The Aftermath of COVID-19: Exploring Long-Term Effects on the Organ Systems (preprint)

Background: Post-acute sequelae of SARS-CoV-2 infection (PASC) is a complicated disease that affects millions of people all over the world. Previous studies have shown that PASC impacts 10% of SARS-CoV-2 infected patients of which 50-70% are hospitalized. It has also been shown that 10-12% of those vaccinated against COVID-19 were affected with PASC and its complications. The severity and the later development of PASC symptoms is positively associated with the early intensity of the infection. Results: The generated health complications caused by PASC involve a vast variety of organ systems. Patients affected by PASC have been diagnosed with neuropsychiatric and neurological symptoms. Cardiovascular system also has been involved and several diseases such as myocarditis, pericarditis, and coronary artery diseases were reported. Chronic hematological problems such as thrombotic endothelialitis and hypercoagulability were described as a condition that could increase the risk of clotting disorders and coagulopathy in PASC patients. Chest pain, breathlessness, and cough in PASC patients were associated with respiratory system in long COVID-19 causing respiratory distress syndrome. The observed immune complications were notable, involving several diseases. Renal system also was impacted and result in raising the risk of diseases such as thrombotic issues, fibrosis, and sepsis. Endocrine gland malfunction can lead to diabetes, thyroiditis, and male infertility. Symptoms such as diarrhea, nausea, loss of appetite and taste were also among reported observations due to several gastrointestinal disorders. Skin abnormalities might be an indication of infection and long-term implications such as persistent cutaneous complaints were linked to PASC. Conclusions: Long COVID is a multidimensional syndrome with considerable public health implications, affecting several physiological systems and demanding thorough medical therapy as well as more study to address its underlying causes and long-term effects.

Post-Discharge Spirometry Evaluation in Patients Recovering from Moderate-to-Critical COVID-19: A Prospective Cohort Study (preprint)

To determine the prevalence and types of spirometry abnormalities among post-COVID-19 patients in Malaysia, with secondary objective focusing on associated factors. Conducted at the COVID-19 Research Clinic, Faculty of Medicine, University Technology MARA, from March 2021 to December 2022, this study included patients three months post-discharge from hospitals following moderate-to-critical COVID-19. Of 408 patients studied, abnormal spirometry was found in 46.8%, with 28.4% exhibiting a restrictive pattern, 17.4% showing preserved ratio impaired spirometry (PRISm), and 1.0% displaying an obstructive pattern. Factors independently associated with abnormal spirometry included older age (OR: 1.0, 95% CI: 1.01–1.04, p = 0.003), underlying cardiovascular disease (OR: 3.5, 95% CI: 1.19–10.47, p = 0.023), history of acute respiratory distress syndrome (p < 0.001), shorter discharge-to-follow-up interval (OR: 0.9, 95% CI: 1.00–1.02, p = 0.035), oxygen desaturation during 6-minute walk test (OR: 1.9, 95% CI: 1.20–3.06, p = 0.007), and presence of consolidation (OR: 8.1, 95% CI: 1.75–37.42, p = 0.008) or ground-glass opacity (OR: 2.6, 95% CI: 1.52–4.30, p < 0.001) on chest X-ray. This study highlights patients recovering from moderate-to-critical COVID-19 often exhibit abnormal spirometry, notably a restrictive pattern and PRISm. Routine spirometry screening for high-risk patients is recommended.

Prognostic Value of Response to Inhaled Nitric Oxide Administration in Patients with ARDS Related to SARS-CoV-2 Infection (preprint)

Background: The role of inhaled Nitric Oxide (iNO) in managing Acute Respiratory Distress Syndrome Covid-19 related (C-ARDS) is debatable. The study aimed to analyze the effect of iNO administration in patients with persistent severe hypoxia and Intensive Care Unit (ICU) mortality. Methods: This retrospective study included 98 consecutive critically ill patients with C-ARDS admitted to ICU from 1 October 2020 to 31 October 2021. Results: Of these patients, 28% had received iNO. Twelve (44.4%) were responders. Kaplan-Mayer plot shows mortality was higher in non-responders (86.6 vs 25.0%). Non-response to iNo was the most important predictive value (p. 0.01). The Receiver Operating Characteristic (ROC) curve for a percentage increase in PaO2 from baseline confirmed that it had a higher predictive value for in-hospital survival. A value of 19% can predict the death event with a sensitivity of 81.8% and a specificity of 81.2%. Conclusions: Therefore, we propose to use iNO as a vasoreactivity test for prognostic stratification in patients with persistent severe hypoxia.

