding site overall (p = 0.019) with TA. TA was associated with significantly higher rates of inpatient death (41.6% vs 15.3% p < 0.0001) compared to those without. All patients who developed CNS hemorrhage died p = 0.011. After multivariable logistic regression, only age OR 1.04 95% CI (1.01 to 1.07) p = 0.008 and therapeutic anticoagulation was associated with inpatient mortality OR 6.16 95% CI (2.96 to 12.83) p ≤ 0.0001. CONCLUSION: The use of TA was significantly associated with increased risk of bleeding. Bleeding in turn exhibited trends towards higher inpatient death among patients with COVID-19. These findings should be interpreted with caution and larger more controlled studies are needed to verify the net effects of anticoagulation in patients with COVID-19.

Characteristics of peripheral blood differential counts in hospitalized patients with COVID-19.

BACKGROUND: A lot remains unknown about the features and laboratory findings that may predict worse outcomes in patients with coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the difference in complete blood count parameters and differential counts in patients hospitalized with COVID-19 who survived compared to those who died. DESIGN: We performed a single-center retrospective study including 242 patients with confirmed COVID-19. We described the characteristics of the complete blood count parameters in these patients. Mann-Whitney U test was used to compare hematologic parameters of patients who died and those who survived; multivariate logistic regression was used to look for associations with mortality. RESULTS: Patients with COVID-19 who died had significantly lower median absolute monocyte count (AMC) (0.4 vs 0.5, P = .039) and median platelet count (169 vs 213, P = .009) compared to those who survived. Patients who died had a significantly higher neutrophil-to-lymphocyte ratio (6.4 vs 4.5, P = .001). The NLR was positively associated with death (OR = 1.038; 95% CI, 1.003-1.074, P = .031), while AMC was inversely associated with death (OR = 0.200; 95% CI, 0.052-0.761, P = .018). CONCLUSION: Among patients with COVID-19, a lower AMC and higher NLR are associated with higher mortality.

Clinical Characteristics and Outcomes of Community- and Hospital-Acquired Acute Kidney Injury with COVID-19 in a US Inner City Hospital System.

INTRODUCTION: Emerging data have described poor clinical outcomes from infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) among African American patients and those from underserved socioeconomic groups. We sought to describe the clinical characteristics and outcomes of acute kidney injury (AKI) in this special population. METHODS: This is a retrospective study conducted in an underserved area with a predominance of African American patients with coronavirus disease 2019 (COVID-19). Descriptive statistics were used to characterize the sample population. The onset of AKI and relation to clinical outcomes were determined. Multivariate logistic regression was used to determine factors associated with AKI. RESULTS: Nearly half (49.3%) of the patients with COVID-19 had AKI. Patients with AKI had a significantly lower baseline estimated glomerular filtration rate (eGFR) and higher FiO2 requirement and D-dimer levels on admission. More subnephrotic proteinuria and microhematuria was seen in these patients, and the majority had a pre-renal urine electrolyte profile. Patients with hospital-acquired AKI (HA-AKI) as opposed to those with community-acquired AKI (CA-AKI) had higher rates of in-hospital death (52 vs. 23%, p = 0.005), need for vasopressors (42 vs. 25%, p = 0.024), and need for intubation (55 vs. 25%, p = 0.006). A history of heart failure was significantly associated with AKI after adjusting for baseline eGFR (OR 3.382, 95% CI 1.121-13.231, p = 0.032). CONCLUSION: We report a high burden of AKI among underserved COVID-19 patients with multiple comorbidities. Those who had HA-AKI had worse clinical outcomes compared to those who with CA-AKI. A history of heart failure is an independent predictor of AKI in patients with COVID-19.

Meta-analysis of outcomes of patients with COVID-19 infection with versus without gastrointestinal symptoms.

This systematic review analyzed whether the presence or absence of gastrointestinal symptoms in patients with SARS-COV-2 infection is associated with adverse outcomes. Searching the Cochrane Center Register of Controlled Trials, we included any studies looking at patients with COVID-19 with gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain) compared to those with COVID-19 but without gastrointestinal manifestations as a control group. The final search yielded 186 articles, all of which were individually screened. Seven studies were identified but three were excluded: one due to lack of a control group without gastrointestinal symptoms, one reported as viral RNA in the stool, and one with only non-critically ill patients. Results of the meta-analysis showed a pooled odds ratio for mortality among those with COVID-19 and gastrointestinal symptoms of 0.91 (confidence interval 0.49-1.68) with heterogeneity of 0% and a pooled odds ratio for acute respiratory distress syndrome of 2.94 (confidence interval 1.17-7.40) with heterogeneity of 0%. In conclusion, gastrointestinal symptoms with COVID-19 are associated with a higher risk of acute respiratory distress syndrome, but do not increase the risk for mortality.

Fulminant Acute Kidney Injury in a Young Patient with Novel Coronavirus 2019.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting more than 200 countries and 180,000 cases in the United States. While the outbreak began in China, the number of cases outside of China exceeded those in China on March 15, 2020 and are currently rising at an exponential rate. The number of fatalities in the United States are expected to exceed more than Italy and China. The disease is characterized predominantly as an acute respiratory illness. However, preliminary data suggests that kidney is a target for the virus and deterioration of renal function was associated with poor outcomes including in-hospital mortality. We pre-sent a report of a patient with COVID-19 who presented with acute onset of symptoms and normal renal function at baseline but rapidly deteriorated resulting in death. The timing of decline in renal function correlated with his worsening clinical status. He was started on continuous veno-venous hemofiltration without signs of clinical benefit. We also present the possible mechanisms for acute kidney injury in these patients. We performed a review of the emerging literature by searching PubMed, Google Scholar, and EMBASE for studies and/or case series published on this topic. Acute kidney injury might help risk stratify critically ill patients on a fatal course of COVID-19.

Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection.

Approximately 90 days of the SARS-CoV-2 (COVID-19) spreading originally from Wuhan, China, and across the globe has led to a widespread chain of events with imminent threats to the fragile relationship between community health and economic health. Despite near hourly reporting on this crisis, there has been no regular, updated, or accurate reporting of hospitalizations for COVID-19. It is known that many test-positive individuals may not develop symptoms or have a mild self-limited viral syndrome consisting of fever, malaise, dry cough, and constitutional symptoms. However some individuals develop a more fulminant syndrome including viral pneumonia, respiratory failure requiring oxygen, acute respiratory distress syndrome requiring mechanical ventilation, and in substantial fractions leading to death attributable to COVID-19. The pandemic is evolving in a clustered, non-inform fashion resulting in many hospitals with preparedness but few or no cases, and others that are completely overwhelmed. Thus, a considerable risk of spread when personal protection equipment becomes exhausted and a large fraction of mortality in those not offered mechanical ventilation are both attributable to a crisis due to maldistribution of resources. The pandemic is amenable to self-reporting through a mobile phone application that could obtain critical information on suspected cases and report on the results of self testing and actions taken. The only method to understand the clustering and the immediate hospital resource needs is mandatory, uniform, daily reporting of hospital censuses of COVID-19 cases admitted to hospital wards and intensive care units. Current reports of hospitalizations are delayed, uncertain, and wholly inadequate. This paper urges all the relevant stakeholders to take up self-reporting and reporting of hospitalizations of COVID-19 as an urgent task in combating this devastating pandemic.