MIS-C, inherited metabolic diseases and methylmalonic acidemia: a case report and review of the literature (preprint)

Bacground Methylmalonic acidemia (MMA) secondary to mutase deficiency, mut0, is an inborn error of metabolism causing complete enzyme deficiency. Multisystem Inflammatory Syndrome in Children (MIS-C) is a hyperinflammatory syndrome characterized by fever, inflammation, multiorgan impairment that manifests 14–60 days after the SARS-CoV-2 infection in patients aged < 21 years. Case presentation We describe the clinical case of a 2-year-old child with MMA secondary to mutase deficiency, with the documented homozygous mutation c.2179 C > T of MMUT gene, associated to mut0 phenotype. One month after SARS-CoV-2 infection, he presented fever, rash, significant increase of C-reactive protein (CRP), ferritin, triglycerides, (interleukin) IL-6, PRO-BNP, compatible with the diagnosis of MIS-C. He was treated with intravenous immunoglobulins (2gr/Kg), methylprednisolone (2 mg/Kg/day), with rapid clinical improvement. Ten days later, he showed the worsening of clinical conditions, with the recurrence of fever, vasculitic rash with palmoplantar extension, further increase of ferritin (1033 ug/l), IL-6 (146 pg/ml), PRO-BNP (5117 pg/ml), triglycerides, anemia, thrombocytopenia, metabolic acidosis with hyperlactatemia (180 mg/dl), increased urinary methylmalonic acid (200 mmol/mCreat), multiorgan failure. He was treated with sodium bicarbonate, thiamine, coenzyme Q, vitamin C, methylprednisolone and anakinra (2 mg/Kg/day). Three days after the start of anakinra, he showed a significant improvement of clinical and biochemical parameters and defervescence. 20 days later, a sepsis from Staphylococcus Aureus and Candida Albicans required the interruption of anakinra, with the worsening of the clinical and haematological parameters and the exitus. Conclusions Only a few cases of patients with inherited metabolic diseases (IMD) and MIS-C are described. However, to our knowledge, this is the first case of MIS-C in MMA described. The description of these clinical cases is a precious lesson for pediatricians to manage IMD therapeutic emergencies. Anakinra must be considered as a safe treatment of choice in IMD patients with MIS-C. The use of anakinra in patients with a severe form of MMA is safe and can be employed to treat MIS-C, gaining a substantial clinical and biochemical improvement.

Evidence associating neutrophilia, lung damage, hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality in critically ill COVID-19 patients (preprint)

Background: COVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis. Since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes and that they are massively recruited to infected lungs, we investigated whether metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients. Methods: Based on prospective mortality outcome, 102 critically ill-hospitalized COVID-19 patients were divided into two groups: ICU-Survivors (ICU-S, n=36) and ICU-Non-survivors (ICU-NS, n=66). Blood samples were collected from patients and control subjects to explore correlations between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils for glycolytic activities and for apoptosis using high-throughput fluorescence imaging complemented with transcriptomic analyses. Stratified survival analyses were conducted to estimate mortality risk associated with higher lactate among predefined subgroups. Results: Neutrophil counts were consistently higher in critically ill patients while exhibiting remarkably lower apoptosis. Transcriptomic analysis revealed miRNAs associated with downregulation of genes involved in neutrophils apoptosis. Both CT lung damage scores and neutrophil counts predicted mortality. Severinghaus fitting of hemoglobin oxygen saturation curve revealed a right-shift indicating lower oxygen capacity in non-survivors, which is consistent with lower blood-pH observed in the same group. Levels of blood lactate were increased in patients but significantly more in the ICU-NS relative to the control group. ROC analysis followed by Kaplan-Meyer survival analysis stratified to the obtained cut-off values showed that CT damage scores, neutrophil counts, and lactate levels are predictors of mortality within 15 days following blood collection. Conclusion: The current results implicate neutrophilia as a potential player in metabolic acidosis and deranged oxygen delivery associating SARS-CoV-2 infection thus contributing to mortality outcome.

Metabolic acidosis during the relapse treatment of idiopathic intracranial hypertension.

