Evaluation of Vitamin D binding protein and 25-hydroxy Vitamin D metabolites in COVID-19 patients

Objectives: The immunomodulatory roles of Vitamin D and Vitamin D binding protein (VDBP) are in interest with incidence or outcome of coronavirus disease-2019 (COVID-19). This study aimed to investigate the association between the severity of COVID-19 with VDBP, total 25-hydroxy Vitamin D (25(OH)D), and its metabolites free Vitamin D (VDfree) and bioavailable Vitamin D (VDbio). Methods: Study group consisted of 68 COVID-19 patients and 20 healthy subjects. Patients were subgrouped as asymptotic, mild/moderately pneumonia, or severe pneumonia. Plasma total 25(OH)D was quantitated by liquid chromatography with mass spectrometry and serum VDBP by a polyclonal sandwich enzyme immunoassay. In addition, routinely used laboratory parameters in follow-up were recorded. VDfree and VDbio were calculated using total 25(OH)D, VDBP, and albumin levels. Results: Plasma total 25(OH)D (13.3±5.7 vs. 30.3±13.3 ng/dL), VDfree (2.18 [1.52–3.44] vs. 4.34 [3.74–6.48] pg/mL), and VDbio (1.86 [1.09–2.81] vs. 4.28 [3.45–6.34] nmol/L) levels were lower in COVID-19 patients (p<0.001). Despite the insignificance of 25(OH)D and metabolites between COVID-19 severity subgroups, serum VDBP was highest in mild/ moderately pneumonia (601.8±278.6 ng/mL) and lowest in severe pneumonia (427.9±147.2 ng/mL) (p<0.001). In addition, VDBP was positively correlated with lymphocyte counts (B:87.9, r2=0.068, p=0.031) and negatively correlated with D-Dimer levels (B:−0.024, r2=0.081, p=0.032). Conclusion: COVID-19 patients have lower plasma 25(OH)D levels and lower 25(OH)D metabolites VDfree, VDbio which are physiologically active. In addition, serum VDBP concentrations significantly decrease in critically ill patients which needs further studies to be associated in the etiopathogenesis of the disease severity. [ FROM AUTHOR] Copyright of International Journal of Medical Biochemistry is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

The Prognostic Value of Lung Injury and Fibrosis Markers, KL-6, TGF-ß1, FGF-2 in COVID-19 Patients.

Background: Biomarkers of lung injury and interstitial fibrosis give insight about the extent of involvement and prognosis in well-known interstitial lung diseases (ILD). Serum Krebs von den Lungen-6 (KL-6) reflects direct alveolar injury and, transforming growth factor-beta1 (TGF-ß1) and fibroblast growth factor-2 (FGF-2) are principal mediators of fibrosis in ILD and in almost all fibrotic diseases. In this sense, we aimed to assess associations of these biomarkers with traditional inflammatory markers and clinical course of COVID-19. Methods: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled and followed up prospectively with a standardized approach one month after diagnosis. Patients were divided into severe and non-severe groups according to National Institutes of Health criteria. Outcome was assessed for the requirement of intensive care unit (ICU) admission, long term respiratory support and death. Blood samples were collected at enrollment and serum levels of KL-6, TGF-ß1, FGF-2 were determined by ELISA. Association between these markers with other prognostic markers and prognosis were analyzed. Results: Overall 31 severe and 28 non-severe COVID-19 patients were enrolled and were compared with healthy control subjects (n = 30). Serum KL-6 levels in COVID-19 patients were significantly higher (median [IQR]; 11.54 [4.86] vs 8.54 [3.98] ng/mL, P = .001] and FGF-2 levels were lower (median [IQR]; 76.84 [98.2] vs 101.62 [210.6] pg/mL) compared to healthy control group. A significant correlation was found between KL-6 values and CRP, fibrinogen, d-dimer and lymphocyte counts. However, we did not find an association between these markers and subsequent severity of COVID-19, mortality and long-term prognosis. Conclusions: Serum KL-6 levels were significantly elevated at the diagnosis of COVID-19 and correlated well with the other traditional prognostic inflammatory markers. Serum levels of principal fibrosis mediators, TGF-ß1, FGF-2, were not elevated at diagnosis of COVID-19, therefore did not help to anticipate long term prognosis.

