POTENTIAL PREDICTORS of OUTCOME for ANAKINRA TREATMENT in COVID-19 PATIENTS with MACROPHAGE ACTIVATION SYNDROME

Background: A hyperinfammatory response compatible with features of macrophage activation syndrome (MAS) contributes to this worse outcome in patients with Coronavirus Disease 2019 (COVID-19). Glucocorticoids have become the standard of care for those requiring oxygen support or mechanical ventilation. More targeted anti-infammatory treatments with tocilizumab and anakinra have also been shown to be effective. Objectives: More studies are being awaited to clarify the features of patients who would beneft more, and we investigated the characteristics of the surviving and dead patients who received anakinra. Methods: The records of hospitalized adult patients between March 2020 and May 2021 in a tertiary referral center were evaluated. Diagnosis of COVID-19-re-lated MAS was based on the expert opinion and preliminary criteria developed by our group that patients with a score of ≥45 were accepted COVID-19-related MAS.1 Patients who received anakinra constituted the study group. Anakinra dose was determined according to the clinical and infammatory parameters;and doses varied between daily 100-300 mg SC to 400-800 mg IV. Laboratory data of surviving and died patients were comparatively analyzed by using the ANCOVA method on the relevant days (baseline, anakinra-onset day, frst response to anakinra treatment, and discharge or death). The temporal variation (drug onset day-frst response day, drug onset day-discharge, or death day) was evaluated using the ANOVA method. A 50% reduction of CRP compared to the anakinra start day was accepted as the frst response to the treatment. Results: Out of 1080 hospitalized patients, 218 (151 male, 67 female, mean age 60.0±14.1) who received anakinra were identifed. Among them, 125 (57.3%) patients were followed in the ward, 21 (9.6%) did not need oxygen treatment during the hospitalization;69 (31.6%) patients were followed at ICU, 40 of them were intubated, 30 (13.7%) died in ICU. Anakinra had been started in a mean of 4.8 days of hospitalization. Twenty had tocilizumab initially and then received anak-inra because of ongoing infammatory parameters. The majority (83.5%) received steroid treatment (79.5% methylprednisolone, 5% of dexamethasone), and 6 received one IV pulse 250 mg of methylprednisolone;36 (16.5%) were followed before September 2020 and received anakinra without steroids because of the standard of care at that period. Only CRP was different between the alive and dead patients for the baseline parameters (p=0.05). On the frst day of drug treatment, CRP and procalcitonin values were signifcantly higher in dead patients (Table 1). A 50% decrease in CRP level was achieved in 3.1 days in survivors and 4.7 days in dead patients. D-dimer (p=0.018), CRP (p=0.006), LDH (p=0.003), procalcitonin (p=0.005), creatinine kinase (p=0.001), and fbrinogen levels (p=0.05) were significantly different between the surviving and dead patients when the measurements between the frst drug administration day and response day were compared. Neu-trophil, lymphocyte count, ferritin, D-dimer, CRP, LDH, AST, procalcitonin, creati-nine kinase, and fbrinogen levels were signifcantly different between the patients when the parameters between the frst drug administration day and discharge/death day were compared. Dead patients had higher CRP values and they did not show a continuing CRP decrease with the steroids and anakinra (Figure 1). Conclusion: Retrospective analysis of 218 patients suggests that starting anakinra earlier in hospitalized patients may provide better results, and a decrease in CRP, ferritin, D-dimer values, as well as an increase in lymphocyte count, are associated with favorable outcomes. Increasing values of D-dimer and troponin during treatment are associated with worse outcomes, possibly indicating cardiovascular and thrombotic pathologies not responding to anakinra. Changes in the CRP values are found to help monitor the response to anakinra. Other infammatory pathways could be targeted in those who are not responding to appropriate doses of anakinra within 5 days.

Dipyridamole does not have any additive effect on the prevention of COVID-19 coagulopathy

Objective: Severe acute respiratory syndrome (SARS) coronavirus 2 (SaRS-Cov-2) associated respiratory disease (COVID-19), announced as a pandemic, is a multisystem syndrome. SARS-CoV-2 directly infects and damages vascular endothelial cells, which leads to microvascular dysfunction and promotes a procoagulant state. Dipyridamole (DP) acts as a reversible phosphodiesterase inhibitor and is used mainly as an antiplatelet agent. It is hypothetised that it has possible activities in COVID-19. Design and Methodology: We report our retrospective, real-world results of DP added to low-molecular weight heparin (LMWH) in the treatment of 462 clinically diagnosed and hospitalized COVID-19 patients. We compared anticoagulation with and without DP addition with no administration of anticoagulation in the same time frame. The primary outcome was proven or highly suspected coagulopathy within 30 days of hospitalization. Results: Definitive coagulopathy has been diagnosed in 3 (3.5%) of 85 LMWH administered patients and 7 (2.13%) of 328 DP + LMWH received patients (P=0.456). Five cases with definitive coagulopathy were not initiated any anticoagulation at the time of the event. The multivariate analysis showed that DP addition to the anticoagulant approach did not have any impact on the risk of demonstrated coagulopathy and highly-suspected coagulopathy. Conclusion: We think that our clinical experience is valuable in showing the real-life results of DP + LMWH treatment in COVID-19. This approach did not affect the coagulopathy rate. Our data did also not document an additive effect of DP in the COVID-19 outcome. Prospective controlled trials would give more convincing results regarding the role of DP in COVID-19 endothelial dysfunction and clinical outcome.