We herein present a 40-year-old female physician who was diagnosed with idiopathic intracranial hypertension (IIH) 4 years ago. In the last years, the patient was in remission without any medications. Since the onset of COVID-19 pandemic, she has been stressfully working in the high-risk area, therefore using personal protective equipment (N95 mask, protective clothing, goggles, and protective cap) during the day for extended periods. Her headaches recurred and the patient was diagnosed with a relapse of IIH; acetazolamide and afterward topiramate were initiated, with diet treatment. Symptomatic metabolic acidosis, which is otherwise a rare side effect of the IIH treatment and not seen in her first attack even with higher doses, developed during the follow-up, presenting with shortness of breath and chest tightening. The emerging problems of IIH diagnosis and management during the COVID-19 pandemic will be discussed.

Acid-base imbalance as a risk factor for mortality among COVID-19 hospitalized patients.

Severe coronavirus disease 2019 (COVID-19) infection can lead to extensive lung infiltrate, a significant increase in the respiratory rate, and respiratory failure, which can affect the acid-base balance. No research in the Middle East has previously examined acid-base imbalance in COVID-19 patients. The present study aimed to describe the acid-base imbalance in hospitalized COVID-19 patients, determine its causes, and assess its impact on mortality in a Jordanian hospital. The study divided patients into 11 groups based on arterial blood gas data. Patients in normal group were defined as having a pH of 7.35-7.45, PaCO2 of 35-45 mmHg, and HCO3- of 21-27 mEq/L. Other patients were divided into 10 additional groups: mixed acidosis and alkalosis, respiratory and metabolic acidosis with or without compensation, and respiratory and metabolic alkalosis with or without compensation. This is the first study to categorize patients in this way. The results showed that acid-base imbalance was a significant risk factor for mortality (P<0.0001). Mixed acidosis nearly quadruples the risk of death when compared with those with normal levels (OR = 3.61, P=0.05). Furthermore, the risk of death was twice as high (OR = 2) for metabolic acidosis with respiratory compensation (P=0.002), respiratory alkalosis with metabolic compensation (P=0.002), or respiratory acidosis with no compensation (P=0.002). In conclusion, acid-base abnormalities, particularly mixed metabolic and respiratory acidosis, were associated with increased mortality in hospitalized COVID-19 patients. Clinicians should be aware of the significance of these abnormalities and address their underlying causes.

Predictive Ability of Complete Blood Count, Mean Platelet Ratio, Mean Platelet Volume, and Neutrophil/Lymphocyte Ratio for Severe Pneumonia among RT-PCR or Radiologically Proven COVID-19 Patients (preprint)

In Rajasthan, the picture of COVID-19 has been very gloomy and on 21st December 2020 there were 12,422 active cases, and 283,957 cumulative cases which included either discharged or cured or migrated to other places. Disease may start with milder clinical manifestation, but it may suddenly progress to acute respiratory failure or acute respiratory distress syndrome or septic shock or metabolic acidosis or coagulopathies. There is an association of neutrophil/lymphocyte ratio (NLR), Mean Platelet Volume (MPV), Mean Platelet Ratio (MPR) and with the progression of the COVID-19 infection and it can be utilized by the physicians for identification of high risk or deteriorating patients at an early stage. In the context of this background, the present study was undertaken to study the predictive ability of these hematological parameters (especially MPV, MPR, NLR) in progression of COVID-19 infection to severe pneumonia among RT-PCR or radiologically proven COVID-19 patients. Materials and method: Analytical cross sectional Hospital based study of 729 COVID-19 patients enrolled between 1st April 2020 to 30th Nov 2021 conducted in Bangur hospital of Pali district, Rajasthan. Socio-demographic information, clinical profile, investigation reports and clinical outcome were collected from the electronic medical records. WHO’s definition for severe pneumonia of COVID-19 (17) was utilized to categorize patients with severe pneumonia. Data was entered in Microsoft Excel and checked for errors. The analyses were done using Jamovi and SPSS v.23.0. Results: It was found that neutrophil/lymphocyte ratio was significantly higher among those participants with evere pneumonia, but there was no such significance appreciated for mean platelet ratio.. Parameters related to acute infection (Total WBC count, granulocyte (%), absolute granulocyte count) were directly correlated with N/L ratio and Mean Platelet ratio (except granulocyte (%)).From multivariable analysis, it was found that increase in N/L ratio and decrease in albumin were significant predictors of severe pneumonia. Conclusion: N/L ratio is good predictor marker of COVID 19 severe pneumonia. MPV, MPR, and PC are nit the good predictive markers of COVID 19 severe pneumonia.

Unusual case of propofol-related infusion syndrome complicating severe COVID-19 ARDS.

