Cytokine fingerprint differences following infection and vaccination - what can we learn from COVID-19?

COVID-19 vaccination and acute infection result in cellular and humoral immune responses with various degrees of protection. While most studies have addressed the difference in humoral response between vaccination and acute infection, studies on the cellular response are scarce. We aimed to evaluate differences in immune response among vaccinated patients versus those who had recovered from COVID-19. This was a prospective study in a tertiary medical centre. The vaccinated group included health care workers, who had received a second dose of the BNT162b2 vaccine 30 days ago. The recovered group included adults who had recovered from severe COVID-19 infection (<94% saturation in room air) after 3-6 weeks. Serum anti-spike IgG and cytokine levels were taken at entry to the study. Multivariate linear regression models were applied to assess differences in cytokines, controlling for age, sex, BMI, and smoking status. In total, 39 participants were included in each group. The mean age was 53 ±14 years, and 53% of participants were males. Baseline characteristics were similar between the groups. Based on multivariate analysis, serum levels of IL-6 (ß=-0.4, p<0.01), TNFα (ß=-0.3, p=0.03), IL-8 (ß=-0.3, p=0.01), VCAM-1 (ß=-0.2, p<0.144), and MMP-7 (ß=-0.6, p<0.01) were lower in the vaccinated group compared to the recovered group. Conversely, serum anti-spike IgG levels were lower among the recovered group (124 vs. 208 pg/mL, p<0.001). No correlation was identified between antibody level and any of the cytokines mentioned above. Recovered COVID-19 patients had higher cytokine levels but lower antibody levels compared to vaccinated participants. Given the differences, these cytokines might be of value for future research in this field.

SARS CoV2 Omicron Infections Among Vaccinated Maintenance Hemodialysis Patients- outcomes and comparison to Delta variant.

Background Infections with B.1.1.529 (Omicron) variants of SARS-CoV-2 became predominant worldwide since late 2021, replacing the previously dominant B.1.617.2 variant (Delta). While those variants are highly transmissible and can evade vaccine protection, population studies suggested that outcomes from infection with Omicron variants are better compared with Delta. Data regarding prognosis of maintenance hemodialysis (MHD) patients infected with Omicron vs. Delta variants, however, is scarce. Methods This retrospective cohort study includes all patients with end-stage kidney disease treated with MHD in Meir Medical Center, Kfar-Saba, Israel that were diagnosed with SARS-CoV-2 infection between June 2021 and May 2022. Results Twenty-six subjects were diagnosed with the Delta variant and 71 with Omicron. Despite comparable age between groups and higher mean vaccine doses prior to the infection among Omicron group (p<0.001), SARS-CoV-2 infection severity was significantly worse among MHD infected with the Delta variant: 50% developed severe or critical COVID-19 vs. 5% in the Omicron group (p<0.001). Over half of MHD infected with Omicron (57%) were asymptomatic during their illness. 30-day mortality rate for the whole cohort was 5.2%. It was significantly higher among MHD in the Delta group than in the Omicron group (5/26, 19.2% vs. 0/71, p<0.001), as was 90-day mortality rate (5/26, 19.2% vs. 3/71, 4.2%, p=0.02). Conclusions Infection with the SARS-CoV-2 Delta variant was associated with worse outcomes compared with Omicron, among subjects on MHD. However, despite mild disease among vaccinated MHD patients, infection with Omicron variant was still associated with significant 90-day mortality rate.

Comparison of clinical remission criteria for severe asthma patients receiving biologic therapy.

BACKGROUND: The concept of remission on biological treatment has been suggested as a therapeutic target for patients with severe asthma, composed of 1. no chronic use of systemic steroids, 2. no exacerbations, 3. minimal symptoms, and 4. optimized lung function, for a significant time. However, the criteria for remission are not clearly defined. OBJECTIVE: Our objective was to compare different criteria for remission in subjects receiving biologicals for severe asthma. METHODS: A cross-sectional study of adult subjects who receive a stable regimen of a biological for severe asthma for at least 6-months. We compared the proportion of subjects who fulfilled different specific criteria in the four domains, as well as those who achieved different composite outcome measures of clinical remission. RESULTS: Of 39 subjects, 28 were females (71.8%), mean age 60.4. Twelve were current or past smokers (30.8%). Twelve had prior different biological treatment (30.8%), and 3/39 had more than one previous treatment (7.7%). Current biological included mepolizumab 12/39 (30.8%), dupilumab 11/39 (28.2%), benralizumab 10/39 (25.6%), omalizumab 5/39 (12.8%), reslizumab 1/39 (2.6%). Different specific criteria were achieved in 39-80% of subjects, being highest for no chronic steroid use and lowest for symptoms control and lung function. Overall remission was obtained by 20-41%, depending on definition, with significant variability in agreement between different sets of remission criteria (Cohen's kappa 0.33-0.89). CONCLUSION: Clinical remission is achievable in real-world severe asthmatics on biological therapies. The core criteria for remission should be better defined.

