Reducing unnecessary routine laboratory testing for noncritically ill patients with COVID-19.

BACKGROUND: Reducing unnecessary routine laboratory testing is a Choosing Wisely® recommendation, and new areas of overuse were noted during the COVID-19 pandemic. OBJECTIVE: To reduce unnecessary repetitive routine laboratory testing for patients with COVID-19 during the pandemic across a large safety net health system. DESIGNS, SETTINGS AND PARTICIPANTS: This quality improvement initiative was initiated by the System High-Value Care Council at New York City Health + Hospitals (H + H), the largest public healthcare system in the United States consisting of 11 acute care hospitals. INTERVENTION: four overused laboratory tests in noncritically ill hospitalized patients with COVID-19 were identified: C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and procalcitonin. A two-pronged electronic health record intervention was implemented consisting of (1) nonintrusive, informational nudge statements placed on selected order sets, and (2) a forcing function of one consecutive day limit on ordering. MAIN OUTCOME AND MEASURES: The average of excess tests per encounter days (ETPED) for each of four target laboratory testing only in patients with COVID-19. OBJECTIVE: Interdisciplinary System High-Value Care Council identified four overused laboratory tests (inflammatory markers) in noncritically ill hospitalized patients with COVID-19: C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and procalcitonin. Within an 11-hospital safety net health system, a two-pronged electronic health record intervention was implemented consisting of (1) nonintrusive, informational nudge statements placed on selected order sets, and (2) a forcing function of one consecutive day limit on ordering. The preintervention period (March 16, 2020 to January 24, 2021) was compared to the postintervention period (January 25, 2021 to March 22, 2022). RESULTS: Time series linear regression showed decreases in CRP (-17.9%, p < .05), ferritin (-37.6%, p < .001), and LDH (-30.1%, p < .001). Slope differences were significant (CRP, ferritin, and LDH p < 0.001; procalcitonin p < 0.05). Decreases were observed across weekly averages: CRP (-19%, p < .01), ferritin (-37.9%, p < .001), LDH (-28.7%, p < .001), and procalcitonin (-18.4%, p < .05). CONCLUSION: This intervention was associated with reduced routine inflammatory marker testing in non-intensive care unit COVID-19 hospitalized patients across 11 hospitals. Variation was high among individual hospitals.

Can ferritin/lymphocyte percentage ratio, a new indicator, predict the clinical course of COVID-19 cases?

OBJECTIVES: COVID-19 maintains its seriousness as a global emergency with its rapid distribution worldwide. Ferritin / lymphocyte percentage ratio (FLPR) may appear as a prognostic value at the initial evaluation stage and thus can be used as a simple, effective, and reliable parameter in critical patient identification with COVID-19. METHODS: In this retrospective cohort study, we evaluated patients over 18 years old, who were hospitalized after being evaluated as COVID-19 and whose PCR results were positive. We calculated FLPRs from complete blood counts taken during emergency department admissions and classified disease severity due to emergency initial evaluation. The relationship between the severity of the thoracic tomography findings, hospitalization, and intensive care needs, and 28-day mortality with the FLPR were evaluated. RESULTS: The difference between the groups classified according to COVID-19 severity and the FLPR means was statistically significant (x2=148.284; SD=3; p=0.000). FLPR levels were found to be high in critical and serious groups. In the ROC analysis for the FLPR level, the area under the curve (AUC) value was found to be 0.909 (95% CI 0.857-0.961). When the cut off value of FLPR was 9.80, the sensitivity was found to be 97.6 %, and the specificity was 65.2 %, whereas, when the cut off value for FLPR was found to be 21.11, the sensitivity was 82.9 % and the specificity was 82.8 %. CONCLUSION: The FLPR, a new parameter, can be used as a significant marker to predict the 28-day mortality in patients (Tab. 5, Fig. 1, Ref. 25).

High mortality among hospitalized adult patients with COVID-19 pneumonia in Peru: A single centre retrospective cohort study.