An elderly man presenting with shortness of breath and hypoxaemia was admitted with acute hypoxic respiratory failure secondary to COVID-19 pneumonia. Due to worsening hypoxaemia, he was transferred to the intensive care unit and required mechanical ventilation. Propofol was infused at 1.5-4 mg/kg/hour. Within 48 hours of initiation, we noticed worsening metabolic acidosis, acute kidney injury, hyperkalaemia, hyperphosphataemia, hypertriglyceridaemia, elevated creatine kinase and elevated myoglobin levels. Suspecting propofol-related infusion syndrome (PRIS), we discontinued his propofol infusion immediately and initiated supportive measures. In 48 hours, there was a significant improvement in metabolic acidosis, hypertriglyceridaemia, rhabdomyolysis and renal function. The propofol infusion rate and cumulative propofol dosage (under 140 mg/kg) were well below levels associated with PRIS. COVID-19's pathogenesis, still under investigation, may have contributed to this presentation. It is imperative for clinicians to maintain a high degree of suspicion once propofol is initiated, regardless of the cumulative dose or rate of infusion.

Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. METHODS: The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. FINDINGS: Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. INTERPRETATION: In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. FUNDING: Swiss National Science Foundation.

Investigating the relationship between arterial blood gases, acid-base disorders, and outcomes in patients with covid-19 (preprint)

Introduction: The worldwide effect of the new coronavirus disease 2019 (COVID-19) since it was proclaimed a pandemic has been unparalleled. The majority of studies have focused on biochemical and hematological laboratory markers, with relatively little information on ABG analysis. We evaluated electrolytes, renal function tests, and any potential effects of RAS upregulation on electrolytes in COVID-19 hospitalized patients to better understand the ABG results, particularly the acid-base results. Material and Methods: The study was conducted at Imam Reza Hospital, a referral hospital in Kermanshah, Iran. 77 patients with COVID-19 identified in the lab who were admitted to the Hospital between March 21 and September 23, 2021, were included in the research. Laboratory and ABG data were collected retrospectively, as well as demographic information such as age, gender, and patient outcome Results: The study population included 77 patients of which 55 (71.4%) were survivors, while 22(44.6%) died from COVID-19 complications. In addition, 57 patients (74%) had severe COVID-19 and 26 (20%) had moderate COVID-19. The mean age of the patients was 61.58 ± 17.76 (range 23–95). There were 35 (45.5%) females and 42 (54.5%) males. Patients on covid-19 have reduced PO2, and SO2 values and higher urea and creatinine levels. Acid–base disturbance was found in 87.7% of the patients, and respiratory alkalosis (22.4%) was the main alteration followed by metabolic alkalosis (20.7%), combined acidosis (12.1%), combined alkalosis (6.9%), respiratory acidosis (3.4%), metabolic acidosis (3.4%) and other compensated acid-base disturbances (12.7%). Conclusion: Patients admitted to the hospital for COVID-19 symptoms were at high risk of acid-base disorders. They were subjected to a variety of acid-base changes. The most common acid-base disorders in this group of patients were metabolic and respiratory alkalosis.

A Variant Mutation in the gene encoding Mitochondrial Seryl-tRNA Synthetase Cause HUPRA Syndrome with Atypical Presentation-A Case Report (preprint)

Background Hyperuricemia, pulmonary hypertension, renal failure, and alkaline intoxication syndrome (HUPRA syndrome) is a rare autosomal recessive mitochondrial disease with prevalence of less than one in a million. Due to mutations in the mitochondrial SARS enzyme encoding seryl-tRNA synthetase on chromosome 19 (19q13.2). Case–Diagnosis/Treatment We investigated two Palestinian girls from the same village presented with progressive renal failure in infancy were diagnosed with this multisystemic disease. presented with atypical clinical manifestations of HUPRA syndrome include leukopenia, anemia, salt wasting resulting in hyponatremia and hypochloremia, renal failure with elevated blood lactate, marked hyperuricemia, hypercholesterolemia and hypertriglyceridemia but  without  pulmonary hypertension or alkaline intoxication that distinguish them from the rest of the usual cases, instead they showed acidosis in routine follow up. By using single exome sequencing analysis, we identified a two homozygous pathogenic mutation c.1175A>G (p.D392G), c.1169A>G (D390G) in SARS2 gene. This sequence identified a new variant mutation of HUPRA syndrome c.1175A>G (p.D392G) with atypical presentation, that will be added to the literature. Conclusion SARS2 gene with pathogenic homozygous mutation variants were detected in our two patients c.1175A>G (p.D392G), c.1169A>G (D390G) in exon 13, with atypical clinical manifestations of HUPRA syndrome, expanding the spectrum of SARS2 pathogenic variants with its characteristic findings, describing the differences in clinical manifestations between homozygous and compound heterozygous mutations.

