Deciphering the host genetic factors conferring susceptibility to severe COVID-19 using exome sequencing.

The COVID-19 pandemic remains a significant public health concern despite the new vaccines and therapeutics. The clinical course of acute SARS-CoV-2 infection is highly variable and influenced by several factors related to the virus and the host. Numerous genetic studies, including candidate gene, exome, and genome sequencing studies, genome-wide association studies, and other omics efforts, have proposed various Mendelian and non-Mendelian associations with COVID-19 course. In this study, we conducted whole-exome sequencing on 90 unvaccinated patients from Turkey with no known comorbidities associated with severe COVID-19. Of these patients, 30 had severe, 30 had moderate, and 30 had mild/asymptomatic disease. We identified rare variants in genes associated with SARS-CoV-2 susceptibility and pathogenesis, with an emphasis on genes related to the regulation of inflammation, and discussed these in the context of the clinical course of the patients. In addition, we compared the frequencies of common variants between each group. Even though no variant remained statistically significant after correction for multiple testing, we observed that certain previously associated genes and variants showed significant associations before correction. Our study contributes to the existing literature regarding the genetic susceptibility to SARS-CoV-2. Future studies would be beneficial characterizing the host genetic properties in different populations.

The Clinical and Laboratory Efficacy of HA 330 Treatment Combined with Continuous Renal Replacement Therapy in Septic Shock Patients: A Case Series.

INTRODUCTION: Blood purification therapy is a method used to enable cytokine removal and to improve disturbed immune homeostasis in patients with sepsis or septic shock. This study aimed to evaluate the impact of HA 330 treatment on biochemical and hemodynamic parameters and cytokine levels in adult patients with septic shock. METHODS: Critically ill patients with septic shock who received continuous veno-venous hemodiafiltration and HA 330 treatment were included in this prospective observational study. Biochemical and hemodynamic parameters were followed throughout HA 330 treatment. Serum interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, high-mobility group box1 (HMGB-1) protein, IL-10 levels were analyzed by ELISA method, before and after each HA 330 session. RESULTS: A total of 18 critically ill patients were included in this study. The median APACHE 2 score was 22.2 ± 7.49 and median SOFA score 9.6 ± 5.44 on intensive care unit admission. SOFA scores were significantly decreased on the 3rd day of HA 330 treatment, compared to 2nd day scores (p = 0.017). Median leukocyte value was significantly decreased (p = 0.027 and p = 0.024), while hemodynamic parameters remained unchanged throughout the HA 330 treatment. Median CRP and procalcitonin levels were significantly reduced at day 3 of HA 330 treatment compared to the baseline (p = 0.015 and p = 0.033, respectively). Serum IL-1 ß, IL-6, IL-8, TNF-a, HMGB-1, and IL-10 levels decreased insignificantly by 11.5%, 26.4%, 11.4%, 37.9%, 0.02%, and 35.5%, respectively, at the end of the hemoperfusion treatment compared to the pre-treatment. CONCLUSION: The administration of HA 330-based hemoperfusion in septic shock patients revealed improvements in SOFA scores, leukocyte count, and CRP and procalcitonin levels. However, there was no statistically significant change in concentrations of inflammatory cytokines and hemodynamic parameters during HA 330 treatment.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.

The use of high-flow nasal oxygen vs. standard oxygen therapy in hematological malignancy patients with acute respiratory failure in hematology wards

Background/aim: High flow nasal cannula (HFNC) was mostly used in intensive care units (ICUs) with few studies in other departments. We hypothesized that HFNC applied at wards is beneficial for acute respiratory failure in hematological malignancy patients. Materials and methods: The study is a single center, randomized controlled study. Inclusion criteria were hypoxemic respiratory failure and hematological malignancy. Patients were randomized to either venturi mask/nasal cannula oxygen treatment or HFNC. Results: One hundred patients were included in the study. Median age was 58.5 (18­86) years and APACHE II score was 17 (5­29). HFNC group was 51 patients and the oxygen treatment group 49 patients. P/F ratios were similar between the groups throughout the study period. Endotracheal intubation was required in 10 (20.0%) patients in oxygen group and 17 (33.0%) patients in HFNC group (p = 0.14). A total of 17 (35.0%) patients in oxygen group and 17 (33.0%) patients in HFNC group received noninvasive mechanical ventilation (p = 0.97). Median VAS comfort scores at the 2nd and 24th hours were not different between groups. The 28-day mortality rate was 36.7% (18 deaths) in the standard group and 45.0% (23 deaths) in the HFNC group (p = 0.39). Conclusion: HFNC applied in wards is not superior to standard oxygen treatment for acute respiratory failure in hematological malignancy patients.

