ABSTRACT
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.
ABSTRACT
Objective: Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory syndrome associated with multiorgan damage that occurs following coronavirus disease 2019 (COVID-19). Research on clinical and laboratory findings, and imaging studies, aiming to predict the progression to severe disease state is limited. This study recruited patients with MIS-C who presented with mild or severe symptoms from a single center in Turkey and evaluated factors related to their symptoms. Methods: This retrospective study included 25 pediatric patients with mild and severe presentations of MIS-C. We explored the differences in demographic and clinical data on clinical severity to understand their possible diagnostic and prognostic values. Results: Patients with MIS-C had cardiovascular symptoms (68%), gastrointestinal symptoms (64%), dermatologic/mucocutaneous findings (64%), lung involvement (36%), and neurological symptoms (16.0%). About 45.1% of patients with MIS-C had manifestations that overlapped with Kawasaki disease. Eleven patients (44%) were admitted to the intensive care unit, and one (4%) patient died. Grouping based on clinical severity did not differ statistically in terms of gender, age, height, weight, body mass index, and duration of hospital stay. Procalcitonin and ferritin levels correlated with disease severity. The receiver operating characteristic curve for D-dimer gave the highest value of area under the curve, among other biomarkers. The cutoff value for D-dimer was determined as more than 6780. Conclusions: Although COVID-19 is usually mild in children, some can be severely affected, and clinical severity in MIS-C can differ from mild to severe multisystem involvement. This study shows that procalcitonin, ferritin, and D-dimer levels may give us information about disease severity.
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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.
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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.
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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.
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RATIONALE: Coronavirus disease 2019 (COVID-19), which is caused by the SARS-CoV-2, has been affecting the world since the end of 2019. Turkey is severely affected with the first case being reported on March 11th 2020. Several studies suggest an association between air pollution and the spread of the infection, and that ambient particulate matters (PM) can present a potential, as virus carriers. The aim of the present study was to investigate the presence of SARS-CoV-2 RNA on ambient PM. METHODS: Ambient PM samples in various size ranges were collected from 13 sites including urban, urban background locations and hospital gardens in 10 cities including Istanbul, Ankara, Izmir, Zonguldak, Tekirdag, Eskisehir, Bolu, Bursa, Konya, and Antalya across Turkey, between 13th of May and 14th of June, 2020. The nucleocapsid (N) 1 gene and RNA dependent RNA polymerase (RdRP) gene expressions were analyzed in PM samples for the presence of SARS-CoV-2 by applying quantitative real time-polymerase chain reaction (qRT-PCR) and three dimensional (3D)-digital PCR methods. RESULTS: A total of 155 daily samples (Total Suspended Particulate [TSP], n=80;PM2.5, n=33;PM2.5-10, n=23;PM10, n=19;and 6 size segregated, n=48) were collected using various samplers in the each city. According to RT-PCR and 3D-RT-PCR analysis, dual RdRP and N1 gene positivity were detected in 20 of the samples (9.8 %). The highest percentage of virus detection on PM samples was from hospital gardens in Tekirda Zonguldak, and Istanbul, especially in PM2.5 mode. Samples collected from two urban sites, Ankara and Eskisehir, were also positive. CONCLUSIONS: These findings suggest that SARS-CoV-2 may be transported by ambient particles, especially at sites close to the infection hot-spots such as hospital gardens. Whether this has an impact on the spread of the virus infection remains to be determined.
ABSTRACT
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.