Diabetic ketoacidosis as a complication of methanol poisoning; a case report.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a complication of diabetes presenting with high anion gap metabolic acidosis. Methanol poisoning, on the other hand, is a toxicology emergency which presents with the same feature. We present a case of methanol poisoning who presented with DKA. CASE PRESENTATION: A 28-year-old male was referred to us with blurred vision and loss of consciousness three days after ingestion of 1.5 L of an unknown mixture of bootleg alcoholic beverage. He had history of insulin-dependent diabetes and had neglected his insulin shots on the day prior to hospital admission due to progressive loss of consciousness. Vital signs were normal and venous blood gas analysis showed severe metabolic acidosis and a methanol level of 10.2 mg/dL. After eight hours of hemodialysis, he remained unresponsive. Diabetic ketoacidosis was suspected due to positive urine ketone and blood sugar of 411 mg/dL. Insulin infusion was initiated which was followed by full awakening and extubation. He was discharged completely symptom-free after 4 weeks. CONCLUSIONS: Diabetic ketoacidosis and methanol poisoning can happen simultaneously in a diabetic patient. Given the analogous high anion gap metabolic acidosis, physicians should pay particular attention to examination of the diabetic patients. Meticulous evaluation for both conditions is highly recommended.

Metabolic alkalosis and mortality in COVID-19 (preprint)

BackgroundAs a new infectious disease affecting the world, COVID-19 has caused a huge impact on countries around the world. At present, its specific pathophysiological mechanism has not been fully clarified. We found in the analysis of the arterial blood gas data of critically ill patients that the incidence of metabolic alkalosis in such patients is high. MethodWe retrospectively analyzed the arterial blood gas analysis results of a total of 16 critically ill patients in the intensive ICU area of Xiaogan Central Hospital and 42 severe patients in the intensive isolation ward, and analyzed metabolic acidosis and respiratory acidosis. Metabolic alkalosis and respiratory alkalosis, and the relationship between metabolic alkalosis and death. ResultAmong the 16 critically ill patients, the incidence of metabolic alkalosis was 100%, while the incidence of metabolic alkalosis in severe patients was 50%; the mortality rate in critically ill patients was 81.3%, and 21.4% in severe patients; The mortality of all patients with metabolic alkalosis is 95.5%,and 4.5% in without metabolic alkalosis. ConclusionThe incidence of metabolic alkalosis in critically ill COVID-19 patients is high, and it is associated with high mortality.

Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation.

BACKGROUND AND PURPOSE: Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles. EXPERIMENTAL APPROACH: Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals. KEY RESULTS: Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47 ± 0.07 and 3.78 ± 0.17 µM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia. CONCLUSION AND IMPLICATIONS: Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.

Clinical Course and Characteristics of COVID-19 in Patients With Inborn Errors of Immunity: A Retrospective Multicenter Experience From Iran (preprint)

Purpose: This study aimed to assess the effect of COVID-19 on patients with IEIs, the potentially at-risk population, regarding the clinical course, complications, severity, and outcomes. Methods This two-phase study was conducted on patients from three referral immunodeficiency centers in Iran. At phase one, 98 IEI patients with COVID-19 infection were evaluated by telephone follow-up (TFU). At phase two, the demographic, clinical, and laboratory records of clinically confirmed 33 IEI patients with COVID-19 infection were collected and analyzed. Results At phase one, 16.3% represented COVID-19 infection without any report of pediatric intensive care unit (PICU) admission or death. During the second phase, combined immunodeficiency (CID) (42.4%) and predominantly antibody deficiencies (PADs) (33.3%) were the predominant immune defects. Atopy (27.3%) and lung disorders (27.3%) were the frequent pre-existing comorbidities. Organomegaly (p=0.030) and renal disorders ( p=0.033 ) were significantly associated with the development of respiratory insufficiency. Cyanosis, tachypnea, intercostal retraction, and seizure were the chief complaints of patients who were more likely to progress respiratory insufficiency (p<0.05) , being admitted to the PICU (p<0.05) , and/or deceased (p<0.05) . Laboratory evaluation revealed a marked positive correlation between D-Dimer ( p=0.045 ), prothrombin time ( p=0.045 ), C-reactive protein ( p=0.041 ), proteinuria ( p=0.013 ), ferritin ( p=0.020 ), metabolic acidosis ( p=0.003 ), and troponin ( p=0.049 ) level with mortality. We detected a significant association between the chest X-ray pattern of COVID-19 infection with PICU admission (p=0.023) and death (p=0.046) . Conclusion In the current study, patients with CID and PAD were introduced as patients at high risk of COVID-19 infection, who may need extra protective and therapeutic measurements.