The humoral response to COVID-19 vaccinations can predict the booster effect on health care workers-toward personalized vaccinations?

BACKGROUND: Waning immunity after the coronavirus disease 2019 (COVID-19) vaccinations creates the constant need of boosters. Predicting individual responses to booster vaccines can help in its timely administration. We hypothesized that the humoral response to the first two doses of the BNT162b2 vaccine can predict the response to the booster vaccine. METHODS: A prospective cohort of hospital health care workers (HCW) that received three doses of the BNT162b2 vaccine. Participants completed serological tests at 1 and 6 months after the second vaccine dose and 1 month after the third. We analyzed predictive factors of antibody levels after the booster using multivariate regression analyses. RESULTS: From 289 eligible HCW, 89 (31%) completed the follow-up. Mean age was 48 (±10) and 46 (52%) had daily interaction with patients. The mean (±standard deviation) antibody level 1 month after the second vaccine was 223 (±59) AU/ml, and 31 (35%) had a rapid antibody decline (>50%) in 6 months. Low antibody levels 1 month after the second vaccine and a rapid antibody decline were independent predictors of low antibody levels after the booster vaccine. CONCLUSIONS: The characteristics of the humoral response to COVID-19 vaccinations show promise in predicting the humoral response to the booster vaccines.

Intra-Cranial Arterial Calcifications in Hemodialysis Patients.

Background and objectives: Vascular calcification is an integral part of atherosclerosis and has been reported to be an independent risk factor for cardiovascular diSsease. Intra Cranial Arterial Calcifications (ICAC) in maintenance hemodialysis (MHD) is highly prevalent. Materials and Methods: The aim of this retrospective study was to assess the predictors and outcomes of ICAC in MHD patients compared to a control group without kidney disease. A blinded neuroradiologist graded ICAC in brain imaging (computerized tomography) of MHD patients. Age- and sex-matched patients with normal kidney function served as the control group. Results: A total of 280 patients were included in the cohort; 140 of them were MHD patients with a mean ICAC score of 2.3 ± 0.2 versus a mean ICAC score of 1.4 ± 0.2 in the control group (p < 0.01). More than 90% of hemodialysis patients in our study had some degree of ICAC. Lower albumin and higher phosphorus and CRP levels were associated with increased ICACs. The multivariate analysis model for predictors of 1-year mortality demonstrated an increased odds ratio for mortality as the ICAC score increased. Conclusions: ICAC is very prevalent among MHD patients and results not simply from passive deposition of calcium and phosphate but rather from complex and active processes involving inflammation and structural changes in blood vessels. ICAC independently predicted all-cause mortality and may help with risk stratification of this high-risk population.

Transbronchial Cryobiopsy Is Superior to Forceps Biopsy for Diagnosing both Fibrotic and Non-Fibrotic Interstitial Lung Diseases.