Effect of apigetrin in pseudo-SARS-CoV-2-induced inflammatory and pulmonary fibrosis in vitro model (preprint)

SARS-CoV-2 has become a global public health problem. Acute respiratory distress syndrome (ARDS) is the leading cause of death due to the SARS-CoV-2 infection. Pulmonary fibrosis (PF) is a severe and frequently reported COVID-19 sequela. In this study, an in vitro model of ARDS and PF caused by SARS-CoV-2 was established in MH-S, THP-1, and MRC-5 cells using pseudo-SARS-CoV-2 (PSCV). Expression of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and HIF-1α was increased in PSCV-infected MH-S and THP-1 cells, ARDS model, consistent with other profiling data in SARS-CoV-2-infected patients have been reported. Hypoxia-inducible factor-1 alpha (HIF-1α) siRNA and cobalt chloride were tested using this in vitro model. Furthermore, apigetrin, a glycoside bioactive dietary flavonoid derived from several plants, including Crataegus pinnatifida, which is reported to be a HIF-1α inhibitor, was tested in this in vitro model [1]. Apigetrin significantly reduced the increased inflammatory cytokine (IL-6, IL-1β, and TNF-α) expression and secretion by PSCV in MH-S and THP-1 cells. Apigetrin inhibited the binding of the SARS-CoV-2 spike protein RBD to the ACE2 protein. An in vitro model of PF induced by SARS-CoV-2 was produced using a conditioned medium of THP-1 and MH-S cells that were PSCV-infected (CMPSCV) into MRC-5 cells. In a PF model, CMPSCV treatment of THP-1 and MH-S cells increased cell growth, migration, and collagen synthesis in MRC-5 cells. In contrast, apigetrin suppressed the increase in cell growth, migration, and collagen synthesis induced by CMPSCV in THP-1 and MH-S MRC-5 cells. Also, compared to control, fibrosis-related proteins (CTGF, COLA1, α-SMA, and HIF-1α) levels were over two-fold higher in CMPSV-treated MRC-5 cells. Apigetrin decreased protein levels in CMPSCV-treated MRC-5 cells. Thus, our data suggest that hypoxia-inducible factor-1 alpha (HIF-1α) might be a novel target for SARS-CoV-2 sequela therapies and apigetrin, representative of HIF-1alpha inhibitor, exerts anti-inflammatory and PF effects in PSCV-treated MH-S, THP-1, and CMPVSC-treated MRC-5 cells. These findings indicate that HIF-1α inhibition and apigetrin would have a potential value in controlling SARS-CoV-2-related diseases.

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, but where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2 - 66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed.

End-expiratory lung volumes as a potential indicator for COVID-19 associated acute respiratory distress syndrome: a retrospective study (preprint)

Background End-expiratory lung volume (EELV) has been observed to decrease in acute respiratory distress syndrome (ARDS). Yet, research investigating EELV in patients with COVID-19 associated ARDS (CARDS) remains limited. It is unclear EELV serve as a potential metric for monitoring disease progression and identifying patients with ARDS at increased risk of adverse outcomes.Study Design and Methods: This retrospective study included mechanically ventilated patients with CARDS during the initial phase of epidemic control in Shanghai. EELV was measured within 48 hours post-intubation, followed by regular assessments every 3–4 days. Chest CT scans, performed within a 24-hour window around each EELV measurement, were analyzed using AI software. Differences in patient demographics, clinical data, respiratory mechanics, EELV, and chest CT findings were assessed using linear mixed models (LMM).Results Out of the 38 enrolled patients, 26.3% survived until discharge from the ICU. In the survivor group, EELV, EELV/PBW and EELV/preFRC were significantly higher than those in the non-survivor group (survivor group vs non-survivor group: EELV: 1455 vs 1162 ml, P = 0.049; EELV/PBW: 24.1 vs 18.5 ml/kg, P = 0.011; EELV/preFRC: 0.45 vs 0.34, P = 0.005). Follow-up assessments showed a sustained elevation of EELV/PBW and EELV/preFRC among the survivors. Additionally, EELV exhibited a positive correlation with total lung volume and residual lung volume, while demonstrating a negative correlation with lesion volume determined through chest CT scans analyzed using AI software.Conclusion EELV is a useful indicator for assessing disease severity and monitoring the prognosis of patients with CARDS.