Specialty-Training Program During COVID-19 Pandemic: A Single Center Survey on over 300 Trainees and Trainers

Objective: COVID-19 pandemic caused significant modifications in education of trainees who are in medical speciality training programs. Limiting the number of residents in the clinics, cancelling elective surgical procedures, stopping face to face practical education, and transforming theoretical education into distance learning platforms resulted in alterations in the curriculum. Limited number of studies in the literature surveyed the impact of the COVID-19 pandemic on specialty training in various medical disciplines. Methods: We addressed to assess the situation of trainees' education using an online questionnaire from the trainees' and directors' perspective during the pandemic. The survey platform SurveyMonkey® was used to distribute the survey and to collect responses. We generated a list of multiple-choice questions about how social distancing affected the delivery of medical education, potential compromise in core training and difficulties in conducting clinical research for the thesis. Results: A total of 364 trainees among 552 (65.9%) under training at our university hospital and 90% of the directors (37 of 41) responded the survey. Almost 78 percent of the trainees claimed that they have been negatively affected during the pandemic. Although majority of the trainees (60.3%) reported that extension of their education program is not necessary, most of the program directors were in tendency of extending the duration of the speciality training period. The participants predominantly considered that online training would keep on being a part of the training program after the pandemic. Conclusion: Education programs are negatively affected during pandemics. However, authorities should manage this deficiency by a new perspective since present trainees are familiar to use technology-driven virtual sources for their education. After the pandemic, computer-assisted online learning and webbased programs should be integrated into educational curriculum. (English) [ FROM AUTHOR] Amaç: COVID-19 pandemisi tıpta uzmanlık eğitimi alan uzmanlık öğrencilerinin eğitim programında belirgin değişikliklere neden olmuştur. Kliniklerde asistan sayıları azaltılmış, elektif ameliyatlar ertelenmiş, yüz yüze pratik eğitim sonlandırılmış ve teorik eğitim uzaktan eğitime dönüştürülerek müfredat düzenlenmiştir. COVID-19 pandemisinin farklı tıp dsiplinlerinde uzmanlık eğitimini nasıl etkilediğine ait çalışma sayısı sınırlıdır. Yöntemler: Pandemi döneminde eğitimin sorgulanması için uzmanlık öğrencilerine ve anabilim dalı başkanlarına yönelik "online" bir anket hazırlanmıştır. Anket "SurveyMonkey®" programında hazırlanmış ve dağıtılmıştır. Sosyal mesafe kurallarının tıp eğitimini nasıl etkilediği, çekirdek eğitim müfredatının nasıl yürütüldüğü, tez çalışmalarının ve klinik araştırmaların durumunu sorgulayan çoktan seçmeli sorular hazırlanmıştır. Sonuçlar: Üniversite hastanemizde eğitim alan toplam 552 uzmanlık öğrencisinden 364'ü (%65.9) ve anabilim dalı başkanlarının %90'ı (41'den 37'si) anketi cevaplandırmıştır. Uzmanlık öğrencilerinin %78'si pandeminin eğitimlerini olumsuz yönde etkilediğini bildirmiş, ancak, çoğunluk (%60.3) uzmanlık eğitim süresinin uzamasını istememiştir. Tersine, anabilim dalı başkanlarının çoğunluğu sürenin uzatılması gerektiğini bildirmiştir. Katılımcıların çoğu uzaktan "online" eğitimin pandemiden sonra da eğitim programına dahil edilmesi gerektiğini bildirmiştir. Tartışma: Pandemi döneminde eğitim olumsuz etkilenmiştir. Ancak, eğitim sorumluları günümüz uzmanlık öğrencilerinin teknolojinin kullanıldığı uzaktan eğitim modellerine daha yatkın olmalarından yararlanarak, eğitim sistemlerini yeni bir bakış açısı ile güncellemelidir. Pandemi sonrasında, bilgisayar temelli eğitim kaynakları uzmanlık eğitim müfredatına yerleştirilmelidir. (Turkish) [ FROM AUTHOR] Copyright of Gazi Medical Journal is the property of Gazi Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Prognostic Value of Serial Measurement of Serum Des-Arg(9)-Bradykinin Levels in Severe COVID-19 Patients.