BACKGROUND: Interstitial lung disease (ILD) evaluation often requires lung biopsy for definite diagnosis. In recent years, transbronchial cryobiopsy (TBCB) emerged as a procedure with higher diagnostic yield than transbronchial forceps biopsy (TBFB), especially for fibrotic ILDs. Nonetheless, studies comparing these modalities in non-fibrotic ILDs and for specific ILD diagnoses are scarce. OBJECTIVES: The aim of this study was to evaluate the diagnostic yield and safety of TBCB and TBFB in patients with fibrotic and non-fibrotic ILDs. METHOD: An observational retrospective multicenter study including patients with ILD diagnosis by multidisciplinary discussion that underwent TBCB or TBFB between 2017 and 2021. Chest CT scans were reviewed by a chest radiologist. Biopsy specimens were categorized as diagnostic (with specific histological pattern), nondiagnostic, or without lung parenchyma. Nondiagnostic samples were reassessed by a second lung pathologist. TBCB and TBFB diagnostic yields were analyzed by multivariate regression. Procedural complications were evaluated as well. RESULTS: 276 patients were included, 116 (42%) underwent TBCB and 160 (58%) TBFB. Fibrotic ILDs were present in 148 patients (54%). TBCB diagnostic yield was 78% and TBFB 48% (adjusted odds ratio [AOR] 4.2, 95% CI: 2.4-7.6, p < 0.01). The diagnostic yield of TBCB was higher than TBFB among patients with fibrotic ILD (AOR 3.8, p < 0.01), non-fibrotic ILD (AOR 5.8, p < 0.01), and across most ILD diagnoses. TBCB was associated with higher risk for significant bleeding (10% vs. 3%, p < 0.01), but similar risk for pneumothorax. CONCLUSIONS: Diagnostic yield of TBCB was superior to that of TBFB for both fibrotic and non-fibrotic ILDs, and across most diagnoses.

Assessment of a close respiratory follow-up schedule at 3 and 6 months after acute COVID-19 and its related investigations.

BACKGROUND: Respiratory sequela after acute COVID-19 is common and requires medical follow-up. Considering its vast economic impact, there is still no consensus regarding the mid-term follow-up plan after recovery. OBJECTIVE: To evaluate the necessity of a close pulmonary follow-up schedule after acute COVID-19 and its related investigations. METHODS: A prospective cohort study including adult patients after acute COVID-19 pneumonia. Patients were invited or referred to a 3- and 6-month follow-up visits at a large pulmonary institute in a tertiary center. Before each visit, patients completed demographic and clinical questionnaires, pulmonary function tests (PFTs), and chest CT scans. RESULTS: 168 patients were included after completing both visits (medians of 80 and 177 days). Their mean age was 58 ± 15 and 52% recovered from severe or critical COVID-19. Between the two visits, there was no change in DLCOc (mean 73 ± 18 %predicted in both visits) and FVC (mean 90 ± 16 vs. 89 ± 16 %predicted). The COPD assessment tool and modified Medical Research Council scale had inverse correlations with the DLCOc, and similarly did not change between the visits. Occupational exposures were the only factor associated with a change in DLCOc during follow-up (3% decrease, p = 0.04). An improvement in chest CT findings at the second visit was not associated with a change in PFTs. CONCLUSIONS: Most clinical variables did not change during a close follow-up schedule in the first six months after acute COVID-19. Such a follow-up plan does not appear necessary and should be personalized to limit excessive costs and resources.

Real-Life Diagnostic Performance of the Hypersensitivity Pneumonitis Guidelines: A Multicenter Cohort Study.

Hypersensitivity pneumonitis (HP) is a heterogeneous interstitial lung disease (ILD) that may be difficult to confidently diagnose. Recently, the 2020 ATS/JRS/ALAT HP diagnostic guidelines were published, yet data validating their performance in real-life settings are scarce. We aimed to assess the diagnostic performance of the HP guidelines compared to the gold-standard multidisciplinary discussion (MDD). For this purpose, we included consecutive ILD patients that underwent diagnostic bronchoscopy between 2017 and 2020 in three large medical centers. Four diagnostic factors (antigen exposure history, chest computed tomography pattern, bronchoalveolar lavage lymphocyte count, and histology results) were used to assign guidelines-based HP diagnostic confidence levels for each patient. A sensitivity analysis was performed, with MDD diagnosis as the reference standard. Overall, 213 ILD patients were included, 45 (21%) with an MDD diagnosis of HP. The guidelines' moderate (≥70%) confidence threshold produced optimal performance with 73% sensitivity for HP, 89% specificity, and a J-index of 0.62. The area under the receiver operating characteristic curve (AUC) for a correct guidelines-based diagnosis was 0.86. The guidelines had better performance for non-fibrotic than fibrotic HP (AUC 0.92 vs. 0.82). All diagnostic factors, except bronchoalveolar lavage lymphocyte count, were independent predictors for MDD diagnosis of HP in a multivariate analysis. In conclusion, the HP guidelines exhibited a good diagnostic performance compared to MDD diagnosis in real-life setting.