Delayed Fatal Pulmonary Hemorrhage Following COVID-19 Vaccination: Case Report, Batch Analysis, And Proposed Autopsy Checklist (preprint)

We present a case of a 47-year-old male who died unexpectedly from acute pulmonary hemorrhage 555 days after completing the BNT162b2 (Pfizer) COVID-19 vaccination primary series. Before death, he exhibited symptoms of a mild respiratory infection. Despite a healthy medical history and no medication use, the patient’s condition rapidly deteriorated and he experienced severe respiratory distress, followed by cardiopulmonary arrest with evidence of profuse pulmonary bleeding. Autopsy findings revealed massive lung congestion without embolism, normal heart size, moderate coronary atherosclerosis without myocardial infarction, and no evidence of other hemorrhagic events. The patient tested negative for COVID-19 and other respiratory pathogens at autopsy. Despite these findings, the medical examiner determined the cause of death was attributed to atherosclerotic and hypertensive cardiovascular disease, without considering the recent pulmonary hemorrhage and unremarkable medical history. Investigation into the vaccine batch indicated a higher-than-average number of serious adverse events, including fatalities. The patient's BNT162b2 batch was among the top 2.8% for reported deaths. Moreover, the autopsy failed to investigate potential contributions from the vaccine, such as the presence of the Spike protein or related antibodies. The evidence suggests that the pulmonary hemorrhage, exacerbated by a viral infection, was the immediate cause of death, with the COVID-19 vaccine potentially playing a role in the development of cardiopulmonary pathology and hemorrhage. We propose autopsy protocols for COVID-19 vaccine recipients to better investigate vaccine-related pathologies among those with one or more prior injections.

Biological Effects of Corticosteroids on Pneumococcal Pneumonia in Mice and Humans (preprint)

Background: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in an observational cohort of mechanically ventilated patients and in a mouse model of bacterial pneumonia with Streptococcus pneumoniae. Methods: We studied gene expression with lower respiratory tract transcriptomes from a cohort of mechanically ventilated patients and in mice. We also carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. Results: Transcriptomic analysis identified pleiotropic effects of steroid therapy on the lower respiratory tract in critically ill patients with pneumococcal pneumonia, findings that were reproducible in mice. In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Conclusions: The gene expression studies in patients and in the mice support the clinical relevance of the mouse studies, which replicate several features of pneumococcal pneumonia and steroid therapy in humans. In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The results from these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

Could SP-A and SP-D Serum Levels Predict COVID-19 Severity? (preprint)

Given the various clinical manifestations that characterize COVID-19, the scientific community is constantly searching for biomarkers with prognostic value. SP-A and SP-D collectins play a crucial role in ensuring proper alveolar function and an alteration of their serum levels have been reported in several pulmonary diseases characterized by ARDS and pulmonary fibrosis. Considering that such clinical manifestations can also occur during SARS-CoV-2 infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n=51) at admission (T0) and after 7 days (T1) and compared with healthy donors (n=11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In the light of these results SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia and the early detection of SP-D serum levels could be crucial for a preventive clinical management

Neutrophil Elastase Inhibitor (Sivelestat) in the Treatment of Acute Respiratory Distress Syndrome Induced by COVID- 19: A Multicenter Retrospective Cohort Study (preprint)