BACKGROUND: Peru is the country with the world's highest COVID-19 death rate per capita. Characteristics associated with increased mortality among adult patients with COVID-19 pneumonia in this setting are not well described. METHODS: Retrospective, single-center cohort study including 1537 adult patients hospitalized with a diagnosis of SARS-CoV-2 pneumonia between May 2020 and August 2020 at a national hospital in Lima, Peru. The primary outcome measure was in-hospital mortality. RESULTS: In-hospital mortality was 49.71%. The mean age was 60 ± 14.25 years, and 68.38% were males. We found an association between mortality and inflammatory markers, mainly leukocytes, D-dimer, lactate dehydrogenase, C-reactive protein and ferritin. A multivariate model adjusted for age, hypertension, diabetes mellitus, and corticosteroid use demonstrated that in-hospital mortality was associated with greater age (RR: 2.01, 95%CI: 1.59-2.52) and a higher level of oxygen requirement (RR: 2.77, 95%CI: 2.13-3.62). Conclusions: In-hospital mortality among COVID-19 patients in Peru is high and is associated with greater age and higher oxygen requirements.

Salivary Ferritin Changes in Patients with COVID-19.

High ferritin serum levels can be found in patients with macrophage activation syndrome, and increased serum ferritin due to cytokine storm have been reported in severe COVID-19 patients. Saliva is being increasingly used in COVID-19 tests as a diagnostic sample for virus detection and quantification. This study aimed to evaluate the possible changes in ferritin in saliva in COVID-19 patients. In addition, the effects of different inactivation SARS-CoV-2 treatments in ferritin measurements in saliva, the correlation between ferritin in saliva and serum, and the possible effects of correction of ferritin values by total protein were assessed. Ferritin was measured in saliva from healthy (n = 30) and COVID-19 (n = 65) patients with severe, (n = 18) or mild (n = 47) disease, depending on the need for nasal flow oxygen or assisted respiration. Ferritin was also measured in paired serum and saliva samples (n = 32) from healthy and COVID-19 patients. The evaluated inactivation protocols did not affect the assay's results except the addition of 0.5% SDS. Significantly higher ferritin was found in the saliva of COVID-19 patients (median; 25-75th percentile) (27.75; 9.77-52.2 µg/L), compared with healthy controls (4.21; 2.6-8.08 µg/L). Individuals with severe COVID-19 showed higher ferritin values in saliva (48.7; 18.7-53.9) than mild ones (15.5; 5.28-41.3 µg/L). Significant correlation (r = 0.425; p < 0.001) was found between serum and saliva in ferritin. Ferritin levels were higher in COVID-19 patients in serum and saliva, and the highest values were found in those patients presenting severe symptomatology. In conclusion, ferritin in saliva has the potential to be a biomarker to evaluate severity in patients with COVID-19.

Finding of the factors affecting the severity of COVID-19 based on mathematical models.

Since 2019, a large number of people worldwide have been infected with severe acute respiratory syndrome coronavirus 2. Among those infected, a limited number develop severe coronavirus disease 2019 (COVID-19), which generally has an acute onset. The treatment of patients with severe COVID-19 is challenging. To optimize disease prognosis and effectively utilize medical resources, proactive measures must be adopted for patients at risk of developing severe COVID-19. We analyzed the data of COVID-19 patients from seven medical institutions in Tokyo and used mathematical modeling of patient blood test results to quantify and compare the predictive ability of multiple prognostic indicators for the development of severe COVID-19. A machine learning logistic regression model was used to analyze the blood test results of 300 patients. Due to the limited data set, the size of the training group was constantly adjusted to ensure that the results of machine learning were effective (e.g., recognition rate of disease severity > 80%). Lymphocyte count, hemoglobin, and ferritin levels were the best prognostic indicators of severe COVID-19. The mathematical model developed in this study enables prediction and classification of COVID-19 severity.

Paediatric post-COVID-19 hyperinflammatory syndrome mimicking appendicitis: a case series.