BACKGROUND: Excessive inflammatory immune response during SARS-CoV-2 infection contributes to severe disease in COVID-19 patients. Recently, some researchers hypothesized that dysregulation of the bradykinin (BK) system may also play a role in the pathogenesis of severe disease. Des-Arg(9)-bradykinin (DABK), an active metabolite of BK, is responsible for vasodilatation and increased permeability in the lungs and regulated by angiotensin converting enzyme 2 (ACE-2). Viral inhibition of ACE-2 by SARS-CoV-2 increases DABK levels. Serum levels of this metabolite may be linked to disease severity in COVID-19 patients. In this study, it is aimed to investigate the prognostic value of serial measurement of serum DABK levels in severe COVID-19 patients. METHODS: This prospective cohort study was conducted in hospitalized severe COVID-19 patients. Serum DABK levels of patients were serially measured on day 0, day 3 and day 5. Patients were categorized as cases with poor or good prognosis and critical or non-critical cases. Serum DABK levels of these patient groups were compared with paired sample t-test. Serum DABK levels on different days in the same patients were compared with repeated measures ANOVA tests. RESULTS: There was no statistically significant difference in serum DABK levels measured at day 0, day 3, and day 5 between good and poor prognosis groups. DABK levels in critical and non-critical COVID-19 patients also did not show any significant difference. CONCLUSIONS: According to our results serially measured serum DABK levels did not correlate with outcome of severe COVID-19 and do not have prognostic value in severe COVID-19 patients.

Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress.

Coronavirus disease 2019 (COVID-19) has resulted in long-term psychiatric symptoms because of the immunologic response to the virus itself as well as fundamental life changes related to the pandemic. This immune response leads to altered tryptophan (TRP)-kynurenine (KYN) pathway (TKP) metabolism, which plays an essential role in the pathophysiology of mental illnesses. We aimed to define TKP changes as a potential underlying mechanism of psychiatric disorders in post-COVID-19 patients. We measured plasma levels of several TKP markers, including KYN, TRP, kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), as well as the TRP/KYN, KYNA/3-HK, and KYNA/QUIN ratios, in 90 post-COVID-19 patients (on the first day of hospitalization) and 59 healthy controls (on the first admission to the Check-Up Center). An online questionnaire that included the Depression, Anxiety and Stress Scale-21 (DASS-21) was used 6 months after the initial assessment in both groups. A total of 32.2% of participants with COVID-19 showed depressive symptoms, 21.1% exhibited anxiety, and 33.3% had signs of stress at follow-up, while 6.6% of healthy controls exhibited depressive and anxiety symptoms and 18.6% had signs of stress. TRP and 3-HK were negative predictors of anxiety and stress, but KYN positively predicted anxiety and stress. Moreover, TRP negatively predicted depression, while KYNA/3-HK was a negative predictor of anxiety. The correlation between depression, anxiety, and stress and TKP activation in COVID-19 could provide prospective biomarkers, especially the reduction in TRP and 3HK levels and the increase in KYN. Our results suggest that the alteration of TKP is not only a potential biomarker of viral infection-related long-term psychiatric disorders but also that the therapy targets future viral infections related to depression and anxiety.

HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism.

