Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection.

We have attempted to explore further the involvement of complement components in the host COVID-19 (Coronavirus disease-19) immune responses by targeted genotyping of COVID-19 adult patients and analysis for missense coding Single Nucleotide Polymorphisms (coding SNPs) of genes encoding Alternative pathway (AP) components. We have identified a small group of common coding SNPs in Survivors and Deceased individuals, present in either relatively similar frequencies (CFH and CFI SNPs) or with stark differences in their relative abundance (C3 and CFB SNPs). In addition, we have identified several sporadic, potentially protective, coding SNPs of C3, CFB, CFD, CFH, CFHR1 and CFI in Survivors. No coding SNPs were detected for CD46 and CD55. Our demographic analysis indicated that the C3 rs1047286 or rs2230199 coding SNPs were present in 60 % of all the Deceased patients (n = 25) (the rs2230199 in 67 % of all Deceased Males) and in 31 % of all the Survivors (n = 105, p = 0.012) (the rs2230199 in 25 % of all Survivor Males). When we analysed these two major study groups using the presence of the C3 rs1047286 or rs2230199 SNPs as potential biomarkers, we noticed the complete absence of the protective CFB rs12614 and rs641153 coding SNPs from Deceased Males compared to Females (p = 0.0023). We propose that in these individuals, C3 carrying the R102G and CFB lacking the R32W or the R32Q amino acid substitutions, may contribute to enhanced association dynamics of the C3bBb AP pre-convertase complex assembly, thus enabling the exploitation of the activation of the Complement Alternative pathway (AP) by SARS-CoV-2.

Genetic prediction of ICU hospitalization and mortality in COVID-19 patients using artificial neural networks.

There is an unmet need of models for early prediction of morbidity and mortality of Coronavirus disease-19 (COVID-19). We aimed to a) identify complement-related genetic variants associated with the clinical outcomes of ICU hospitalization and death, b) develop an artificial neural network (ANN) predicting these outcomes and c) validate whether complement-related variants are associated with an impaired complement phenotype. We prospectively recruited consecutive adult patients of Caucasian origin, hospitalized due to COVID-19. Through targeted next-generation sequencing, we identified variants in complement factor H/CFH, CFB, CFH-related, CFD, CD55, C3, C5, CFI, CD46, thrombomodulin/THBD, and A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS13). Among 381 variants in 133 patients, we identified 5 critical variants associated with severe COVID-19: rs2547438 (C3), rs2250656 (C3), rs1042580 (THBD), rs800292 (CFH) and rs414628 (CFHR1). Using age, gender and presence or absence of each variant, we developed an ANN predicting morbidity and mortality in 89.47% of the examined population. Furthermore, THBD and C3a levels were significantly increased in severe COVID-19 patients and those harbouring relevant variants. Thus, we reveal for the first time an ANN accurately predicting ICU hospitalization and death in COVID-19 patients, based on genetic variants in complement genes, age and gender. Importantly, we confirm that genetic dysregulation is associated with impaired complement phenotype.

Genetic justification of severe COVID-19 using a rigorous algorithm.

Recent studies suggest excessive complement activation in severe coronavirus disease-19 (COVID-19). The latter shares common characteristics with complement-mediated thrombotic microangiopathy (TMA). We hypothesized that genetic susceptibility would be evident in patients with severe COVID-19 (similar to TMA) and associated with disease severity. We analyzed genetic and clinical data from 97 patients hospitalized for COVID-19. Through targeted next-generation-sequencing we found an ADAMTS13 variant in 49 patients, along with two risk factor variants (C3, 21 patients; CFH,34 patients). 31 (32%) patients had a combination of these, which was independently associated with ICU hospitalization (p = 0.022). Analysis of almost infinite variant combinations showed that patients with rs1042580 in thrombomodulin and without rs800292 in complement factor H did not require ICU hospitalization. We also observed gender differences in ADAMTS13 and complement-related variants. In light of encouraging results by complement inhibitors, our study highlights a patient population that might benefit from early initiation of specific treatment.

Central Venous Oxygen Saturation as a Predictor of a Successful Spontaneous Breathing Trial from Mechanical Ventilation: A Prospective, Nested Case-Control Study.

BACKGROUND: Weaning from mechanical ventilation is a key element in the care of critically ill patients, and Spontaneous Breathing Trial (SBT) is a crucial step in this procedure. This nested case-control study aimed to evaluate whether central oxygen saturation (ScvO2) values and their changes could independently predict the SBT outcome among mechanically ventilated patients. METHODS: A prospective cohort of patients who were mechanically ventilated for at least 48hours and fulfilled the criteria of readiness to wean constituted the study population. All patients attempted a SBT and were then categorized in SBT success group and SBT failure group, based on a combination of criteria which indicated whether SBT was successful or not. Multivariate binary logistic regression analysis was utilized to indicate the independent predictors of SBT success, while the Receiver Operating Characteristic (ROC) curves were used to demonstrate the diagnostic accuracy of these independent predictors. RESULTS: Seventy-seven patients 69(18-86) years old; 62.3% male) constituted the study population. SBT was successful among 63.6% of them. A decrease in ScvO2 values (ΔScvO2) < 4% between the beginning and the end of the trial independently predicted the successful outcome (OR=18.278; 95% CI=4.017-83.163), along with age, Hemoglobin concentration (Hb) and arterial oxygen saturation (SaO2). Diagnostic accuracy for ΔScvO2 alone (ROC area=0.715) was slightly superior to that of either SaO2 (0.625) or Hb (0.685) to predict SBT success. CONCLUSION: ScvO2 is an independent predictor of the weaning outcome and its evaluation may further facilitate the accurate categorization among those patients who pass or fail the SBT.

Post-traumatic lung pseudocysts: two case reports in ICU patients.

INTRODUCTION: The traumatic lung pseudocyst is a rare complication of closed thoracic injury. We present two cases with traumatic lung pseudocyst who were admitted in our ICU. CASE 1: A 19 year old man was admitted in the ICU after a motorcycle accident. Chest CT revealed two well defined densities in the right upper lung lobe with presence of air bubbles within them. Four days after admission chest CT showed two cavitary lesions in the upper lobe. The patient showed gradual clinical improvement. Repeated chest CT after 6 months was normal. CASE 2: A 41 year old man was involved in a car-bicycle accident. The patient was admitted in the ICU with respiratory failure and flail chest. Chest CT revealed multiple bilateral rib fractures, right pneumothorax and contusions of the right lung. Two days after admission chest CT showed formation of lung pseudocyst. The patient was gradually stabilised and 22 days after the accident the chest CT revealed resolution of the pseudocysts. DISCUSSION: The traumatic lung pseudocyst is a rare complication of blunt thoracic trauma. The clinical course of traumatic lung pseudocyst is usually benign, unless complications such as pneumothorax or infection of the cavitary lesion arise. These lesions are more common in children and young adults.