Background Recent studies suggest that neutrophil elastase inhibitor (Sivelestat) may improve pulmonary function and reduce mortality in patients with acute respiratory distress syndrome. We examined the association between receipt of sivelestat and improvement in oxygenation among patients with acute respiratory distress syndrome (ARDS) induced by COVID-19.Methods A large multicentre cohort study of patients with ARDS induced by COVID-19 who had been admitted to intensive care units (ICUs). We used propensity score matching to compare the outcomes of patients treated with sivelestat to those who were not. The differences in continuous outcomes were assessed with the Wilcoxon signed-rank test. Kaplan-Meier method was used to show the 28-day survival curves in the matched cohorts. A log-rank P-test stratified on the matched pairs was used to test the equality of the estimated survival curves. A Cox proportional hazards model that incorporated a robust sandwich-type variance estimator to account for the matched nature of the data was used to estimate hazard ratios (HR). All statistical analyses were performed with SPSS 26.0 and R 4.2.3. A two-sided p-value of < 0.05 was considered statistically significant.Results A total of 387 patients met inclusion criteria, including 259 patients (66.9%) who were treated with sivelestat. In 158 patients matched on the propensity for treatment, receipt of sivelestat was associated with improved oxygenation, decreased Murray lung injury score, increased non-mechanical ventilation time within 28 days, increased alive and ICU-free days within 28 days (HR, 1.85; 95% CI, 1.29 to 2.64; log-rank p < 0.001), shortened ICU stay and ultimately improved survival (HR, 2.78; 95% CI, 1.32 to 5.88; log-rank p = 0.0074).Conclusions Among patients with ARDS induce by COVID-19, sivelestat administration is associated with improved clinical outcomes.

The Interleukin 6 (IL-6) blockade for coronavirus disease 2019 (COVID-19) In Lung (preprint)

COVID-19 has caused global pandemics since the emergent outbreak and resulted in a large number of deaths. IL-6, as an important autoimmune cytokine, had been suggested for the treatment of acute respiratory distress syndrome (ARDS) patients in COVID-19. A review of the relevant literature revealed more than one role for IL-6 in the lung infection because of its diverse biological effects. It may have a variety of different physiological functions in the development of lung infection. We have summarized its role in different progress of COVID-19, including lung infection, pneumonia, ALI, pulmonary fibrosis, and lung translation and even lung cancer. This will facilitate a deeper understanding of the role of IL-6 in the treatment of COVID-19.

The Role of Serum Albumin and Blood Urea Nitrogen to Serum Albumin Ratio in Prediction of Disease Severity and Thirty--day Mortality in Patients with COVID--19 (preprint)

Background: Considering the role of higher blood urea nitrogen and lower serum albumin (SA) levels in deceased COVID-19 patients, increased blood urea nitrogen to SA (B/A) ratio may help to determine those at higher risk of becoming critically ill. This study evaluated the association of SA level and B/A ratio with disease severity and 30–day mortality and also their predictive value for disease severity in COVID–19 patients. Methods: 433 adult patients with COVID–19, admitted to a referral medical center in Tehran, Iran, from February to May 2020 were included. The laboratory markers were measured on admission. Disease severity was categorized into mild disease, severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and septic shock. The mortality was followed up for thirty days after admission. Results: Thirty–day mortality rate was 27.25%. The frequency of mild, severe pneumonia, ARDS, sepsis, and septic shock was 30.72%, 36.95%, 24.02%, 6.00%, and 2.31%, respectively. Mean B/A ratio was different among different disease severities. The odds of thirty-day mortality increased by 16% by each unit increase in B/A ratio and decreased by 57% by each unit increase in SA level. B/A ratio had the AUC of 0.45 for disease severity prediction with 71% sensitivity and 22% specificity. Conclusion: The results showed that B/A ratio and SA levels are associated with mortality in COVID–19 patient, while they had low predictive value for disease severity. High B/A ratio is, additionally, associated with disease severity. Therefore, we suggest to use this marker for clinical assessment of patients with COVID–19.