The Clinical Significance of LDL-Cholesterol on the Outcomes of Hemodialysis Patients with Acute Coronary Syndrome.

Background and objectives: Dyslipidemia is one of the most important modifiable risk factors in the pathogenesis of cardiovascular disease in the general population, but its importance in the hemodialysis (HD) population is uncertain. Materials and Methods: This retrospective cohort study includes HD patients hospitalized due to acute coronary syndrome (ACS) in the period 2015-2020 with lipid profile data during ACS. A control group with preserved kidney function was matched. Risk factors for 30-day and 1-year mortality were assessed. Results: Among 349 patients included in the analysis, 246 were HD-dependent ("HD group"). HD group patients had higher prevalence of diabetes, hypertension, and heart disease than the control group. At ACS hospitalization, lipid profile and chronic statin treatment were comparable between groups. Odds ratios for 30-day mortality in HD vs. control group was 5.2 (95% CI 1.8-15; p = 0.002) and for 1-year, 3.4 (95% CI 1.9-6.1; p <0.001). LDL and LDL < 70 did not change 30-day and 1-year mortality rates in the HD group (p = 0.995, 0.823, respectively). However, survival after ACS in HD patients correlated positively with nutritional parameters such as serum albumin (r = 0.368, p < 0.001) and total cholesterol (r = 0.185, p < 0.001), and inversely with the inflammatory markers C-reactive protein (CRP; r = -0.348, p < 0.001) and neutrophils-to-lymphocytes ratio (NLR; r = -0.181, p = 0.019). Multivariate analysis demonstrated that heart failure was the only significant predictor of 1-year mortality (OR 2.8, p = 0.002). LDL < 70 mg/dL at ACS hospitalization did not predict 1-year mortality in the HD group. Conclusions: Despite comparable lipid profiles and statin treatment before and after ACS hospitalization, mortality rates were significantly higher among HD group. While malnutrition-inflammation markers were associated with survival of dialysis patients after ACS, LDL cholesterol was not. Thus, our study results emphasize that better nutritional status and less inflammation are associated with improved survival among HD patients.

Interactions and clinical implications of serological and respiratory variables 3 months after acute COVID-19.

Medical follow-up of symptomatic patients after acute Coronavirus Disease 2019 (COVID-19) results in major burdens on patients and healthcare systems. The value of serological markers as part of this follow-up remains undetermined. We aimed to evaluate the clinical implications of serological markers for follow-up of acute COVID-19. For this purpose, we conducted an observational cohort study of patients 3 months after acute COVID-19. Participants visited a respiratory-clinic between October 2020 and March 2021, and completed pulmonary function tests (PFTs), serological tests, symptom-related questionnaires, and chest CT scans. Overall, 275 patients were included at a median of 82 days (IQR 64-111) post infection. 162 (59%) patients had diffusing capacity for carbon monoxide corrected for hemoglobin (DLCOc) below 80%, and 69 (25%) had bilateral chest abnormalities on CT scan. In multivariate analysis, anti-S levels were an independent predictor for DLCOc (ß = - 0.14, p = 0.036). Anti-S levels were also associated with severe COVID-19 and older age, and correlated with anti-nucleocapsid (r = 0.30, p < 0.001) and antibodies to receptor binding domain (RBD, r = 0.37, p < 0.001). Other serological variables were not associated with clinical outcomes. In conclusion, symptomatic patients 3-months after COVID-19 had high respiratory symptomatic burden, in which anti-S levels were significantly associated with previous severe COVID-19 and DLCOc.

Clinical efficacy of the fourth dose of the BNT162b2 vaccine in maintenance dialysis patients.