Cross-talk between the Inflammatory Response and Coagulopathy: Single-center Report

Background : Covid-19 appeared quaint with evolving hyperinflammation phase, vasculoendothelial dysfunction, and a distinct coagulopathy. Aims : We present our experience regarding coagulopathy predictive factors in hospitalized Covid-19 patients just after pandemic declaration. Methods : The data were obtained retrospectively by screening the institution's electronic data system between March and May 2020. The treatment protocol based on Health Ministry guidelines, includes hydroxychloroquine, azithromycin, favipiravir, low-molecular-weight heparin, dipyridamole, and anti-cytokine agents on the hyperinflammation phase. We stratified 3 groups, patients with proven coagulopathy, highly suspected coagulopathy, and patients without coagulopathy. Highly suspected coagulopathy encompasses clinical deterioration with sudden and inconsistent D-dimer elevation. Results : A total of 511 patients were screened. Forty-nine of them were excluded due to accompanying conditions resulting in high D-dimer levels. The median age of the remaining patients was 56 years with a male/female ratio of 284/178. Proven coagulopathy as documented thrombosis developed in 3.2% with a male predominance (60%). Highly suspected coagulopathy was decided in 10.1% of patients. Among predictive factors for coagulopathy, the risk factors at admission were being over 65-year-old, having coronary artery disease, dyspnea, severe lymphopenia (<500/μl), monocytopenia (<300/ μl), and elevated LDH. For highly suspected coagulopathy, in addition to these having more than 3 comorbidities, high initial ferritin (>1000 ng/ml) and d-dimer levels as greater than 3600 U/ml were also predictive. The clinical pictures in the proven coagulopathy group included 5 myocardial infarctions, 4 disseminated intravascular coagulation (DIC), 2 deep vein thrombosis, 1 catheter-related venous thrombosis, 1 catheter-related venous thrombosis, and pulmonary embolism, 1 lower extremity arterial thrombosis, 1 stroke. All DIC cases had gram-negative bacterial sepsis. Conclusions : Our data suggest coagulopathy is not directly correlated with inflammation severity but patients in hyperinflamation phase should be pursued for possible proven coagulopathy.

Preliminary criteria for macrophage activation syndrome associated with coronavirus disease-19

Background: COVID-19 runs a severe disease associated with acute respiratory distress syndrome in a subset of patients, and a hyperinflammatory response developing in the second week contributes to the worse outcome. Inflammatory features are mostly compatible with macrophage activation syndrome (MAS) observed in other viral infections despite resulting in milder changes. Early detection and treatment of MAS may be associated with a better outcome. However, available criteria for MAS associated with other causes have not been helpful. Objectives: To identify distinct features of MAS associated with COVID-19 using a large database enabling to assess of dynamic changes. Methods: PCR-confirmed hospitalized COVID-19 patients followed between March and September 2020 constituted the discovery set. Patients considered to have findings of MAS by experienced physicians and given anakinra or tocilizumab were classified as the MAS group and the remaining patients as the non-MAS group. The MAS group was then re-grouped as the cases with exact-MAS and borderline-MAS cases by the study group. Clinical and laboratory data including the Ct values of the PCR test were obtained from the database, and dynamic changes were evaluated especially for the first 14 days of the hospitalization. The second set of 162 patients followed between September-December 2020 were used as the replication group to test the preliminary criteria. In the second set, hospitalization rules were changed, and all patients required oxygen support and received dexamethasone 6mg/day or equivalent glucocorticoids. Daily changes were calculated for the laboratory items in MAS, borderline, and non-MAS groups to see the days differentiating the groups, and ROC curves and lower and upper limits (10-90%) of the selected parameters were calculated to determine the cutoff values. Results: A total of 769 PCR-confirmed hospitalized patients were analysed, and 77 of them were classified as MAS and 83 as borderline MAS patients. There was no statistically significant difference in the baseline viral loads of MAS patients compared to the non-MAS group according to the Ct values. Daily dynamic changes in the MAS group differed from the non-MAS group especially around the 6th day of hospitalization, and more than a twofold increase in ferritin and a 1.5-fold increase in D-dimer levels compared to the baseline values help to define the MAS group. Twelve items selected for the criteria are given in Table 1 below. The total score of 45 provided 79.6% sensitivity for the MAS (including borderline cases) and 81.3% specificity around days 5 and 6 in the discovery set, and a score of 60 increased the specificity to 94.9% despite a decrease in sensitivity to 40.8%. The same set provided a similar sensitivity (80.3%) in the replication, but a lower specificity (47.4-66% on days 6 to 9) due to a group of control patients with findings of MAS possibly masked by glucocorticoids. Conclusion: This study defined a set of preliminary criteria using the most relevant items of MAS according to the dynamic changes in the parameters in a group of COVID-19 patients. A score of 45 would be helpful to define a possible MAS group with reasonable sensitivity and specificity to start necessary treatments as early as possible.