IMPACT OF METHYLPREDNISOLONE PULSE ON THE MORTALITY OF PATIENTS WITH ACUTE RESPIRATORY DISTRESS SYNDROME SECONDARY TO COVID-19 (preprint)

Corticosteroids are the most important factor to reduce the mortality in patients with moderate-severe COVID-19. The aim of the study was to analyze the impact of methylprednisolone pulse (MPP) on in-hospital mortality of patients with acute respiratory distress syndrome (ARDS) due to COVID-19. We conducted a retrospective, single-center observational study We selected adult patients admitted to the hospital with the diagnosis of COVID-19 between March and June 2020. A total of 306 patients were analyzed. In-hospital crude mortality rate was 17%. Diabetes mellitus (HR 5.5, 95% CI 1.40–4.55), dementia (HR 7.7, 95% CI 4.25-13.87) and ARDS (HR 4.2, 95% CI 2.34-7.46) were associated with in -hospital mortality. In patients diagnosed of ARDS, the only in-hospital mortality risk factor was dementia (HR 5.2, 95% CI 2.44–11.07), whereas MPP was a protective factor (HR 0.2, 95% CI 0.09–0.63)

Successful ECMO therapy in a child with COVID-19-associated ARDS and Ewing's Sarcoma. (preprint)

Most children and adolescents with SARS-CoV-2 infection shows asymptomatically or with mild symptoms. There are few reported cases of extracorporeal membrane oxygenation (ECMO) in pediatric patients with coronavirus disease 2019 (COVID-19). We present a previously healthy 13-year-old male, diagnosed with metastatic Ewing’s sarcoma at the same time as catastrophic acute respiratory distress syndrome due to COVID-19, which was successfully supported by veno-venous ECMO, while he received the corresponding chemotherapy protocol. ECMO can be used as salvage therapy in oncology pediatric patients with respiratory failure secondary to COVID-19. In addition, successful chemotherapy can be administered while patients are supported on ECMO.

Transcriptome Heterogeneity in COVID-19-induced Acute Respiratory Distress Syndrome (preprint)

COVID-19 is a major etiology of acute respiratory distress syndrome (ARDS). The biological phenotypes and underlying mechanisms in COVID-19-induced ARDS are not fully understood. Bronchoalveolar lavage fluid (BALF) cells and clinical data were collected from patients with COVID-19-induced ARDS. Principal component analysis of genome-wide expression data obtained from bulk RNA sequencing of BALF cells subgrouped COVID-19-induced ARDS patients. Moreover, comparing transcriptome profiles between the subgroups showed two biological phenotypes, illustrated by up- and down-regulation of interferon (IFN) responses, despite no significant differences in clinical characteristics including onset and outcomes. In the low-IFN phenotype, in contrast to the high-IFN phenotype, the TLR-MyD88-IFN regulatory factor (IRF) 5 and cGAS-STING1 axes related to type Ⅰ IFN and the IRF8-interleukin (IL)-12-STAT4 and IRF1-IL-15-DNAX-activation protein 10 axes related to type Ⅱ IFN were inactivated at the transcriptional level, together with the PERK-C/EBP homologous protein axis and the IL-10-hemoglobin scavenger receptor CD163 axis. The pathogenesis of ARDS in the low-IFN phenotype was illustrated by damage to type II alveolar epithelial cells due to increased viral replication by reduced antiviral response, cytotoxicity, and apoptotic signaling and impaired free hemoglobin catabolism. Our data uncovered heterogeneous IFN responses, the underlying mechanisms, and related pathogenesis in COVID-19-induced ARDS.

Combination of multiple omics and machine learning identifies diagnostic genes for ARDS and COVID-19 (preprint)