INTRODUCTION: A novel hyperinflammatory syndrome has emerged in the paediatric population: paediatric inflammatory multisystem syndrome - temporally associated with SARS-CoV-2 (PIMS-TS). Up to 50% of patients develop shock with cardiac dysfunction but presentation with acute abdominal pain is common and difficult to distinguish from appendicitis. METHOD: Prospective case series of PIMS-TS patients presenting to a single UK tertiary paediatric centre. RESULTS: As of 16 September 2020, 89 patients have presented with PIMS-TS to our institution; 19 (21.3%) were referred for surgical review. Pyrexia and acute abdominal pain were seen in all 19 patients. Diarrhoea was reported in 14 (73%) and vomiting in 12 (63%). On examination, eight (42%) had right abdominal tenderness, of which five had right iliac fossa (RIF) peritonism. C-reactive protein (CRP) was universally raised: median 176 (15-463)mg/l. Abdominal imaging was performed in 17 (89%), with 11 undergoing abdominal ultrasonography (65%) and 8 abdominal computed tomography (47%); two required both. Findings included nonspecific features of inflammation in the RIF. Eight patients (42%) had an abnormal echocardiogram at admission. Two (10%) patients, with classical signs and symptoms of appendicitis, underwent appendicectomy without radiological imaging and were subsequently diagnosed with PIMS-TS. During the same period, 18 patients underwent appendicectomy for histologically confirmed appendicitis. Serum CRP and ferritin levels were significantly higher in the PIMS-TS cohort compared with children with appendicitis. CONCLUSIONS: PIMS-TS is a novel paediatric condition that may mimic appendicitis. It should be considered in patients presenting with abdominal pain to avoid unnecessary surgery in children at risk of cardiovascular instability.

Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger?

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.

Analysis of laboratory blood parameter results for patients diagnosed with COVID-19, from all ethnic group populations: A single centre study.

INTRODUCTION: Although factors such as age, sex, diabetes, obesity and changes in certain laboratory investigations are important prognostic factors in COVID-19 infection, these may not apply to all ethnic/racial groups. We hypothesized differences in routine biochemistry and haematology indices in Caucasian and a combined group of Black, Asian and Minority Ethnic (BAME) patients who tested positive for COVID-19 who died, compared to survivors. METHODS: We tested our hypothesis in 445 patients (229 Caucasian, 216 BAME) admitted to secondary care with proven COVID-19 infection, in whom standard routine laboratory indices were collected on admission. RESULTS: After 28 weeks, 190 (42.7%) had died within 28 days of COVID diagnosis (97 Caucasians [42.4%], 93 BAMEs [43.1%], P = .923). A general linear model analysis found the ethnicity interaction with mortality to be significant for fibrinogen, ferritin and HbA1 c (after controlling for age). In a multivariate analysis, a neutrophil/lymphocyte ratio > 7.4 and a urea/albumin ratio > 0.28 increased the odds of death for both the Caucasian and the BAME group. Additional factors increasing the odds ratio in the BAME group included age >60 years and being diabetic. CONCLUSION: Neutrophil/lymphocyte ratio and urea/albumin ratio are simple metrics that predict death to aid clinicians in determining the prognosis of COVID-19 and help provide early intensive intervention to reduce mortality. In the BAME groups, intensive monitoring even at younger age and those with diabetes may also help reduce COVID-19 associated mortality.

A digital protein microarray for COVID-19 cytokine storm monitoring.

Despite widespread concern regarding cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of the technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4 pg mL-1), inter-assay repeatability (∼10% CV), and rapid operation providing feedback on the progress of therapy within 4 hours. This test allowed us to perform serial monitoring of two critically ill patients with respiratory failure and to support immunomodulatory therapy using the selective cytopheretic device (SCD). We also observed clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as ferritin and C-reactive protein (CRP). Our data revealed large subject-to-subject variability in patients' response to COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.

Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients.

Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

Lack of tocilizumab effect on mortality in COVID19 patients.

Off-label tocilizumab use in COVID-19 patients reflects concern for cytokine release syndrome. Comparison of matched COVID-19 pneumonia patients found elevated IL-6 levels correlated with mortality that did not change with tocilizumab administration. Correlating mortality with increased IL-6 doesn't imply causality however lack of improvement by tocilizumab requires further clinical trial alterations.

Advancement in biosensors for inflammatory biomarkers of SARS-CoV-2 during 2019-2020.