BACKGROUND AND AIM: Pathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache. METHODS: This cross-sectional study enrolled 88 COVID-19 patients, hospitalized on a regular ward during the second wave of the pandemic. Clinical characteristics of COVID-19 patients were recorded, and laboratory tests were studied. RESULTS: The mean ages of 48 COVID-19 patients with headache (47.71 ± 10.8) and 40 COVID-19 patients without headache (45.70 ± 12.72) were comparable. COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups. Angiotensin II level was significantly decreased in the headache group. COVID-19 patients with headache showed an increased frequency of pulmonary involvement and increased D- dimer levels. Furthermore, COVID-19 was more frequently associated with weight loss, nausea, and diarrhea in patients with headache. Serum NLRP3 levels were correlated with headache duration and hospital stay, while headache response to paracetamol was negatively correlated with HMGB1 and positively associated with IL-10 levels. CONCLUSION: Stronger inflammatory response is associated with headache in hospitalized COVID-19 patients with moderate disease severity. Increased levels of the circulating inflammatory and/or nociceptive molecules like HMGB1, NLRP3, and IL-6 may play a role in the potential induction of the trigeminal system and manifestation of headache secondary to SARS-CoV-2 infection.

Early predictors of acute kidney injury in COVID-19 patients.

AIM: This study aims to determine the frequency of COVID-19 related AKI and to identify the early predictors of AKI. METHODS: This study is a single-center, retrospective, observational study. Hospitalized COVID-19 patients between 24/03/2020 and 31/05/2020 were included in the study. All patients were evaluated for renal dysfunctions with urine dipstick, protein/creatinine ratio, albumin/creatinine ratio in spot urine, serum cystatin C, serum creatinine level on hospital admission, and 28th day of hospital admission. To assess the utility of these parameters to predict AKI, a receiver-operating characteristic curve was generated and the area under the curve (AUC) was calculated. RESULTS: 348 patients were included. The average incidence of AKI was 4.9% (n = 17). The incidence of AKI in mild, moderate and severe COVID-19 cases was 1.3% (n = 4), 9.0% (n = 3) and 76.9% (n = 10), respectively. Proteinuria was detected in 7.8% (n = 27) of patients with a urine dipstick test. In spot urine analysis, proteinuria was found in 20.1% (n = 70) of patients. The frequency of persistent proteinuria was 5.2% (n = 18). The AUC alue of serum cystatin C, D-dimer and albumin/creatinine ratio to predict COVID-19 related AKI were 0.96 (0.90 to 1.0), 0.94 (0.89-0.98), and 0.95 (0.91-0.98). CONCLUSION: In COVID-19 patients with normal serum creatinine levels on hospital admission, albuminuria, serum cystatin C and D-dimer levels may be an early predictor of COVID-19 related AKI and these patients should be monitored closely for AKI. Since the sample size in the AKI group was small, our study results should be confirmed with larger cohort studies.

The assessment of serum ACE activity in COVID-19 and its association with clinical features and severity of the disease.

Angiotensin-converting enzyme (ACE)/Angiotensin (Ang) II pathway has crucial regulatory effects on circulatory hemostasis and immune responses. This pathway has a major role in the development of acute lung injury and acute respiratory distress syndrome (ARDS), which is a devastating complication of SARS-CoV-2 infection. The aim of this study is to investigate the serum ACE activity and its correlation with clinical features and the disease severity in patients with COVID-19. Patients with confirmed COVID-19 by detecting SARS-CoV-2 nucleic acid RT-PCR were included in the study. Demographic data, clinical features, laboratory and radiologic investigations were recorded. Patients were classified by disease severity; asymptomatic, mild, and severe pneumonia. The serum ACE activity was evaluated with an autoanalyzer based on a spectrophotometric method. Fifty-five patients (50.9% female) and 18 healthy subjects (33.3 % female) were enrolled in the study. The median age of patients was 40 years, ranging from 22 to 81 years. Eighteen healthy subjects were served as the control group. The baseline characteristics were comparable between groups. The median serum ACE activity of patients and controls (38.00 [IQR 21] U/L and 32.00 [IQR 24] U/L, respectively) and of between patients grouped by disease severity (38.5 [IQR 19], 36 [IQR 25], and 38 [IQR 22] U/L, asymptomatic, mild and severe pneumonia group, respectively) were similar. There was no correlation between the serum ACE activity and conventional inflammatory markers. In this study, we did not find an association between serum ACE activity and COVID-19 and serum ACE activity on admission did not reflect disease severity.