Usefulness of the HACOR score in predicting success of CPAP in COVID-19-related hypoxemia.

INTRODUCTION: In COVID-19 associated hypoxemic acute respiratory failure (ARF) without mandatory indication for urgent endotracheal intubation, a trial of CPAP may be considered. We aimed to evaluate HACOR (heart rate, acidosis, consciousness, oxygenation, respiratory rate) score performance in these patients as predictor of CPAP failure. METHODS: Prospective observational multicentric study (three centers in different countries), including adult patients with SARS-CoV-2 pneumonia admitted to a respiratory intermediate care unit, presenting PaO2/FiO2 < 300 and PaCO2 < 45 mmHg, who received CPAP. One hour after starting CPAP, HACOR was calculated. RESULTS: We enrolled 128 patients, mean age 61,7 years. Mean HACOR at 1 h after starting CPAP was 3,27 ± 3,84 and mean PaO2/FiO2 was 203,30 ± 92,21 mmHg; 35 patients (27,3 %) presented CPAP failure: 29 underwent oro-tracheal intubation and 6 died due to COVID-19 (all having a do-not-intubate order). HACOR accuracy for predicting CPAP failure was 82,03 %, while PaO2/FiO2 accuracy was 81,25 %. CONCLUSION: Although HACOR score had a good diagnostic performance in predicting CPAP failure in COVID-19-related ARF, PaO2/FiO2 has also shown to be a good predictor of failure.

Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial.

BACKGROUND: Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. METHODS: A retrospective analysis of the 'Artesunate versus quinine in the treatment of severe falciparum malaria in African children' (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. RESULTS: There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51-6.2), hypoglycaemia (OR: 5.16, CI 2.74-9.75), coma (OR: 1.72 CI 1.17-2.51), respiratory distress (OR: 1.46, CI 1.02-2.1) and prostration (OR: 1.88 CI 1.35-2.59). Features associated with uraemia were coma (3.18, CI 2.36-4.27), Prostration (OR: 1.78 CI 1.37-2.30), decompensated shock (OR: 1.89, CI 1.31-2.74), black water fever (CI 1.58. CI 1.09-2.27), jaundice (OR: 3.46 CI 2.21-5.43), severe anaemia (OR: 1.77, CI 1.36-2.29) and hypoglycaemia (OR: 2.77, CI 2.22-3.46) CONCLUSION: Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

Development and Validation of a Dynamic 48-Hour In-Hospital Mortality Risk Stratification for COVID-19 in a UK Teaching Hospital: A Retrospective Cohort Study (preprint)

Background: While numerous point-of-admission disease severity models for COVID-19 have been proposed, disease stratification that accounts for changes in a patient’s condition while in hospital is urgently needed to facilitate patient management and resource allocation.Methods: We developed a prognostic model for 48-hour in-hospital mortality using 473 consecutive patients with COVID-19 presenting to a UK hospital between March 1 and September 12, 2020; and temporally validated using data on 405 patients presenting between September 13, 2020 and January 3, 2021.The primary outcome was all-cause in-hospital mortality. We additionally considered the competing risks of discharge from hospital and transfer to a tertiary Intensive Care Unit for extracorporeal membrane oxygenation. We adopted a landmarking approach to dynamic prediction that accounts for competing risks and informative missingness, and selected predictors using penalised regression. The model estimates, at any point during a hospital visit, the probability of in-hospital mortality during the next 48 hours.Results: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, SpO2/FiO2 ratio, white cell count, presence of acidosis (pH < 7.35) and Interleukin-6. Internal validation achieved an AUROC of 0.90 (95% CI 0.87–0.93) and temporal validation gave an AUROC of 0.91 (95% CI 0.88-0.95). Interpretation: Our model uniquely incorporates both static risk factors (e.g. age) and evolving clinical and laboratory data, to provide a dynamic risk prediction model that adapts to both sudden and gradual changes in an individual patient’s clinical condition. External validation outside the study hospital will be required before adoption.Funding: NIHR Cambridge Biomedical Research Centre, UKRI Medical Research CouncilDeclaration of Interest: None to declare. Ethical Approval: The study was approved by a UK Health Research Authority ethics committee (20/WM/0125). Patient consent was waived because the de-identified data presented here were collected during routine clinical practice; there was no requirement for informed consent.