COVID-19 pandemic has affected everyone throughout the world and has resulted in the loss of lives of many souls. Due to the restless efforts of the researchers working hard day and night, some success has been gained for the detection of virus. As on date, the traditional polymerized chain reactions (PCR), lateral flow devices (LFID) and enzyme linked immunosorbent assays (ELISA) are being adapted for the detection of this deadly virus. However, a more exciting avenue is the detection of certain biomarkers associated with this viral infection which can be done by simply re-purposing our existing infrastructure. SARS-CoV-2 viral infection triggers various inflammatory, biochemical and hematological biomarkers. Because of the infection route that the virus follows, it causes significant inflammatory response. As a result, various inflammatory markers have been reported to be closely associated with this infection such as C-reactive proteins, interleukin-6, procalcitonin and ferritin. Sensing of these biomarkers can simultaneously help in understanding the illness level of the affected patient. Also, by monitoring these biomarkers, we can predict the viral infections in those patients who have low SARS-CoV-2 RNA and hence are missed by traditional tests. This can give more targets to the researchers and scientists, working in the area of drug development and provide better prognosis. In this review, we propose to highlight the conventional as well as the non-conventional methods for the detection of these inflammatory biomarkers which can act as a single platform of knowledge for the researchers and scientists working for the treatment of COVID-19.

Clinical characteristics of 16 patients with fecal severe acute respiratory syndrome coronavirus 2 nucleic acid-positive. / 16ä¾‹ç²ªä¾¿ä¸¥é‡æ€¥æ€§å‘¼å¸ç»¼åˆå¾å† çŠ¶ç— æ¯’2æ ¸é ¸é˜³æ€§æ‚£è€ çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: To analyze the clinical characteristics of fecal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid-positive in patients with coronavirus dasease 2019 (COVID-19) and to provide a scientific basis for the prevention and control of this disease. METHODS: The clinical data of 16 patients with fecal SARS-CoV-2 nucleic acid positive, who hospitalized in the North Branch of the First Hospital of Changsha (Changsha Public Health Rescue Center) from January to February 2020, were retrospectively analyzed. Their clinical manifestations, laboratory data and imaging data were summarized. RESULTS: Among the 16 patients, there were 9 males (56.25%) and 7 females (43.75%), the ratio of males to females was 1∶1.29. The age of onset was (43.3±14.6) years. There were 15 patients with contact history of Wuhan, 1 patient with contact history of local patient.Twelve patients were common type (75%), and 4 patients were severe type (25%). Clinical symptoms included fever in 14 patients (87.5%), cough in 12 patients (75%), shortness of breath in 5 patients (31.25%), pharyngalgia in 10 patients (62.5%), fatigue in 7 patients (43.75%), and diarrhea in 4 patients (25%). There were 14 patients (87.5%) with normal or decreased white blood cell count, 11 patients (68.75%) with decreased lymphocyte count, 15 patients (93.75%) with increased erythrocyte sedimentation rate, 13 patients (81.25%) with increased hypersensitivity C-reactive protein, 5 patients (31.25%) with increased procalcitonin, and 8 patients (50%) with increased serum ferritin in peripheral blood, and stool routine was basically normal. Compared with the common type, there was significant difference in the white blood cell and lymphocyte counts in the severe type (P<0.01); the infection indicators, such as hypersensitivity C-reactive protein and serum ferritin, were significantly increased, with significant difference (all P<0.01); but the procalcitonin and erythrocyte sedimentation rate was not significantly different (both P>0.05). Chest CT mainly showed patchy shadows and interstitial changes. According to imaging examination, 4 patients (25%) showed unilateral pneumonia and 12 patients (75%) showed bilateral pneumonia. CONCLUSIONS: The patients have the clinical symptoms of COVID-19, but gastrointestinal symptoms (such as diarrhea) are more common, and the changes of white blood cell count, lymphocyte count, hypersensitivity C-reactive protein, ferritin are more obvious in severe patients.The positivity of fecal nucleic acid suggests the possibility of digestive tract transmission of SARS-CoV-2, and fecal nucleic acid testing can be used as a routine testing method in clinical practice.

JAK/STAT Pathway Inhibition May Be a Promising Therapy for COVID-19-Related Hyperinflammation in Hematologic Patients.

COVID-19 has rapidly become a major concern for the health systems worldwide. Its high contagiousness and associated mortality demand the discovery of helpful interventions with promising safety profile. Here, we report 3 severe COVID-19 cases, which achieved rapid and sustained improvement in outcome with the use of ruxolitinib, a JAK/STAT pathway inhibitor.