Effects of oral/enteral nutrition alone versus plus pantoprazole on gastrointestinal bleeding in critically ill patients with low risk factor: a multicenter, randomized controlled trial

Background/aim: Critically ill patients are at risk of developing gastrointestinal (GI) bleeding due to stress causing mucosal damage. Aim of the study was to determine the effect of oral/enteral nutrition with or without concomitant pantoprazole on upper GI bleeding in low risk critically ill patients. Materials and methods: This was a prospective, randomized, open-label, multicenter study conducted with intensive care unit (ICU) patients receiving oral/enteral nutritional support. Patients were randomly assigned into two groups including intervention group (received oral/EN plus pantoprazole) and control group (received only oral/EN). Results: A total of 300 patients (intervention group: 152, control group: 148) participated in the study. Overall, 226 (75%) patients were fed by orally and 74 (25%) patients fed by enteral tube feeding. Median duration of nutritional support 4 (range: 2­33) days. Overt upper GI bleeding was noted only in one patient (0.65%) who was in the intervention group. The overall length of ICU stay of 4 (2­105) days, while ICU stay was significantly longer in the intervention group than in the control group (P = 0.006). Conclusions: Our findings seems to indicate that in patients who are at low risk for GI bleeding and under oral/enteral nutritional support, the use of PPIs may not reduce the risk of bleeding, however these results are imprecise because of low event (GI bleeding) rate and limited power.

The association between the route of nutrition and serum levels of adipokines in critical illness: a pilot study

Background/aim: Adipokines play an important role in the regulation of metabolism. In critical illness, they alter serum levels and are suspected to worsen clinical outcomes. But the effect of the route of nutrition on adipokines is not known. The purpose of this study was to evaluate the association between the route of nutrition and adipokine levels in critically ill patients. Materials and methods: This prospective study was performed in an intensive care unit (ICU). Patients admitted to the ICU for least 72 h and receiving either enteral nutrition (EN) via tube feeding or parenteral nutrition (PN) were enrolled. Serum was obtained at baseline, 24 h, and 72 h for concentrations of leptin, adiponectin, resistin, glucagon­like peptide 1 (GLP­1), insulin­like growth factors 1 (IGF­1), and ghrelin. Results: A total of 26 patients were included in the study. Thirteen patients received EN and 13 patients received PN. In the PN group, leptin level significantly increased (P = 0.037), adiponectin and ghrelin significantly decreased during follow up (P = 0.037, P = 0.008, respectively). There was no significant change between all adipokines in the EN group and resistin, IGF­1 and GLP­1 in the PN group during follow up. Resistin levels were markedly lower in the EN group at both 24 h (P = 0.015) and 72 h (P = 0.006) while GLP­1 levels were higher in the EN group at baseline, 24 h, and 72 h (P = 0.018, P = 0.005, and P = 0.003, respectively). There were no differences in leptin, adiponectin, IGF­1, and ghrelin levels over time. Conclusion: The delivery of EN in critical illness was associated with decreased resistin levels and increased GLP­1 levels. Thus, the route of nutrition may impact the clinical outcome in critical illness due to adipokines.

Outcomes for haematological cancer patients admitted to an intensive care unit in a university hospital.

BACKGROUND: Haematological cancer (HC) patients are increasingly requiring intensive care (ICUs). The aim of this study was to investigate the outcome of HC patients in our ICU and evaluate 5 days-full support as a breakpoint for patients' re-assessment for support. METHODS: Retrospective study enrolling 112 consecutive HC adults, requiring ICU in January-December 2015. Patients' data were collected from medical records and Infection Control Committee surveillance reports. Logistic regression analysis was performed to identify independent risk factors for ICU mortality. RESULTS: Sixty-one were neutropenic, and 99 (88%) had infection at ICU admission. Acute myeloid leukaemia was diagnosed in 43%. Thirty-five (31%) were hematopoietic stem cell transplant recipients. Only 17 (15%) were in remission. Eighty-nine underwent mechanical ventilation on admission. Fifty-three patients acquired ICU-infection (35 bacteremia) being gram negative bacteria (Klebsiella pneumoniae and non-fermenters) the top pathogens. However, ICU-acquired infection had no impact on mortality. The overall ICU and 1-year survival rate was 27% (30 patients) and 7% (8 patients), respectively. Moreover, only 2/62 patients survived with APACHE II score ≥25. The median time for death was 4 days. APACHE II score ≥25 [OR:35.20], septic shock [OR:8.71] and respiratory failure on admission [OR:10.55] were independent risk factors for mortality in multivariate analysis. APACHE II score ≥25 was a strong indicator for poor outcome (ROC under curve 0.889). CONCLUSIONS: APACHE II score ≥25 and septic shock were criteria of ICU futility. Our findings support the full support of patients for 5 days and the need to implement a therapeutic limitations protocol.