Erratum to: Older Adults Hospitalized with COVID-19: Clinical Characteristics and Early Outcomes from a Single Center in Istanbul, Turkey (The journal of nutrition, health & aging, (2020), 24, 9, (928-937), 10.1007/s12603-020-1499-9)

Two unrelated tables have interfered with our article. There are two Table 1 and Table 2 in the original publication. We request readers to disregard “Table 1. General characteristics of the subjects by sex” and age and “Table 2. Parameters of the ROC analysis for the diagnostic performance of SPPB in identifying high risk for frailty phenotype and geriatric syndromes for community-dwelling older adults by sex”. The correct Table 1 and Table 2 is found in the manuscript as “Table 1. Baseline demographic and clinical characteristics of the hospitalized Covid-19 patients stratified by age” and “Table 2. Laboratory and radiological findings of the hospitalized Covid-19 patients at hospital admission stratified by age. We apologize to the readers for this error on proof stage ”

Older adults hospitalized with COVID-19: clinical characteristics and early outcomes from a single center in Istanbul, Turkey

Objective: Older adults have been continuously reported to be at higher risk for adverse outcomes of Covid-19. We aimed to describe clinical characteristics and early outcomes of the older Covid-19 patients hospitalized in our center comparatively with the younger patients, and also to analyze the triage factors that were related to the in-hospital mortality of older adults. Design: Retrospective;observational study. Setting: Istanbul Faculty of Medicine hospital, Turkey. Participants: 362 hospitalized patients with laboratory-confirmed Covid-19 from March 11 to May 11, 2020. Measurements: The demographic information;associated comorbidities;presenting clinical, laboratory, radiological characteristics on admission and outcomes from the electronic medical records were analyzed comparatively between the younger (<65 years) and older (65 years) adults. Factors associated with in-hospital mortality of the older adults were analyzed by multivariate regression analyses.

Initial complete blood count score and predicting disease progression in COVID-19 patients

Introduction: Coronavirus has caused a pandemic since it was first detected in Wuhan in December 2019. The mortality rate is high in moderate and severe cases. Our study aimed to screen the CBC parameters as a useful predictive factor for COVID-19 resulting in critical illness. Methods: A total of 285 patients with positive PCR results were analyzed. The median age was 55 (24-90), and 64.2% of patients were male. Sixty-eight percent of cases were hospitalized with moderate, 32% with severe disease at initial admission. Results: We found that lymphocyte count <620/mcl, neutrophil-to-lymphocyte ratio (NLR) >6, and platelet to lymphocyte ratio (PLR) >350 were predictive of the outcome. We scored our cohort 0-3 for these three parameters. Patients with a score of 2-3 were more likely to have progressive disease, anti-cytokine treatment, intensive care admission, intubation, and death, compared to patients with a score of 0-1. Additionally, they tended to be hospitalized for longer (median 11.5 days, mean 15.6), compared to those with a score 0 or 1 (median 9 days, mean 11.3). Twenty-eight of 38 cases with scores of 2-3 were discharged (73.6%), whereas the rate was 89% for patients with a score of 0-1 (P=0.009). Conclusion: Based on the absolute lymphocyte count (<620/mcl, NLR >6, PLR >350), our three-parameter score was able to predict disease progression, and the likelihood of anti-cytokine treatment, intubation, and death. We think that COVID-19 patients presenting with moderate to severe pneumonia, and having scores of 2 or 3 on our scale, should be closely monitored and robustly supported.

Older Adults Hospitalized with Covid-19: Clinical Characteristics and Early Outcomes from a Single Center in Istanbul, Turkey.