BACKGROUND Acute respiratory distress syndrome (ARDS) is a common acute clinical syndrome of the respiratory system with a high mortality rate and difficult prognosis.COVID-19 is a serious respiratory infectious disease caused by coronaviruses in a global pandemic. Some studies have suggested a possible association between COVID-19 and ARDS, but few studies have investigated the mechanism of interaction between them.METHODS Microarray data of ARDS (GSE32707 and GSE66890) and COVID-19 (GSE213313) were downloaded from the GEO database and searched for common differential genes for enrichment analysis.WGCNA was used to identify co-expression modules and genes associated with ARDS and COVID-19. RF and LASSO were performed for candidate gene identification. Machine learning XGBoost improved the diagnosis of hub genes in ARDS and COVID-19. The degree of immune cell infiltration in ARDS and COVID-19 samples was assessed using the CIBERSORT algorithm, and the relationship between hub genes and infiltrating immune cells was investigated. Changes in pathway activity per cell were visualized using Seurat standard flow down clustering (seurat) to visualize peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data from patients with sepsis-combined ARDS and patients with sepsis alone.RESULTS Limma difference analysis identified 314 up-regulated genes and 241 down-regulated genes in ARDS and COVID-19.WGCNA identified the purple-red co-expression module as the core module of ARDS and COVID-19. Five candidate genes, namely HIST1H2BK, TCF4, OLFM4, KIF14 and HK1, were screened using two machine learning algorithms, RF and LASSO. XGBoost constructed diagnostic models to evaluate the hub genes with high diagnostic efficacy in ARDS and COVID-19. Single-cell sequencing revealed the presence of alterations in five immune subpopulations, including monocytes, B cells, T cells, NK cells and platelets, with high expression levels and cellular occupancy of TCF4 and HK1, which are involved in oxidative reactions.

HIF-1α is Associated with Improved Survival in ARDS due to COVID-19: A Prospective Study (preprint)

Background Acute respiratory distress syndrome(ARDS) due to COVID-19 is accompanied by severe hypoxemia and hyperinflammation. Hypoxia-inducible factor(HIF) pathway plays a fundamental role in detecting hypoxia and developing appropriate responses. The epidemiological report claimed a lower rate of disease in the population living at high altitudes and hypothesized that adaptation to hypoxia might be advantageous for SARS-CoV-2 infection. This study was designed to examine the frequency of polymorphisms in the HIF-1α and PHD2(prolyl hydroxylase domain 2) genes, which are involved in the adaptation to hypoxia, and the relationship of existing polymorphisms with survival in the ARDS clinic developed due to COVID-19. Methods The study included 297 patients who developed ARDS due to COVID-19 infection and were admitted to the tertiary intensive care unit. Age, gender, hospitalization diagnosis, arterial blood pressure, heart rate, APACHEII score, SOFA laboratory parameters during hospitalization, vasopressor, dialysis and mechanical ventilation need during treatment, length of hospital stay, and 30-day mortality status were recorded. DNA was isolated from the blood samples by spin colon method with the QIAamp DNA MiniKit (Cat.No.51106, QIAGEN, Germany). Results Patients were divided into 3 groups according to their Hypoxia Inducible Factor-1α (C/T SNP [11549465]) genotypes. Frequencies were 71.13% for the homozygous CC genotype, 26.4% heterozygous CT genotype, and 2.36% for the homozygous TT genotype. Median age (p=0.631), APACHE II (p=0.205), and SOFA (p=0.077) scores were similar in all three groups. However, the need for dialysis, mechanical ventilation, and vasopressor was less in the homozygous TT-genotype group than in the other groups (p<0.05). The mortality rate was also lower in this group compared to other groups (p<0.05). PND2 (C/T SNP [480902] and [516651]) polymorphism, clinical and laboratory features were similar in all groups. Moreover, 30-day mortality did not differ between the groups. Conclusion In conclusion, we revealed polymorphism in HIF-lα and PHD2 genes in ARDS patients due to COVID-19. The rate of HIF-lα polymorphism was 26.4% heterozygous CT-genotype and 2.36% for homozygous TT-genotype. 30-day mortality and adverse outcome (dialysis, vasopressor use, MV need) were significantly lower in TT homozygous. However, none of the polymorphisms in the PHD2 genes affected mortality and adverse outcome.