A rare cause of acute mesenteric ischemia: JAK2 positivity and chronic active hepatitis B.

Short bowel syndrome occurs as a result of insufficiency in the total length of the small intestine to provide adequate supply of nutrients. Seventy-five percent of cases are due to massive intestinal resection. A 35-year-old male complaining of abdominal pain was admitted to the gastroenterology department. A CT scan was performed, showing total occlusion of the portal vein and superior mesenteric vein. During the operation, widespread edema and necrosis of the small intestine were found. The necrotic segments of the small intestine were resected. The spleen was larger than normal and, in some parts, infarcts were evident, thus asplenectomy was also performed during surgery. A second-look procedure was performed 24 hours later, and an additional 10 cm jejunal resection and anastomosis was performed. His further evaluations revealed myeloproliferative disease and chronic active hepatitis B leading to thrombosis. Essential thrombocytosis and portal vein thrombosis are common in hepatitis B infection. Patients with complaints of abdominal pain in the context of essential thrombocytosis and hepatitis B should be handled with caution as they are at risk of developing portal vein thrombosis.

Parenteral nutrition consensus report from KEPAN.

OBJECTIVES: Medical nutrition therapy is one of the core components of patient management, although its implication is still limited in Daily practice globally. Clinicians are in need of guidance that will ease the application of medical nutrition therapy. The pre- and post-graduate curriculum for medical nutrition therapy is limited in most regions, worldwide. A report that is short, clear, and having clear-cut recommendations that will guide the primary healthcare professionals in indications, choice, practical application, follow-up, and stopping parenteral nutrition (PN) would facilitate the application and success of medical nutrition therapy. KEPAN is the Clinical Enteral and Parenteral Nutrition Society of Turkey and is an active member of the European Society for Clinical Nutrition and Metabolism (ESPEN). METHOD: In this study, we present the KEPAN PN consensus report on optimal PN use in medical nutrition therapy as outlined by the works of academicians experienced in the clinical application of PN (nine working group academicians and 10 expert group academicians). RESULTS: This report provides 22 clear-cut recommendations in a question-answer format. CONCLUSIONS: We believe that this report could have a significant impact on the optimum use of PN in the context of medical nutrition therapy when clinicians manage everyday patients.

LLL 44 - 2 - Micronutrients in clinical nutrition: Vitamins.

Vitamins are essential organic molecules, which are required in the diet in relatively small amounts in any form of nutrition (oral, enteral, parenteral). Despite the small amounts that are required, the vitamins are essential both for maintenance of health, growth, and treatment of disease. After reminding about the principal function of all the vitamins, their needs and the clinical consequences of their deficit, the text present some common clinical problems: the impact of inflammation on the assessment of status. The reasons and diseases which cause increased requirements are presented, with the indications to monitoring of blood levels which remain the classical way to assess status in clinical settings. The text summarises the most relevant clinical manifestations of vitamins depletion and deficiency, the difficulties in assessing status, and makes recommendations for provision for medical nutrition therapy.

LLL 44-4 : Micronutrients in acute disease and critical illness.

Micronutrients (MN), i.e. trace elements and vitamins, are essential components of the diet in relatively small amounts in any form of nutrition, with special needs in critically ill patients. Critical illness is characterised by the presence of inflammation and oxidative stress. MNs are tightly involved in antioxidant and immune defences. In addition, some conditions, and treatments result in large losses of biological fluids containing MNs: therefore, acute renal injury requiring renal replacement therapy, acute intestinal failure, and major burns and trauma are at high risk of acute depletion of body stores, and of deficiency. MN requirements are increased above standard DRI. Blood level interpretation is complicated by inflammation: some biomarkers assist the status determination. Due to the acute challenges of critical illness, it of utmost importance to cover the needs to maintain the organism's endogenous immune and antioxidant defences, and capacity to repair tissues. Practical strategies are proposed.

