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.

Tigecycline Pharmacokinetic and Pharmacodynamic Profile in Patients with Chronic Obstructive Pulmonary Disease Exacerbation.

BACKGROUND: We aimed to evaluate the pharmacokinetic profile of tigecycline in plasma and its penetration to sputum in moderately ill patients with an infectious acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Eleven patients hospitalized with acute respiratory failure due to an acute COPD exacerbation with clinical evidence of an infectious cause received tigecycline 50 mg twice daily after an initial loading dose of 100 mg. Blood and sputum samples were collected at steady state after dose seven. RESULTS: In plasma, mean Cmax pl was 975.95 ± 490.36 ng/mL and mean Cmin pl was 214.48 ±140.62 ng/mL. In sputum, mean Cmax sp was 641.91 ± 253.07 ng/mL and mean Cmin sp was 308.06 ± 61.7 ng/mL. In plasma, mean AUC 0-12 pl was 3765.89 ± 1862.23 ng*h/mL, while in sputum mean AUC 0-12 sp was 4023.27 ± 793.37 ng*h/mL. The mean penetration ratio for the 10/11 patients was 1.65 ± 1.35. The mean Free AUC0-24 pl/MIC ratio for Streptococcus pneumoniae and Haemophilus influenzae was 25.10 ± 12.42 and 6.02 ± 2.97, respectively. CONCLUSIONS: Our findings support the clinical effectiveness of tigecycline against commonly causative bacteria in COPD exacerbations and highlight its sufficient lung penetration in pulmonary infections of moderate severity.

Persistent Sleep Quality Deterioration among Post-COVID-19 Patients: Results from a 6-Month Follow-Up Study.

Background: To date, evidence about sleep disturbances among post-COVID-19 patients is limited. This study aimed to evaluate sleep quality after hospitalization due to SARS-CoV-2 infection. Methods: In-person follow-up was conducted in patients with prior hospitalization due to COVID-19 1(Τ1), 3(Τ2), and 6 (Τ3) months after hospital discharge. Patients were asked to complete questionnaires concerning sleep quality: the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Athens Insomnia Scale (AIS), the Fatigue Severity Scale (FSS), and the Stop-BANG (S-B) questionnaire. Results: In total, 133 patients were enrolled (mean age: 56.0 ± 11.48 years, 59.4% males). The most frequently reported comorbidity was arterial hypertension (29.8% of patients), while 37.4% of patients had no comorbidities. The majority of participants exhibited poor sleep quality (global PSQI ≥ 5) at T1 (84.3%), T2 (75.7%), and T3 (77.4%). Insomnia was observed in 56.5%, 53.5%, and 39.2% of participants, respectively (AIS ≥ 6). An FSS score ≥ 4 was observed in 51.2%, 33.7%, and 29.1% of participants at T1, T2, T3, respectively. Elapsed time was found to be negatively and independently associated with the global PSQI, PSQI C5-Sleep disturbance, PSQI C7-Daytime dysfunctions, FSS, and AIS after adjustment for possible confounders. No significant difference was found between groups with good and poor sleep quality (based on the global PSQI) with respect to gender (p = 0.110), age (p = 0.528), BMI (p = 0.816), smoking status (p = 0.489), hypertension (p = 0.427), severity of disease (p = 0.224), the Charlson Comorbidity Index (p = 0.827), or the length of hospital stay (p = 0.162). Participants with excessive daytime sleepiness (EDS) and patients with severe fatigue (FSS ≥ 4) were significantly younger. Females presented a higher rate of insomnia symptoms (55.7% vs. 44.3%, p < 0.001). Conclusions: Several sleep disturbances were observed after hospital discharge for COVID-19 pneumonia at certain time points; However, the improvement over time was remarkable in most domains of the assessed questionnaires.

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.

Modification Tadalafil and Macitentan tablets to aerosol.

INTRODUCTION: Aerosolised drugs have been approved for several diseases such as cystic fibrosis and diabetes. Moreover; there are already drugs for pulmonary hypertension in aerosol form already on the market. MATERIALS AND METHODS: Two drugs for pulmonary hypertension (Tadalafil and Macitentan) were milled and transformed from tablets to powder. Three different jet-nebulizers with seven different residual cups were combined. Moreover, we used 3 different ultrasound nebulizers with two different release methods. RESULTS: The drug and residual cup designs produce alone or jointly different MMAD diameters. The three large (10 mls) residual cups with the jet-nebulisers produced the smallest aerosol droplets. Both ultrasound nebulisers are capable of producing optimal size aerosol droplets ≤5 µm mmad. CONCLUSIONS: These two drugs can be easily administered as aerosol and an vivo clinical study will prove the safety for the airways.