BACKGROUND AND OBJECTIVES: Highly effective vaccines against severe acute respiratory syndrome virus 2 have been developed and administered worldwide. However, protection from coronavirus disease 2019 is not absolute and an optimal vaccination regimen needs to be established. This study assessed the clinical efficacy of the coronavirus disease 2019 vaccine among dialysis patients receiving 3 or 4 doses of vaccine. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This retrospective study was conducted using the electronic database of Clalit Health Maintenance Organization in Israel. Chronic dialysis patients treated with either hemodialysis or peritoneal dialysis during the coronavirus disease 2019 pandemic were included. We compared clinical outcomes of patients who had received three or four doses of the severe acute respiratory syndrome virus 2 vaccine. RESULTS: This study included 1,030 patients on chronic dialysis, with a mean age of 68 ± 13 years. Among them, 502 patients had received 3 doses of the vaccine and 528 received 4 doses. Severe acute respiratory syndrome virus 2 infection rates, severe COVID-19 that resulted in hospitalizations, COVID-19-related mortality and all-cause mortality rates were lower among chronic dialysis patients who received a fourth dose of vaccine as compared to those who received only 3 doses (after controlling for age, sex and comorbidities). Despite lower mortality rates observed with the Omicron variant, the fourth dose was significantly associated with reduced COVID-19-related mortality (1.7% vs. 3.8%, p = 0.04). Odds ratio for COVID-19-related mortality was 0.44 with 95% CI 0.2-0.98. CONCLUSIONS: As seen in the general population and with previous vaccine boosters, the fourth dose of the BNT162b2 vaccine reduced rates of severe COVID-19-related hospitalization and mortality among chronic dialysis patients. Further studies are needed to establish the optimal regimens of vaccination for patients on chronic dialysis.

Dialysis modality, humoral response to vaccine, and SARS-CoV-2 infection risk: Comparative prospective evaluation.

BACKGROUND: COVID-19 vaccinations have a central role in decreasing severe SARS-CoV-2 disease complications. This study investigated the long-term humoral immune response to BNT162b2 vaccine among hemodialysis (HD) versus peritoneal dialysis (PD) patients, and their relative risk for COVID-19 infection. METHODS: This prospective, observational study included maintenance HD and PD patients who had received at least two BNT162b2 vaccine doses. Levels of antibodies targeting SARS-CoV-2 spike protein were measured 6 and 12 months after the first vaccine dose, and 2-3 weeks after the third and fourth vaccine doses. Patients were divided according to dialysis modality (HD or PD). Humoral response was evaluated at different time points among different vaccine regimens (two vs. three vs. four doses of vaccine). An adjusted multivariate model was used to assess cumulative risk for SARS-CoV-2 infection. RESULTS: Eighty-seven HD and 36 PD patients were included. Among them, 106 (86%) received at least three vaccine doses. Both HD and PD patients demonstrated marked increases in humoral response 2-3 weeks after the third dose (mean anti-S antibody increased from 452 ± 501 AU/mL to 19,556 ± 14,949 AU/mL, p < 0.001). By 6 months after the third dose, antibody titers had declined significantly (mean anti-S antibody 9841 ± 10,493 AU/mL, p < 0.001). HD patients had higher risk for SARS-CoV-2 infection than PD patients (OR 4.4 [95% CI 1.4-13.6], p = 0.006). In multivariate analysis, the most important predictor for SARS-CoV-2 infection was dialysis modality. CONCLUSION: This study found a high antibody response rate after the third and fourth doses of BNT162b2 vaccine among dialysis patients. Hemodialysis as dialysis modality is an important predictor of COVID-19 infection, despite similar humoral responses to vaccine in peritoneal dialysis.

One-year dynamics of antibody titers after three doses of SARS-CoV-2 BNT162b2 vaccine.

BACKGROUND: A third dose of the BNT162b2 SARS-CoV-2 vaccine leads to a significant increase in antibody levels, however, concerns regarding the long-term persistence of this response exist. We assessed the humoral response for one year following vaccination. METHODS: A prospective study among immunocompetent healthcare workers (HCW) who received three doses of BNT162b2. anti-spike antibody titers were measured at six predefined timepoints, from before the second vaccine dose, and up to one year afterwards, which is 4-6 months after the third dose. HCW with a history of SARS-CoV-2 infection were excluded. RESULTS: Seventy-six HCW had all the six serological measurements. Antibody titers significantly increased shortly following the third vaccine dose, and while declining, remained higher from all previous measurements for up to six months. CONCLUSIONS: A third dose of BNT162b2 leads to a profound humoral response, which remains significantly higher than previous measurements, even after 6 months.

Negative impact of high-performance flights on aviators with mitral valve prolapse.

