Association Between COVID-19 Infection and Pulmonary Fibrosis: A Nested Case-Control Study.

BACKGROUND: Pulmonary fibrosis is associated with significant morbidity. Data are scarce on the link between coronavirus disease (COVID-19) and pulmonary fibrosis. We aimed to assess the association between COVID-19 with pulmonary fibrosis. METHODS: We conducted a nested case-control study in a cohort of 2,894,801 adults without a diagnosis of pulmonary fibrosis. The underlying cohort consisted of members of the largest healthcare provider in Israel aged 18 years or older as of May 1, 2020. Subjects were followed up from cohort entry until June 30, 2022, for the occurrence of pulmonary fibrosis. Ten randomly selected controls were matched to each case of pulmonary fibrosis on age, sex, and calendar time. To account for surveillance bias a lag time of 60 days was used for ascertainment of prior COVID-19 and COVID-19 severity. RESULTS: During follow-up 1284 patients were newly diagnosed with pulmonary fibrosis and matched with 12,840 controls. Multivariable conditional logistic-regression models showed that the odds ratio for pulmonary fibrosis was 1.80 (95% confidence interval, 1.47-2.19) in patients with COVID-19 compared with no COVID-19. The multivariable odds ratio for pulmonary fibrosis was 1.33 (1.06-1.68), 2.98 (1.16-7.65), and 9.30 (5.77-14.98) for mild, moderate, and severe COVID-19, respectively, compared with no COVID-19. The magnitude of the association was attenuated but remained statistically significant for severe disease when the lag time was extended to 180 days (1.08 [0.78-1.49], 2.37 [0.75-7.46], and 5.34 [2.75-10.36] for mild, moderate, and severe COVID-19, respectively). CONCLUSIONS: COVID-19 appears to be associated with an increased risk of pulmonary fibrosis and the magnitude of the association increases with COVID-19 severity.

Effectiveness of Paxlovid in Reducing Severe Coronavirus Disease 2019 and Mortality in High-Risk Patients.

BACKGROUND: Paxlovid was granted an Emergency Use Authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19), based on the interim analysis of the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial. Paxlovid effectiveness needs to be assessed in a noncontrolled setting. In this study we used population-based real-world data to evaluate the effectiveness of Paxlovid. METHODS: The database of the largest healthcare provider in Israel was used to identify all adults aged 18 years or older with first-ever positive test for severe acute respiratory syndrome coronavirus 2 between January and February 2022, who were at high risk for severe COVID-19 and had no contraindications for Paxlovid use. Patients were included irrespective of their COVID-19 vaccination status. Cox hazard regression was used to estimate the 28-day hazard ratio (HR) for severe COVID-19 or mortality with Paxlovid examined as time-dependent variable. RESULTS: Overall, 180 351 eligible patients were included; of these, only 4737 (2.6%) were treated with Paxlovid, and 135 482 (75.1%) had adequate COVID-19 vaccination status. Both Paxlovid and adequate COVID-19 vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted HRs of 0.54 (95% confidence interval [CI], .39-.75) and 0.20 (95% CI, .17-.22), respectively. Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction P < .05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status. CONCLUSIONS: This study suggests that in the era of Omicron and in real-life settings, Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality.

Effectiveness of Molnupiravir in High-Risk Patients: A Propensity Score Matched Analysis.

BACKGROUND: Molnupiravir was granted emergency use authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19). In this study, we used population-based real-world data to evaluate the effectiveness of molnupiravir. METHODS: The database of the largest healthcare provider in Israel was used to identify all adults with first-ever positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) performed in the community during January-February 2022, who were at high risk for severe COVID-19, and had no contraindications for molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status. A total of 2661 patients who received molnupiravir were propensity score matched with 2661 patients who have not received molnupiravir (control group). Patients were followed through 10 March 2022 for up to 28 days for the first occurrence of the composite severe COVID-19 or COVID-19-specific mortality. RESULTS: The composite outcome occurred in 50 patients in the molnupiravir group and 60 patients in the control group. Molnupiravir was associated with a nonsignificant reduced risk of the composite outcome: hazard ratio, 0.83 (95% confidence interval, .57-1.21). However, subgroup analyses showed that molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients 0.54 (0.34-0.86), in females 0.41 (0.22-0.77), and in patients with inadequate COVID-19 vaccination 0.45 (0.25-0.82). The results were similar when each component of the composite outcome was examined separately. CONCLUSIONS: This study suggests that in the era of Omicron and in real-life setting, molnupiravir might be effective in reducing the risk of severe COVID-19 and COVID-19-related mortality, particularly in specific subgroups.