OBJECTIVE: Older adults have been continuously reported to be at higher risk for adverse outcomes of Covid-19. We aimed to describe clinical characteristics and early outcomes of the older Covid-19 patients hospitalized in our center comparatively with the younger patients, and also to analyze the triage factors that were related to the in-hospital mortality of older adults. DESIGN: Retrospective; observational study. SETTING: Istanbul Faculty of Medicine hospital, Turkey. PARTICIPANTS: 362 hospitalized patients with laboratory-confirmed Covid-19 from March 11 to May 11, 2020. MEASUREMENTS: The demographic information; associated comorbidities; presenting clinical, laboratory, radiological characteristics on admission and outcomes from the electronic medical records were analyzed comparatively between the younger (<65 years) and older (≥65 years) adults. Factors associated with in-hospital mortality of the older adults were analyzed by multivariate regression analyses. RESULTS: The median age was 56 years (interquartile range [IQR], 46-67), and 224 (61.9%) were male. There were 104 (28.7%) patients ≥65 years of age. More than half of the patients (58%) had one or more chronic comorbidity. The three most common presenting symptoms in the older patients were fatigue/myalgia (89.4%), dry cough (72.1%), and fever (63.5%). Cough and fever were significantly less prevalent in older adults compared to younger patients (p=0.001 and 0.008, respectively). Clinically severe pneumonia was present in 31.5% of the study population being more common in older adults (49% vs. 24.4%) (p<0.001). The laboratory parameters that were significantly different between the older and younger adults were as follows: the older patients had significantly higher CRP, D-dimer, TnT, pro-BNP, procalcitonin levels, higher prevalence of lymphopenia, neutrophilia, increased creatinine, and lower hemoglobin, ALT, albumin level (p<0.05). In the radiological evaluation, more than half of the patients (54.6%) had moderate-severe pneumonia, which was more prevalent in older patients (66% vs. 50%) (p=0.006). The adverse outcomes were significantly more prevalent in older adults compared to the younger patients (ICU admission, 28.8% vs. 8.9%; mortality, 23.1% vs. 4.3%, p<0.001). Among the triage evaluation parameters, the only factor associated with higher mortality was the presence of clinically severe pneumonia on admission (Odds Ratio=12.3, 95% confidence interval=2.7-55.5, p=0.001). CONCLUSION: Older patients presented with more prevalent chronic comorbidities, less prevalent symptomatology but more severe respiratory signs and laboratory abnormalities than the younger patients. Among the triage assessment factors, the clinical evaluation of pulmonary involvement came in front to help clinicians to stratify the patients for mortality risk.

Acute ischemic stroke presentation of otherwise asymptomatic covid-19 patient

Objective: Coronavirus disease 2019 (COVID-19), first identified in Wuhan, China in December 2019, become widespread and may be mortal, especially in some high-risk group. Most of the reported experiences suggested that COVID-19 is associated with a distinct coagulation disorder resulting in fibrin thrombi within small vessels and capillaries. Data focusing on arterial thrombotic events is few. In milder COVID cases, both hemorrhagic and ischemic stroke may occur. Acute ischemic stroke seems to be higher than the rate identified among patients who visited the emergency departments (ED). On the other hand, SARS-CoV-2 has the potential for neurotropism. We here present a case who had neurological symptoms during pandemic days and has been diagnosed with imaging-proven ischemic stroke with COVID-19. Case report: A 40-year-old female patient presented to the ED with an articulation of speech and numbness in the right arm and leg. She is not a smoker and denied any environmental exposure. Physical examination revealed fever and hypotension with a respiratory rate was 18 breaths/min. She had dysarthria, hypoesthesia, and frustrated hemiparesis on the right arm and leg. Oxygen saturation was 98% on room air. Mild normocytic anaemia and lymphopenia associated with a mild elevation in transaminases (AST 73 U/L, ALT 103 U/L) and in D-Dimer (1440 ng/ml) associated the clinical picture. Thoracic CT showed bilateral multifocal peripheral ground glass infiltrations (Picture-1). Conventional MRI imaging is consistent with acute ischemia of millimetre in size on the left parietal lobe (Picture-2). The patient was accepted as having COVID-19 and acute ischemic stroke. She commenced on hydroxychloroquine and azithromycin with enoxaparin. Nasopharynx swab sample was found to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive by RT-PCR. She did not progress to the hyperinflammation phase and discharged on 10th day of admission. One month later on, outpatient visit her neurological findings resolved, no weakness was detected. Conclusion: For each patient with an acute stroke clinic, thoracic CT and SARS-CoV-2 PCR should be performed before transferring to stroke or neurointensive care unit. For our patient, she did not have apparent risk factors for stroke. She was nearly asymptomatic apart of the stroke-related clinic, which points to the direct effect of coronavirus on vascular endothelial cells apart of the relationship between inflammation and coagulopathic complications in COVID-19.