Epidemiological characteristics and outcomes from 187 patients with COVID-19 admitted to 6 reference centers in Greece: an observational study during the first wave of the COVID-19 pandemic.

INTRODUCTION: Epidemiological data from patients with COVID-19 has been recently published in several countries. Nationwide data of hospitalized patients with COVID-19 in Greece remain scarce. MATERIAL AND METHODS: This was an observational, retrospective study from 6 reference centers between February 26 and May 15, 2020. RESULTS: The patients were mostly males (65.7%) and never smokers (57.2%) of median age 60 (95% CI: 57.6-64) years. The majority of the subjects (98%) were treated with the standard-of-care therapeutic regimen at that time, including hydroxychlo-roquine and azithromycin. Median time of hospitalization was 10 days (95% CI: 10-12). Twenty-five (13.3%) individuals were intubated and 8 died (4.2%). The patients with high neutrophil-to-lymphocyte ratio (NLR) ( > 3.58) exhibited more severe disease as indicated by significantly increased World Health Organization (WHO) R&D ordinal scale (4; 95% CI: 4-4 vs 3; 95% CI: 3-4, p = 0.0001) and MaxFiO2% (50; 95% CI: 38.2-50 vs 29.5; 95% CI: 21-31, p < 0.0001). The patients with increased lactate dehydrogenase (LDH) levels ( > 270 IU/ml) also exhibited more advanced disease compared to the low LDH group ( < 270 IU/ml) as indicated by both WHO R&D ordinal scale (4; 95% CI: 4-4 vs 4; 95% CI: 3-4, p = 0.0001) and MaxFiO2% (50; 95% CI: 35-60 vs 28; 95% CI: 21-31, p < 0.0001). CONCLUSION: We present the first epidemiological report from a low-incidence and mortality COVID-19 country. NLR and LDH may represent reliable disease prognosticators leading to timely treatment decisions.

Changes in the respiratory function of COVID-19 survivors during follow-up: A novel respiratory disorder on the rise?

BACKGROUND: The Human Coronavirus Disease 2019 (COVID-19) is a highly contagious respiratory disorder that may result in acute respiratory distress syndrome. The aim of this review was to investigate the incidence and type of respiratory function abnormalities during the follow-up of patients who recovered from COVID-19. METHODS: A systematic search of MEDLINE was conducted, utilising various term combinations. Studies that assessed any respiratory function parameter during the re-evaluation of patients who recovered from COVID-19 and were published as full-text articles in English are included in this review. RESULTS: Amongst 183 articles initially retrieved, 8 fulfilled the criteria and were included in this review; they involved a total of 341 adult patients. Four were retrospective studies, one was a prospective cohort study, one was a randomised control trial and two were case reports/case series. The follow-up time ranged from 1 month since symptom onset to 3 months after discharge. The most frequent abnormality was reduced lung diffusion for carbon monoxide (DLCO), followed by a restrictive pattern. Other findings are the lack of resting hypoxemia, the reduced respiratory muscle strength and the decreased exercise capacity, although relative data are extremely limited. CONCLUSION: Patients who recovered from COVID-19 present with abnormal respiratory function at short-term follow-up, mainly with reduced lung diffusion and a restrictive pattern. However, results are currently very limited in order safe conclusions to be made, regarding the exact incidence of these abnormalities and whether they may be temporary or permanent.