Sialoglycan recognition is a common connection linking acidosis, zinc, and HMGB1 in sepsis.

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.

Automatic real-time analysis and interpretation of arterial blood gas sample for Point-of-care testing: Clinical validation.

BACKGROUND: Point-of-care arterial blood gas (ABG) is a blood measurement test and a useful diagnostic tool that assists with treatment and therefore improves clinical outcomes. However, numerically reported test results make rapid interpretation difficult or open to interpretation. The arterial blood gas algorithm (ABG-a) is a new digital diagnostics solution that can provide clinicians with real-time interpretation of preliminary data on safety features, oxygenation, acid-base disturbances and renal profile. The main aim of this study was to clinically validate the algorithm against senior experienced clinicians, for acid-base interpretation, in a clinical context. METHODS: We conducted a prospective international multicentre observational cross-sectional study. 346 sample sets and 64 inpatients eligible for ABG met strict sampling criteria. Agreement was evaluated using Cohen's kappa index, diagnostic accuracy was evaluated with sensitivity, specificity, efficiency or global accuracy and positive predictive values (PPV) and negative predictive values (NPV) for the prevalence in the study population. RESULTS: The concordance rates between the interpretations of the clinicians and the ABG-a for acid-base disorders were an observed global agreement of 84,3% with a Cohen's kappa coefficient 0.81; 95% CI 0.77 to 0.86; p < 0.001. For detecting accuracy normal acid-base status the algorithm has a sensitivity of 90.0% (95% CI 79.9 to 95.3), a specificity 97.2% (95% CI 94.5 to 98.6) and a global accuracy of 95.9% (95% CI 93.3 to 97.6). For the four simple acid-base disorders, respiratory alkalosis: sensitivity of 91.2 (77.0 to 97.0), a specificity 100.0 (98.8 to 100.0) and global accuracy of 99.1 (97.5 to 99.7); respiratory acidosis: sensitivity of 61.1 (38.6 to 79.7), a specificity of 100.0 (98.8 to 100.0) and global accuracy of 98.0 (95.9 to 99.0); metabolic acidosis: sensitivity of 75.8 (59.0 to 87.2), a specificity of 99.7 (98.2 to 99.9) and a global accuracy of 97.4 (95.1 to 98.6); metabolic alkalosis sensitivity of 72.2 (56.0 to 84.2), a specificity of 95.5 (92.5 to 97.3) and a global accuracy of 93.0 (88.8 to 95.3); the four complex acid-base disorders, respiratory and metabolic alkalosis, respiratory and metabolic acidosis, respiratory alkalosis and metabolic acidosis, respiratory acidosis and metabolic alkalosis, the sensitivity, specificity and global accuracy was also high. For normal acid-base status the algorithm has PPV 87.1 (95% CI 76.6 to 93.3) %, and NPV 97.9 (95% CI 95.4 to 99.0) for a prevalence of 17.4 (95% CI 13.8 to 21.8). For the four-simple acid-base disorders and the four complex acid-base disorders the PPV and NPV were also statistically significant. CONCLUSIONS: The ABG-a showed very high agreement and diagnostic accuracy with experienced senior clinicians in the acid-base disorders in a clinical context. The method also provides refinement and deep complex analysis at the point-of-care that a clinician could have at the bedside on a day-to-day basis. The ABG-a method could also have the potential to reduce human errors by checking for imminent life-threatening situations, analysing the internal consistency of the results, the oxygenation and renal status of the patient.

Management of COVID-19 infection in organic acidemias.

The COVID-19 pandemic has affected the health and healthcare of individuals of all ages worldwide. There have been multiple reports and reviews documenting a milder effect and decreased morbidity and mortality in the pediatric population, but there have only been a small number of reports discussing the SARS-CoV-2 infection in the setting of an inborn error of metabolism (IEM). Here, we report two patients with underlying metabolic disorders, propionic acidemia and glutaric aciduria type 1, and discuss their clinical presentation, as well as their infectious and metabolic management. Our report demonstrates that individuals with an underlying IEM are at risk of metabolic decompensation in the setting of a COVID-19 infection. The SARS-CoV-2 virus does not appear to cause a more severe metabolic deterioration than is typical.