LLL 44-1 Micronutrients in clinical nutrition: Trace elements.

BACKGROUND: Trace elements are an essential component of metabolism and medical nutrition therapy, with key roles in metabolic pathways, antioxidation, and immunity, which the present course aims at summarizing. RESULTS: Medical nutrition therapy includes the provision of all essential trace elements. The clinical essential issues are summarized for Copper, Iron, Selenium, Zinc, Iodine, Chromium, Molybdenum, and Manganese: the optimal analytical techniques are presented. The delivery of all these elements occurs nearly automatically when the patient is fed with enteral nutrition, but always requires separate prescription in case of parenteral nutrition. Isolated deficiencies may occur, and some patients have increased requirements, therefore a regular monitoring is required. The clinicians should always consider the impact of inflammation on blood levels, mostly lowering them even in absence of deficiency. CONCLUSION: This text summarises the most relevant clinical manifestations of trace element depletion and deficiency, the difficulties in assessing status, and makes practical recommendations for provision for enteral and parenteral nutrition.

LLL 44 - Module 3: Micronutrients in Chronic disease.

Micronutrients (MN), i.e. trace elements and vitamins, are essential organic molecules, which are required in the diet in relatively small amounts in any form of nutrition (oral, enteral, parenteral). The probability of MN depletion or deficiencies should be considered in all chronic illnesses, especially in those that can interfere with intake, digestion, or intestinal absorption. Low socio-economic status and food deprivation are recognized as the most prevalent reasons for MN deficiencies world-wide. Elderly multimorbid patients with multimodal therapy, as well as patients with long-lasting menu restrictions, are at high risk for both disease related malnutrition as well as multiple MN deficiencies, needing careful specific follow-up. The importance of monitoring MN blood levels along with CRP is essential for optimal care. Drug interactions are also highlighted. In patients with chronic conditions depending on medical nutrition therapy, the provision of adequate dietary reference intakes (DRI) of MN doses and monitoring of their adequacy belongs to standard of care.

ESPEN practical short micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. The importance of MNs in common pathologies is recognized by recent research, with deficiencies significantly impacting the outcome. OBJECTIVE: This short version of the guideline aims to provide practical recommendations for clinical practice. METHODS: An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL for the initial guideline. The search focused on physiological data, historical evidence (for papers published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: The limited number of interventional trials prevented meta-analysis and led to a low level of evidence for most recommendations. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90 % of votes. Altogether the guideline proposes 3 general recommendations and specific recommendations for the 26 MNs. Monitoring and management strategies are proposed. CONCLUSION: This short version of the MN guideline should facilitate handling of the MNs in at-risk diseases, whilst offering practical advice on MN provision and monitoring during nutritional support.

Furosemide-related thiamine deficiency in hospitalized hypervolemic patients with renal failure and heart failure.

BACKGROUND: We aimed to describe the thiamine status in hospitalized hypervolemic heart failure (HF) and/or renal failure (RF) patients treated with furosemide and to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF. METHODS: Patients who were diagnosed as hypervolemia and treated with intravenous furosemide (at least 40mg/day) were included in this prospective observational study. Whole blood thiamine concentrations were measured 3 times during hospital follow-up of patients. RESULTS: We evaluated 61 hospitalized hypervolemic patients, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00±10.39 (45-90) years. The baseline and post-hospital admission days 2 and 4 mean thiamine levels were 51.71±20.66ng/ml, 47.64±15.43ng/ml and 43.78±16.20ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p=0.029). There was a significant decrease in thiamine levels in patients who had HF (p=0.026) and also, thiamine was significantly lower in HF patients who had previously used oral furosemide before hospitalization. However, these findings were not present in patients with RF. CONCLUSIONS: Thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion.

Gastric ultrasound, citrulline, and intestinal fatty acid-binding protein as markers of gastrointestinal dysfunction in critically ill patients: A pilot prospective cohort study.