BACKGROUND: While it appears not to affect healthy aviators' hearts, there are scarce data regarding the impact of high-performance flights on aviators with mitral valve prolapse (MVP). METHODS: A retrospective, comparative cohort study of military aviators with MVP. Subjects were categorized to either high-performance (jet fighter) or low-performance (transport and helicopter) aviators. The primary outcomes were the rates of mitral interventions and of adverse cardiovascular events since being an aircrew candidate and up to the end of flying career. Additional outcomes were echocardiographic measurements and the cumulative proportion of mitral valve interventions over time. RESULTS: Of 33 male aviators with MVP, 18 were high-performance aviators. On average, follow-up started at age 18.5 years and lasted 27.8 ±â€¯10.1 years. Baseline characteristics were similar between the study groups. Aviators of high-performance aircraft had increased rates of mitral valve surgery (33 % vs. 0, p = 0.021), MVP-related complications (39 % vs. 6.7 %, p = 0.046), and a higher incidence of mitral valve repair over time (p = 0.02). High-performance flight was associated with increased intraventricular septum thickness (IVS, 9.7 mm vs 8.9 mm, p = 0.015) and IVS index (p = 0.026) at the last echocardiographic assessment. High-performance aviators tended to develop worsening severity of mitral regurgitation. CONCLUSIONS: High-performance flight may be associated with an increased risk for valvular deterioration and need for mitral surgery in aviators with MVP.

Chylothorax associated with sarcoidosis: a review of the literature.

OBJECTIVE: To review the medical literature regarding chylothorax associated with sarcoidosis. METHODS: A literature review of all reported cases of sarcoidosis-associated chylothorax, we included a novel case report to the analysis. RESULTS: Of sixteen cases included in the study, 10 were women (62.5%), mean age 47±17years. In 6 subjects (37.5%) chylothorax was part of the initial presentation of sarcoidosis. Four subjects (25%) additionally suffered from lymphedema and chylous ascites, and one from chylous ascites only. Thoracic lymphadenopathy was reported for 13/16 subjects (81.3%) and lung parenchymal disease in 8/16 (50%). Compression of the thoracic duct was considered as a causative factor in 10 cases (62.5%). One case was attributed to granulomatous pleural inflammation, one to generalized lymphangiectasia, and no specific causative factors were identified in 4 remaining cases (25%). Overall mortality rate was 18.8% (3/16 subjects). Of note, all the subjects treated with corticosteroids survived. CONCLUSIONS: Since the association of sarcoidosis with chylothorax is exceedingly rare, alternative etiologies should be pursued even when chylothorax develops in a subject with preexisting sarcoidosis. However, the possibility of sarcoidosis should be entertained when other etiologies for a newly diagnosed chylothorax are ruled out. A multidisciplinary approach is required for optimal management, both for elucidating the diagnosis and for employing therapy, which could be multimodal. A trial of immunosuppressive therapy with corticosteroids should be considered.

Effect of aspirin on primary prevention of cardiovascular disease and mortality among patients with chronic kidney disease.

Chronic kidney disease is associated with an increased risk for cardiovascular and bleeding events. Data regarding the effectiveness and risks of aspirin therapy for primary prevention in the high-risk group of patients with chronic kidney disease are scant and controversial. This retrospective study included patients with chronic kidney disease. Participants were divided according to aspirin use. Outcomes included non-fatal cardiovascular events, major bleeding events and all-cause mortality. Among 10,303 patients, 2169 met the inclusion criteria and 1818 were included after 1:1 propensity-score matching. Our final cohort included patients with mean age of 73.4 ± 11.6 years, estimated glomerular filtration rate of 31.5 ± 10.5 ml/min/1.73m2 with follow up of 4.9 ± 1.5 years. There were no significant differences in all-cause mortality and bleeding events (odds ratio = 1.03, confidence interval [0.62, 1.84], p = .58 and odds ratio = 1.09, confidence interval [0.65, 1.72], p = .87 respectively). The incidence of cardiovascular events was higher in aspirin users versus non-users on univariate analysis (p < 0.01) and was comparable after controlling for possible risk-factors (OR = 1.05, CI [0.61, 3.14], p = .85). Chronic aspirin use for primary prevention of cardiovascular disease was not associated with lower mortality, cardiovascular events or increased bleeding among patients with chronic kidney disease. Those results were unexpected and should prompt further research in this field.