Adherence to Guidelines in Heart Failure, Is It Valid for Elderly Patients?

BACKGROUND: Current guidelines for the treatment of heart failure with reduced ejection fraction (HFrEF) are based on studies that have excluded or underrepresented older patients. OBJECTIVES: To assess the value of guideline directed medical therapy (GDMT) in HFrEF patients 80 years of age and older. METHODS: A single-center retrospective study included patients hospitalized with a first and primary diagnosis of acute decompensated heart failure (ADHF) and ejection fraction (EF) of ≤ 40%. Patients 80 years of age and older were stratified into two groups: GDMT, defined as treatment at hospital discharge with at least two drugs of the following groups: beta-blockers, angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or mineralocorticoid antagonists; and a personalized medicine group, which included patients who were treated with up to one of these drug groups. The primary outcomes were 90-day all-cause mortality, 90-day rehospitalization, and 3-years mortality. RESULTS: The study included 1152 patients with HFrEF. 254 (22%) patients who were at least 80 years old. Of the group, 123 were GDMT at discharge. When GDMT group was compared to the personalized medicine group, there were no statistically significant differences in terms 90-day mortality (17% vs. 13%, P = 0.169), 90-day readmission (51 % vs. 45.6%, P = 0.27), or 3-year mortality (64.5% vs. 63.3%, P = 0.915). CONCLUSIONS: Adherence to guidelines in the older adult population may not have the same effect as in younger patients who were studied in the randomized clinical trials. Larger prospective studies are needed to further address this issue.

Immunity waning after COVID vaccine booster vs. infection-better than expected.

BACKGROUND: Rapid decline in antibody-titres after BNT162b2 mRNA COVID-19 vaccine was reported; thus, a booster dose, and recently a second booster were approved. The study aims to discuss immunogenicity throughout the pandemic, especially after booster dose. METHODS: A prospective study conducted in EMMS-Nazareth hospital, Israel. Anti-SARS-CoV-2 IgG antibody titres were monitored every 5 weeks starting from the vaccine's second dose. To detect symptomatic and asymptomatic infections, nasopharyngeal swabs for COVID-19 PCR were obtained bi-weekly, and on suggestive symptoms. Third dose of the vaccine was suggested for all participants 5 months after the second one. A comparison was made between those who received three doses (booster-group), and those who were infected after having two doses (infection-group) or three doses (booster-infection) group. RESULTS: One-hundred participants were included; 66 finished 14 months of follow-up, out of whom 40 received a third dose, 10 received only two doses-all were infected (mean time for infection 5 ± 12.15 weeks before the designated booster), and 12 received three doses and were infected. The mean titres of these three groups 7 months after the designated booster dose (regardless of receiving it) were 1756 ± 2279; 3483 ± 3016 and 6925 ± 3720 BAU/mL, respectively. The booster group had high titres 7 months after the booster dose, comparable to two months after the second dose (p = .69); The booster-infected group had even higher titres. CONCLUSION: Immunogenicity decline rate after the booster dose is slower than the second dose. Timing of second booster in general population is still to be determined; neutralizing-antibody titres might be helpful.

Cognitive dysfunction following COVID-19 infection.