BACKGROUND: Gastrointestinal (GI) dysfunction is common in the intensive care unit (ICU), although there is no consensus on biomarkers of GI dysfunction. We aimed to evaluate ultrasound-based gastric antrum measurements and serum intestinal fatty acid-binding protein (IFABP) and citrulline levels in relation to GI dysfunction in critically ill patients. METHODS: Adult critically ill patients receiving enteral nutrition and stayed for in the ICU for ≥48 h was included. GI dysfunction was described using Gastrointestinal Dysfunction Score (GIDS). Gastric antrum measurements, including craniocaudal (CC) diameter, anteroposterior diameter, and antral-cross sectional area (CSA), as well as serum levels for IFABP and citrulline, were prospectively recorded at baseline and on day 3 and day 5 of enteral nutrition. The receiver operating characteristic (ROC) analysis was performed to evaluate gastric ultrasound parameters, serum IFABP, and citrulline concentrations in predicting GI dysfunction. RESULTS: Thirty-nine participants with a median age of 60 years were recruited and 46.2% of participants had GI dysfunction. ROC analysis revealed that the cutoff value of CSA score to predict GI dysfunction was 4.48 cm2 , which provided 72.7% sensitivity and 77.2% specificity (area under the curve = 0.768, 95% CI: 0.555-0.980). At baseline, gastric residual volume was highly correlated with CC diameter and CSA (r = 0.764, P < 0.001 and r = 0.675, P < 0.001, respectively). Serum IFABP and citrulline levels had no correlation with GI dysfunction or gastric ultrasound parameters (P > 0.05). CONCLUSION: CSA was associated with GI dysfunction in critically ill patients. Serum IFABP and citrulline concentrations were poor in predicting GI dysfunction.

Frequency and Related Risk Factors of Refeeding Hypophosphatemia in Patients with Liver Cirrhosis: A Pilot Study.

BACKGROUND AND AIM: Refeeding hypophosphatemia (RH) is associated with poor clinical outcomes and mortality. The presence of RH in patients with liver cirrhosis remains unclear. This study aims to determine the frequency of RH related to nutritional status and disease severity in liver cirrhosis. METHODS: This study was prospectively conducted in a-single center gastroenterology clinic. Malnutrition was identified by Subjective Global Assessment (SGA). The disease severity was defined using Child score and MELD score. Serum phosphate levels <2.0 mg/dl are defined as hypophosphatemia. RESULTS: Twelve of 50 cirrhotic patients (24%) had RH during hospitalization. The most common RH was determined in 4 patients on day 4 during study follow up. The sharpest decline of serum phosphate levels was on day 4 (median: 2.3mg/dL). The Child score and MELD score were not significantly different between RH and Non-RH groups (p>0.05). The rate of malnutrition according to SGA was 56.0%. A total of 82%, 4%, 8%, and 4% of participants received regular diet and oral nutritional supplements, only enteral tube feeding, only parenteral nutrition, and combined enteral and parenteral nutrition, respectively. In the RH group, 32% of participants received only parenteral nutrition and had a higher presence of RH than patients receiving only oral or enteral tube feding (p<0.05). CONCLUSIONS: RH developed in » of the study participants. This study also showed that artificial feeding carries a significant risk in terms of RH. Malnourished patients with liver cirrhosis receiving parenteral nutrition, closely monitored regarding high risk of RH.

High-Resolution Plasma Metabolomics and Thiamine Status in Critically Ill Adult Patients.

Background and Aim: Thiamine (Vitamin B1) is an essential micronutrient and a co-factor for metabolic functions related to energy metabolism. We determined the association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites using high resolution metabolomics in critically ill patients. Methods: Cross-sectional study performed in Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were ≥ 18 years of age, with an expected length of ICU stay longer than 48 hours, receiving furosemide therapy for at least 6 months before ICU admission. Results: Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP concentrations were measured using high-performance liquid chromatography (HPLC). Liquid chromatography/mass spectrometry was used for plasma high-resolution metabolomics. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies. We also compared metabolomic features from patients in the highest TPP concentration tertile to patients in the lowest TPP tertile as a secondary analysis. We enrolled 76 participants with a median age of 69 (range, 62.5-79.5) years. Specific metabolic pathways associated with whole blood TPP levels, using both regression and tertile analysis, included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways. Conclusions: Plasma high-resolution metabolomics analysis showed that whole blood TPP concentrations are significantly associated with metabolites and metabolic pathways linked to the metabolism of energy, amino acids, lipids, and the gut microbiome in adult critically ill patients.