Vaccinated and Convalescent Donor-Derived Severe Acute Respiratory Syndrome Coronavirus 2-Specific T Cells as Adoptive Immunotherapy for High-Risk Coronavirus Disease 2019 Patients.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic poses an urgent need for the development of effective therapies for coronavirus disease 2019 (COVID-19). METHODS: We first tested SARS-CoV-2-specific T-cell (CοV-2-ST) immunity and expansion in unexposed donors, COVID-19-infected individuals (convalescent), asymptomatic polymerase chain reaction (PCR)-positive subjects, vaccinated individuals, non-intensive care unit (ICU) hospitalized patients, and ICU patients who either recovered and were discharged (ICU recovered) or had a prolonged stay and/or died (ICU critical). CoV-2-STs were generated from all types of donors and underwent phenotypic and functional assessment. RESULTS: We demonstrate causal relationship between the expansion of endogenous CoV-2-STs and the disease outcome; insufficient expansion of circulating CoV-2-STs identified hospitalized patients at high risk for an adverse outcome. CoV-2-STs with a similarly functional and non-alloreactive, albeit highly cytotoxic, profile against SARS-CoV-2 could be expanded from both convalescent and vaccinated donors generating clinical-scale, SARS-CoV-2-specific T-cell products with functional activity against both the unmutated virus and its B.1.1.7 and B.1.351 variants. In contrast, critical COVID-19 patient-originating CoV-2-STs failed to expand, recapitulating the in vivo failure of CoV-2-specific T-cell immunity to control the infection. CoV-2-STs generated from asymptomatic PCR-positive individuals presented only weak responses, whereas their counterparts originating from exposed to other seasonal coronaviruses subjects failed to kill the virus, thus disempowering the hypothesis of protective cross-immunity. CONCLUSIONS: Overall, we provide evidence on risk stratification of hospitalized COVID-19 patients and the feasibility of generating powerful CoV-2-ST products from both convalescent and vaccinated donors as an "off-the shelf" T-cell immunotherapy for high-risk patients.

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.

Endothelial Dysfunction during Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Chronic obstructive pulmonary disease (COPD) is characterized by high cardiovascular risk, which is further amplified during acute COPD exacerbations (AECOPD). Endothelial dysfunction has been previously suggested as one of the potential pathogenetic mechanisms. In order to study the effects of AECOPD on endothelial function assessed by available functional methods, we performed a literature search involving Pubmed and Scopus databases. Eligible studies were those that included adult patients with COPD and evaluated endothelial damage via semi-invasive or noninvasive functional methods, during AECOPD and after recovery or in stable condition. Newcastle-Ottawa Scale was applied to evaluate the quality of retrieved studies. Endothelial function was significantly impaired during AECOPD compared to recovery/stable condition (SMD: -0.87, 95%CI [-1.19, -0.55]). Patients during AECOPD presented a significantly worse response in endothelium-dependent (flow-mediated dilatation WMD: -2.59, 95%CI [-3.75, -1.42]) and independent vasodilation (nitroglycerine-mediated dilatation WMD: -3.13, 95%CI [-5.18, -1.09]) compared to recovery. Sensitivity analyses confirmed the above results. In conclusion, endothelium-dependent and independent vasodilation is worse during AECOPD compared to the stable condition. Endothelial dysfunction could play a role in the high cardiovascular risk during AECOPD.

Severe Pulmonary Disease Caused by Mycolicibacter kumamotonensis.

Severe Mycolicibacter kumamotonensis-pulmonary disease was diagnosed in a 68-year-old immunocompetent woman in Greece; the disease was initially treated as tuberculosis. The patient responded favorably to a new treatment regimen of azithromycin, amikacin, moxifloxacin, and linezolid. Complete symptom resolution and radiologic improvement resulted.

Asthma and rhinitis in Greek furniture workers.

Objective: The detection of asthma and rhinitis in furniture workers exposed to chemicals in the area of Thessaloniki Greece and the determination of the most useful tests for diagnosing the above occupational diseases.Methods: Eighty-three workers (76 men), 35 exposed to chemicals (CW), 23 to wood dust (WW), and 25 office workers (OW), serving as controls, filled in a specialized European Community Respiratory Health Survey (ECRHS) questionnaire for asthma and were submitted to clinical evaluation, spirometry, bronchodilation test, PEF computer algorithm OASYS-2, FeNO, skin prick tests (SPTs), rhinomanometry and methacholine inhalation challenge. Working conditions and protective measurements were also recorded. According to the results of all conducted tests, each subject was distributed to a subgroup: (a) normal, (b) asthma, (c) rhinitis, (d) asthma and rhinitis. Comparisons were performed among work groups.Results: The presence of asthma and/or rhinitis was higher among CW and WW compared to OW (p = 0.004). Significant differences among groups were observed in the questions «better weekend¼ (p < 0.034) and "improvement on vacation¼ (p < 0.000), in OASYS-2 Score (p < 0.000), in ABC Score (p < 0.000), and in methacholine score (p < 0.022). Rhinomanometry, FeNO, spirometry, and spirometry after bronchodilation had no significant differences among groups. Working conditions, ventilation system, work practice, use and type of mask revealed no significant differences.Conclusion: Asthma and rhinitis are significantly common among CW. Protective measurements used were not adequate to prevent asthma and or work related rhinitis. Early diagnosis might contribute to disease prevention and control.