The coronavirus (COVID-19) pandemic is still evolving, causing hundreds of millions of infections around the world. The long-term sequelae of COVID-19 and neurologic syndromes post COVID remain poorly understood. The present study aims to characterize cognitive performance in patients experiencing cognitive symptoms post-COVID infection. Patients evaluated at a post COVID clinic in Northern Israel who endorsed cognitive symptoms were referred for neurologic consultation. The neurologic work-up included detailed medical history, symptom inventory, neurological examination, the Montreal Cognitive Assessment (MoCA), laboratory tests and brain CT or MRI. Between December 2020 and June 2021, 46 patients were referred for neurological consultation (65% female), mean age 49.5 (19-72 years). On the MoCA test, executive functions, particularly phonemic fluency, and attention, were impaired. In contrast, the total MoCA score, and memory and orientation subscores did not differ from expected ranges. Disease severity, premorbid condition, pulmonary function tests and hypoxia did not contribute to cognitive performance. Cognitive decline may affect otherwise healthy patients post-COVID, independent of disease severity. Our examination identified abnormalities in executive function, attention, and phonemic fluency. These findings occurred despite normal laboratory tests and imaging findings.

Bronchial epithelium epithelial-mesenchymal plasticity forms aberrant basaloid-like cells in vitro.

Although epithelial-mesenchymal transition (EMT) is a common feature of fibrotic lung disease, its role in fibrogenesis is controversial. Recently, aberrant basaloid cells were identified in fibrotic lung tissue as a novel epithelial cell type displaying a partial EMT phenotype. The developmental origin of these cells remains unknown. To elucidate the role of EMT in the development of aberrant basaloid cells from the bronchial epithelium, we mapped EMT-induced transcriptional changes at the population and single-cell levels. Human bronchial epithelial cells grown as submerged or air-liquid interface (ALI) cultures with or without EMT induction were analyzed by bulk and single-cell RNA-Sequencing. Comparison of submerged and ALI cultures revealed differential expression of 8,247 protein coding (PC) and 1,621 long noncoding RNA (lncRNA) genes and revealed epithelial cell-type-specific lncRNAs. Similarly, EMT induction in ALI cultures resulted in robust transcriptional reprogramming of 6,020 PC and 907 lncRNA genes. Although there was no evidence for fibroblast/myofibroblast conversion following EMT induction, cells displayed a partial EMT gene signature and an aberrant basaloid-like cell phenotype. The substantial transcriptional differences between submerged and ALI cultures highlight that care must be taken when interpreting data from submerged cultures. This work supports that lung epithelial EMT does not generate fibroblasts/myofibroblasts and confirms ALI cultures provide a physiologically relevant system to study aberrant basaloid-like cells and mechanisms of EMT. We provide a catalog of PC and lncRNA genes and an interactive browser (https://bronc-epi-in-vitro.cells.ucsc.edu/) of single-cell RNA-Seq data for further exploration of potential roles in the lung epithelium in health and lung disease.

The prognostic value of heart rate at discharge in acute decompensation of heart failure with reduced ejection fraction.

AIMS: The effect of elevated heart rate (HR) on morbidity and mortality is evident in chronic stable heart failure; data in this regard in acute decompensated heart failure (ADHF) setting are scarce. In this single-centre study, we sought to address the prognostic value of HR and beta-blocker dosage at discharge on all-cause mortality among patients with heart failure and reduced ejection fraction and ADHF. METHODS AND RESULTS: In this retrospective observational study, 2945 patients were admitted for the first time with the primary diagnosis of ADHF between January 2008 and February 2018. Patients were divided by resting HR at discharge into three groups (HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m.). Evidence-based beta-blockers were defined as metoprolol, bisoprolol, and carvedilol. The doses of prescribed beta-blockers were calculated into a percentage target dose of each beta-blocker and divided to four quartiles: 0 < Dose ≤ 25%, 25% < Dose ≤ 50%, 50% < Dose ≤ 75%, and >75% of the target dose. Cox regression was used to calculate the hazard ratio for various HR categories and adjusting for clinical and laboratory variables. At discharge, 1226 patients had an HR < 70 b.p.m., 1347 patients had an HR at range 70-90 b.p.m., and 372 patients with an HR > 90 b.p.m. The 30 day mortality rate was 2.2%, 3.7%, and 12.1% (P < 0.001), respectively. Concordantly, 1 year mortality rate was 14.6%, 16.7%, and 30.4% (P < 0.001) among patients with HR < 70 b.p.m., HR 70-90 b.p.m., and HR > 90 b.p.m., respectively. The adjusted hazard ratio was significantly increased only in HR above 90 b.p.m. category (hazard ratio, 2.318; 95% confidence interval, 1.794-2.996). CONCLUSIONS: Patients with ADHF and an HR of <90 b.p.m. at discharge had significantly a lower 1 year mortality independent of the dosage of beta-blocker at discharge. It is conceivable to discharge these patients with lower HR.