Prognostic value of interleukin-18 and its association with other inflammatory markers and disease severity in COVID-19.

BACKGROUND: The effectual immune response is crucial to defeat viral infections. However, exuberant immune response with features of macrophage activation syndrome (MAS) lead detrimental consequences in COVID-19 patients. Interleukin (IL)-18 is one of the leading cytokines in MAS which has not been studied in COVID-19. OBJECTIVE: To investigate the association of IL-18 with the other inflammatory markers and disease severity in COVID-19 for predicting disease prognosis. METHODS: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled into the study. Data on demographic and clinical characteristics, and laboratory values of CRP, ferritin, d-dimer and procalcitonin were measured on admission. Patients were followed up prospectively with a standardized approach until hospital discharge or death. Individuals were classified as asymptomatic, mild and severe pneumonia according to their clinical, laboratory and radiological characteristics. Worse outcome was defined as requirement of intensive care unit (ICU) admission or death. Blood samples were collected at enrollment and serum levels of IL-6 and IL-18 were determined by ELISA. Association between IL-18 and other inflammatory markers and prognosis were analyzed. RESULTS: There were 58 COVID-19 patients (50% male) with a median age of 43 (min 22-max 81) years. Twenty age and sex matched healthy subjects were served as control group. The study population was divided into three groups according to disease severity: asymptomatic (n = 20), mild pneumonia group (n = 27) and a severe group (n = 11). During follow up nine (15.5%) patients required ICU admission and three of them were died eventually. Serum IL-18 were correlated with other inflammatory markers and biochemical markers of organ injury; creatinine, liver enzymes and troponin. Serum IL-18 levels were remarkably higher in COVID-19 patients compared to healthy subjects with being highest in severe pneumonia group (p < 0.001). IL-18 serum concentrations were almost four-fold higher in patients with worse outcome compared to good outcome (p < 0.001). Serum IL-18 above the cut off value of 576 pg/mL on admission was associated with 11.7 fold increased risk of ICU admission. CONCLUSIONS: The serum concentrations of IL-18 correlate with other inflammatory markers and reflect disease severity. Results of the present study shed light on role of IL-18 on COVID-19 pathogenesis and might provide an evidence for the clinical trials on IL-18 antagonists for the treatment of severe COVID-19 patients.

The factors predicting pneumonia in COVID-19 patients: preliminary results from a university hospital in Turkey

Background/aim: Pneumonia is the most serious clinical presentation of COVID-19. This study aimed to determine the demographic, clinical, and laboratory findings that can properly predict COVID-19 pneumonia. Materials and methods: This study was conducted in the Gazi University hospital. All hospitalized patients with confirmed and suspected SARS-CoV-2 infection between 16 March 2020 and 30 April 2020 were analyzed retrospectively. COVID-19 patients were separated into two groups, pneumonia and nonpneumonia, and then compared to determine predicting factors for COVID-19 pneumonia. Variables that had a P-value of less than 0.20 and were not correlated with each other were included in the logistic regression model. Results: Of the 247 patients included in the study 58% were female, and the median age was 40. COVID-19 was confirmed in 70.9% of these patients. Among the confirmed COVID-19 cases, 21.4% had pneumonia. In the multivariate analysis male sex (P = 0.028), hypertension (P = 0.022), and shortness of breath on hospital admission (P = 0.025) were significant factors predicting COVID-19 pneumonia. Conclusion: Shortness of breath, male sex, and hypertension were significant for predicting COVID-19 pneumonia on admission. Patients with these factors should be evaluated more carefully for diagnostic procedures, such as thorax CT.