Longitudinal changes in exercise capacity among adult cystic fibrosis patients.

INTRODUCTION: Longitudinal data regarding changes in exercise capacity among adult cystic fibrosis (CF) patients are currently scarce. The aim of this brief report was to assess changes in exercise capacity among adult CF patients with stable and mild-to-moderate disease eight years after their initial evaluation. MATERIAL AND METHODS: Maximum cardiopulmonary exercise testing (CPET) was utilized. Other assessments included Doppler echocardiography, the 6-minute walking test, spirometry, and lung volume evaluation. RESULTS: Eleven (6 male, 5 female) patients completed both evaluations (initial and after eight years). During follow-up, indices of ventilatory impairment (such as ventilatory reserve; p=0.019, and ventilatory equivalent for carbon dioxide; p = 0.047) deterio-rated significantly following a decline in respiratory function measurements. Peak oxygen uptake (VO2), both as an absolute (26.6 ± 8.46 vs 23.89 ± 6.16 mL/kg/min; p = 0.098) and as a % of predicted value (71.21 ± 16.54 vs 70.60 ± 15.45; p = 0.872), did not deteriorate. This is also true for oxygen pulse (p = 0.743), left heart ejection fraction (p = 0.574), and pulmonary artery systolic pressure (p = 0.441). However, the anaerobic threshold, both as an absolute (p = 0.009) and as a % of predicted value (p = 0.047), was significantly lower during follow-up. CONCLUSION: In adult CF patients with stable, mild-to-moderate disease, a peak VO2 may be preserved for several years. However, even in these patients, deconditioning is present.

18F-FDG PET/CT contribution to tuberculous vertebral osteomyelitis diagnosis: a case report.

Tuberculous vertebral osteomyelitis (TVO) is an extrapulmonary tuberculosis form characterized by difficulty and delay in diagnosis. PET/CT is a valuable, well-established tool in the diagnostic workup of cancer and fever of unknown origin, which is increasingly appreciated in the management of infectious diseases. We report a TVO case where PET/CT had a valuable contribution towards diagnosis and monitoring of treatment response, highlighting its advantages and future perspectives when dealing with infectious diseases.

Nicotine treatment and smoking cessation in the era of COVID-19 pandemic: an interesting alliance.

In the era of this pandemic, the role of medicinal nicotine in the prevention and treatment of #COVID19 disease should be evaluated in placebo-controlled trials, while smoking cessation should be further promoted as a general public health measure https://bit.ly/3fpsBdq.

Cardiopulmonary exercise testing in patients with asthma: What is its clinical value?

Asthma is one of the most common respiratory disorders, characterized by fully or largely reversible airflow limitation. Asthma symptoms can be triggered or magnified during exertion, while physical activity limitation is often present among asthmatic patients. Cardiopulmonary exercise testing (CPET) is a dynamic, non-invasive technique which provides a thorough assessment of exercise physiology, involving the integrative assessment of cardiopulmonary, neuromuscular and metabolic responses during exercise. This review summarizes current evidence regarding the utility of CPET in the diagnostic work-up, functional evaluation and therapeutic intervention among patients with asthma, highlighting its potential role for thorough patient assessment and physician clinical desicion-making.

Cardiopulmonary exercise testing in chronic obstructive pulmonary disease: An update on its clinical value and applications.

Chronic obstructive pulmonary disease is a debilitating disorder, characterized by airflow limitation, exercise impairment, reduced functional capacity and significant systemic comorbidity, which complicates the course of the disease. The critical inspiratory constraint to tidal volume expansion during exercise (that may be further complicated by the presence of dynamic hyperinflation), abnormalities in oxygen transportation and gas exchange abnormalities are the major pathophysiological mechanisms of exercise intolerance in COPD patients, and thus, exercise testing has been traditionally used for the functional evaluation of these patients. Compared to various laboratory and field exercise tests, cardiopulmonary exercise testing (CPET) provides a thorough assessment of exercise physiology, involving the integrative respiratory, cardiovascular, muscle and metabolic responses to exercise. This review highlights the clinical utility of CPET in COPD patients, as it provides important information for the determination of the major factors that limit exercise among patients with several comorbidities, allows the assessment of the severity of dynamic hyperinflation, provides valuable prognostic information and can be used to evaluate the response to several therapeutic interventions.

A rare pulmonary pathology complicated with an unusual condition.

Differential diagnosis should never be limited to the obvious diagnoses http://ow.ly/ybTM30obh6H.