COVID-19 vaccine - Long term immune decline and breakthrough infections.

BACKGROUND: Since the introduction of BNT162b2 mRNA COVID-19 vaccine by Pfizer in late 2020, efficacy and immunogenicity waning of COVID-19 vaccines was reported, and decision making regarding a booster remains a top priority worldwide, a decision that should be made based on breakthrough infection rate and antibody titer decline overtime. METHODS: We conducted a 5-month longitudinal prospective study involving vaccinated healthcare personnel, who were tested monthly for antibody titer, and sampled biweekly and on clinical indication for SARS-COV-2 polymerase chain reaction (PCR), to determine antibody decline and breakthrough infection. RESULTS: 100 participants were recruited to the study. Antibody titer reached the climate after one month of the second dose of the vaccine, and declined rapidly thereafter: the median antibody levels were 895; 22,266; 9,682; 2,554 and 1,401 AU/ml in the day of the second dose, and in one month interval thereafter, respectively. In other words, four months after vaccination, the mean antibody level was 6% of the peak levels. During the study period, 4 breakthrough infections were diagnosed, 2 of which were asymptomatic, and the remaining two were mild cases; sharp elevation of antibody titer was seen after infection. CONCLUSION: Antibody titer drops rapidly one month after the second dose of the vaccine. All infections within the study period were mild or asymptomatic, after which titer elevations were seen.

Direct antiviral agents for chronic hepatitis C virus infection improve health-related quality of life significantly in the long term.

INTRODUCTION: Direct antiviral agents (DAAs) are new drugs for the treatment of chronic hepatitis C virus (HCV) infection. These drugs are very effective and well tolerated. HCV can cause liver disease as well as extrahepatic manifestations, including a profound negative impact on health-related quality of life (HRQL). AIM OF THE STUDY: To evaluate HRQL in the long term (> 6 months after finishing treatment) after successful treatment with DAAs. To the best of our knowledge, this is the first study that evaluates quality of life in the long term after DAA treatment. MATERIAL AND METHODS: This is an observational study which included 100 patients treated with DAAs for chronic HCV infection between January 2015 and August 2018. Patients were assigned randomly. The average time after finishing treatment was 29.96 months. The Liver Disease Symptom Index (LDSI) 2.0 Questionnaire was used to evaluate quality of life before and after treatment. RESULTS: Seven of 9 parameters of the LDSI 2.0 Questionnaire showed significant improvement in the long term after successful treatment with DAAs. Two parameters (arthralgia and jaundice) did not improve significantly. Quality of life improved in both males and females similarly. Improvement did not correlate with the severity of liver fibrosis. CONCLUSIONS: Treatment with DAAs improves HRQL significantly in the long term.

Point Shear Wave Elastography for Assessing Liver Stiffness in Chronic Liver Diseases of Different Etiologies Compared to Biopsy.

BACKGROUND: Point shear-wave elastography (pSWE) is a new method to assess the degree of liver fibrosis. It has been shown to be effective in detecting stiffness in viral hepatitis. OBJECTIVES: To determine the feasibility of pSWE for assessing liver stiffness and fibrosis in liver diseases of different etiologies. METHODS: This prospective single-center study included a population of adult patients with chronic liver diseases from different etiologies, who were scheduled for liver biopsy, and a control group of healthy adults who prospectively underwent pSWE. Ten consecutive pSWE measurements of the liver were performed using a Philips iU22 ultrasound system. Stiffness degree was compared to liver biopsy results. Fibrosis degree was staged according to METAVIR scoring system. RESULTS: The study group was comprised of 202 patients who underwent liver biopsy and pSWE test and a control group consisting of 14 healthy adults who underwent pSWE for validation. In the study group, the median stiffness was 5.35 ± 3.37 kilopascal (kPa). The median stiffness for F0-1, F2, F3, and F4 as determined by liver biopsy results were 4.9 kPa, 5.4 kPa, 5.7 kPa, and 8 kPa, respectively. The median stiffness in the control group was 3.7 ± 0.6 kPa. Subgroup analyses were conducted for viral hepatitis vs. non-viral hepatitis and steatohepatitis vs. non-steatohepatitis groups. CONCLUSIONS: pSWE is a reproducible method for assessing liver stiffness and is in a linear relationship with fibrosis degree as seen in pathology. Compared with patients with non-significant fibrosis, healthy controls showed significantly lower values.