Leveraging informative missing data to learn about acute respiratory distress syndrome and mortality in long-term hospitalized COVID-19 patients throughout the years of the pandemic (preprint)

Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only under-utilized but oftentimes unaccounted for is missing data. However, missingness can provide valuable information about comorbidities and best practices for monitoring patients, which could save lives and reduce burden on the healthcare system. We characterize patterns of missing data in laboratory measurements collected at the University of Pennsylvania Hospital System from long-term COVID-19 patients and focus on the changes in these patterns between 2020 and 2021. We investigate how these patterns are associated with comorbidities such as acute respiratory distress syndrome (ARDS), and 90-day mortality in ARDS patients. This work displays how knowledge and experience can change the way clinicians and hospitals manage a novel disease. It can also provide insight into best practices when it comes to patient monitoring to improve outcomes.

Analysis of pathogenic factors of retinopathy of prematurity in Heilongjiang Province (preprint)

Background and purpose Retinopathy of prematurity is a vascular development disorder in immature retinas of premature infants, which is the leading cause of blindness in children worldwide. Because the screening delay may lead to the occurrence of blindness in children, it is particularly important to conduct timely screening for children with high risk factors. Currently, the pathogenesis of ROP may be related to multiple factors such as gestational age and birth weight of premature infants. In this study, the prevalence and risk factors of ROP in Heilongjiang Province were determined through screening for premature infants in the region, aiming to proceed early prevention of the disease. Methods Retrospectively analyzed 714 premature infants admitted to the Ophthalmology Clinic of the Second Affiliated Hospital of Harbin Medical University from January 2016 to February 2022. 12 related factors was recorded including patients’ gender, gestational age, birth weight, oxygen duration, blood transfusions, anemia, neonatal infections, respiratory distress syndrome, maternal feeding way, childbirth way, pregnancy age and parity. The prevalence of ROP and the differences in related factors between ROP patientsand non-ROP patients were found. Results Among 714 premature infants, 188 had ROP of which the incidence is 26.3%，and 61 patients received treatment. There were statistically significance(P<0.05) in gestational age, birth weight, oxygen duration, blood transfusion, anemia, neonatal infection, respiratory distress syndrome and childbirth way between the 188 ROP patients and non-ROP patients in univariate regression analysis. Variables with statistical significance for single factor were selected and conducted by multivariate regression analysis, which showed that gestational age, birth weight, and oxygen duration had remarkable statistical significance(P<0.05) with the occurrence of ROP. Gestational age and birth weight were the protective factors of disease (OR=0.43 and OR=0.8), while oxygen duration was the risk factor of disease (OR=1.02), and the diagnostic value of the model was high (AUC=0.776). five of the 61 patients who received treatment for ROP accepted two treatments, with gestational age < 32 weeks, birth weight < 1500g, and oxygen inhalation time > 20 days. The Kendall grade relative analysis of 188 patients with ROP showed that disease severity was significantly correlated with gestational age, birth weight, oxygen duration, anemia, blood transfusion and respiratory distress syndrome(P<0.05), in which the gestational age, birth weight, anemia, blood transfusion and respiratory distress syndrome were negatively correlated with the severity of the disease, while oxygen duration was positively correlated with severity of the disease. 507 children were screened from 2016 to December 31th in 2019, 138 of which were ROP patients, 36 children were treated (7.1%). Due to the spread of the COVID-19, 207 children were screened after January 1th in 2020, 50 children were ROP patients, and 25 of whom got treatment (12%), 21were treated after 8 weeks of birth or more than 37 weeks of corrected gestational age. Four out of five children who received the second treatment happened after the epidemic, and three of them missed treatment due to the epidemic. Conclusions The gestational age, birth weight and oxygen duration are significantly correlated with the incidence and severity of the disease in premature infants screening of Heilongjiang Province. Premature infants screening and subsequent visit were affected due to the spread of the COVID-19 in the past two years, the proportion of children needed to be cured augmented apparently, therefore, it matters a lot for premature infants to be screened standardly and timely.

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study (preprint)

Background Cadmium exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19).Methods We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed.Results A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68), and 149 patients (26%) required invasive mechanical ventilation. The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Both blood and urine cadmium concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariate logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.648 [95% CI 1.064–2.552], p = 0.025), and that a urine cadmium/creatinine value > 2.05 µg/g had the highest predictive value (adjusted OR 5.391, [95% CI 1.127–25.794], p = 0.035).Conclusions Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.