SOFA score and short-term mortality in acute decompensated heart failure.

Acute decompensated heart failure (ADHF) is one of the leading causes for hospitalization and mortality. Identifying high risk patients is essential to ensure proper management. Sequential Organ Function Assessment Score (SOFA) is considered an excellent score to predict short-term mortality in sepsis and other life-threatening conditions. To assess the capability of SOFA score in predicting short-term mortality in ADHF. We retrospectively identified patients with first hospitalization with primary diagnosis of ADHF between the years (2008-2018). The SOFA score was calculated for all patients. A total 3232 patients were included in the study. The SOFA score was significantly associated with in-hospital mortality and 30-day mortality. The odds ratios for 1-point increase in the SOFA score were 1.86 (95% CI 1.68-1.96) and 1.627 (95% CI 1.523-1.737) respectively. The SOFA Score demonstrated a good predictive accuracy. The areas under the curve of receiver operating characteristic curves for in-hospital mortality and 30-day mortality were 0.765 (95% CI 0.733-0.798) and 0.706 (95% CI 0.676-0.736) respectively. SOFA score is associated with increased risk of short-term mortality in ADHF. SOFA can be used as a complementary risk score to screen high risk patients who need strict monitoring.

ERS International Congress, Madrid, 2019: highlights from the Pulmonary Vascular Diseases Assembly.

The 2019 European Respiratory Society (ERS) International Congress, held in Madrid, Spain, had exciting sessions regarding the field of pulmonary vascular disease. The symposia related to the new ERS/European Society of Cardiology (ESC) Guidelines for the diagnosis and management of acute pulmonary embolism were well received, as were sessions on pulmonary hypertension related to lung disease, demonstrating the concept of pulmonary hypertension not being the rarity that it was previously thought to be. The use of risk stratification in relation to pulmonary arterial hypertension (PAH) was heavily featured and the scientific sessions informing the respiratory community of potential biomarkers and targets for future therapies were thought-provoking. This article discusses highlights of the 2019 pulmonary vascular disease sessions as a summary of current knowledge and practice. We have summarised the key points from the sessions pertaining to the new ERS/ESC Guidelines for the management of acute pulmonary embolism. We have also focused on prognostic factors and potential therapies in pulmonary hypertension related to interstitial lung disease. Relating to PAH, we have reviewed the symposia on risk stratification, along with the use of noninvasive measures and the sessions relating to biomarkers in PAH.

Histomorphometric Findings May Help Predicting Response in Patients with Chronic Liver Disease.

BACKGROUND: Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Several viral and host factors related to viral response have been reported in the era of treatment with pegylated (PEG)-interferon and ribavirin. OBJECTIVES: To quantify histological findings from patients with chronic HCV using computerized morphometry and to investigate whether the results can predict response to medical treatment with peg-interferon and ribavirin. METHODS: We followed 58 patients with chronic HCV infection with METAVIR score F1 and F2 in our liver unit who were grouped according to treatment response sustained viral response (SVR) and non-SVR. Liver needle biopsies from these patients were evaluated and histological variables, such as inflammatory cells, collagen fibers and liver architecture, were quantified using computerized morphometrics. The pathologist who performed the histomorphometric analysis was blinded to previous patient clinical and histological information. RESULTS: Histomorphometric variables including the density of collagen fibers were collected. The number of inflammatory cells in the portal space and textural variable were found to be statistically significant and could be used together in a formula to predict response to treatment, with a sensitivity of 93% and a 100% specificity. CONCLUSIONS: Histomorphometry may help to predict a patient's response to treatment at an early stage.