Leveraging global multi-ancestry meta-analysis in the study of Idiopathic Pulmonary Fibrosis genetics

The research of rare and devastating orphan diseases such as Idiopathic Pulmonary Fibrosis (IPF) has been limited by the rarity of the disease itself. The prognosis is poor – the prevalence of IPF is only ∼4-times the incidence of the condition, limiting the recruitment of patients to trials and studies of the underlying biology of the disease. However, global biobanking efforts can dramatically alter the future of IPF research.Here we describe the largest meta-analysis of IPF, with 8,492 patients and 1,355,819 population controls from 13 biobanks around the globe. Finally, we combine the meta-analysis with the largest available meta-analysis of IPF so far, reaching 11,160 patients and 1,364,410 population controls in analysis.We identify seven novel genome-wide significant loci, only one of which would have been identified if the analysis had been limited to European ancestry individuals. We observe notable pleiotropy across IPF susceptibility and severe COVID-19 infection, beyond what is known to date. We also note a significant unexplained sex-heterogeneity effect at the strongest IPF locus MUC5B.

Surveillance of COVID-19 vaccine effectiveness - a real-time case-control study in southern Sweden

The extensive register infrastructure available for COVID-19 surveillance in Scania county, Sweden, makes it possible to classify cases with respect to hospitalization and disease severity, stratify on time since last dose and demographic factors, account for prior infection, and extract data for population controls automatically. Estimated vaccine effectiveness 0-3 months after the last dose remained stable during the study period but waned markedly 6 months after the last dose in older persons.

Quality of life, distress, and posttraumatic growth 5 years after colorectal cancer diagnosis according to history of inpatient rehabilitation

Purpose In Germany, almost every other colorectal cancer (CRC) patient undergoes inpatient cancer rehabilitation (ICR), but research on long-term outcomes is sparse. We aimed to assess health-related quality of life (HRQOL), distress, and posttraumatic growth among former rehabilitants and non-rehabilitants as well as respective differences and to estimate disease-related quality of life deficits in both groups. Methods HRQOL (EORTC-QLQ-C30/CR29), distress (QSC-R10), and posttraumatic growth (PTGI) were assessed according to past ICR in patients 5-year post-CRC-diagnosis in the German DACHS study. Least square mean differences in HRQOL scores and elevated distress levels (QSC-R10 > 14 points) by ICR were estimated by confounder-adjusted linear and logistic regression, respectively. Differences in PTGI scales were tested for statistical significance. EORTC-QLQ-C30 reference scores from population controls were accessed from the LinDE study to estimate disease-related deficits in both treatment groups. Results 49% of the included 1906 CRC survivors had undergone ICR. Rehabilitants reported lower HRQOL scores than non-rehabilitants in several dimensions of the EORTC-QLQ-C30/CR29. Differences were pronounced among younger survivors (< 70 years). In younger survivors, past ICR also predicted elevated distress. However, rehabilitants showed higher posttraumatic growth. When compared to 934 population controls, non-rehabilitants and older rehabilitants reported HRQOL scores (EORTC-QLQ-C30) similar to controls except higher levels of bowel dysfunctions, whereas younger rehabilitants experienced deficits regarding most scales (13/15). Conclusion Our findings suggest a high disease burden 5 years after diagnosis in particular among younger CRC survivors who had undergone ICR. Observed HRQOL deficits are possibly linked to the initial indication for ICR and rehabilitants may benefit from effective follow-up concepts after ICR.

Gestational Diabetes Mellitus Risk in Pregnant Women with Systemic Lupus Erythematosus

Objective To investigate the risk of gestational diabetes mellitus (GDM) associated with systemic lupus erythematosus (SLE) by comparing pregnancies in women with SLE to general population controls. Methods We identified singleton pregnancies among women with SLE and general population controls in the Swedish Medical Birth Register (MBR; 2006-2016), sampled from the populationbased register linkage SLINK (1987-2012). SLE was defined by ≥2 International Classification of Diseases (ICD)-coded visits in the National Patient Register (NPR) and MBR, with ≥1 visit before pregnancy. GDM was defined by ≥1 ICD-coded visit in the NPR or MBR. Glucocorticoid (GC) and hydroxychloroquine (HCQ) dispensations 6 months before and during pregnancy were identified in the Prescribed Drug Register. Risk ratios and 95% confidence intervals (RRs; 95% CI) of GDM associated with SLE were estimated using modified Poisson regression models, stratified by parity and adjusted for maternal age at delivery, year of birth, and obesity. Results We identified 695 SLE pregnancies including 18 (2.6%) with GDM and 4,644 non-SLE pregnancies including 65 (1.4%) with GDM. Adjusted RRs of GDM associated with SLE were 1.11 (95% CI 0.38-3.27) for first deliveries and 2.03 (95% CI 1.21-3.40) for all deliveries. Among SLE pregnancies, GDM occurred in 7/306 (2.3%) with ≥1 GC before and/or during pregnancy, 11/389 (2.8%) without GC, 7/287 (2.4%) with ≥1 HCQ before and/or during pregnancy, and in 11/408 (2.7%) without HCQ. Conclusion When looking at all deliveries, SLE was associated with a two-fold higher risk of GDM. GDM occurrence did not differ by GC or HCQ.

Risk of severe COVID-19 and mortality in patients with established chronic liver disease: a nationwide matched cohort study

Background and aims Some, but not all, prior studies have suggested that patients with chronic liver disease are at increased risk of contracting COVID-19 and developing more severe disease. However, nationwide data are lacking from well-phenotyped cohorts with liver histology and comparisons to matched general population controls. Methods We conducted a nationwide cohort study of all Swedish adults with chronic liver disease (CLD) confirmed by liver biopsy between 1966 and 2017 (n = 42,320), who were alive on February 1, 2020. CLD cases were matched to ≤ 5 population comparators by age, sex, calendar year and county (n = 182,147). Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 hospitalization and severe COVID-19 (intensive care admission or death due to COVID-19). Results Between February 1 and July 31, 2020, 161 (0.38%) CLD patients and 435 (0.24%) general population controls were hospitalized with COVID-19 (aHR = 1.36, 95% CI = 1.11–1.66), while 65 (0.15%) CLD patients and 191 (0.10%) controls developed severe COVID-19 (aHR = 1.08, 95% CI = 0.79–1.48). Results were similar in patients with CLD due to alcohol use, nonalcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, and other etiologies. Among patients with cirrhosis (n = 2549), the aHRs for COVID-19 hospitalization and for severe COVID-19 were 1.08 (95% CI 0.48–2.40) and 1.23 (95% CI = 0.37–4.04), respectively, compared to controls. Moreover, among all patients diagnosed with COVID-19, the presence of underlying CLD was not associated with increased mortality (aHR = 0.85, 95% CI = 0.61–1.19). Conclusions In this nationwide cohort, patients with CLD had a higher risk of hospitalization for COVID-19 compared to the general population, but they did not have an increased risk of developing severe COVID-19.

Risk of cancer among sarcoidosis patients with biopsy-verified non-necrotizing granulomatous inflammation: Population-based cohort study

Objective To assess the long-term risk of hematologic cancers, invasive solid tumors, and nonmelanoma skin cancer (NMSC) among sarcoidosis patients with biopsy-verified non-necrotizing granulomatous inflammation. Methods We used Danish administrative registers with nationwide coverage to construct a cohort of 3892 sarcoidosis patients and an age- and gender-matched comparison cohort of 38.920 population-controls. For all patients, a biopsy demonstrating non-necrotizing granulomatous inflammation had been obtained from the lower respiratory tract at time of diagnosis. Study outcome was time to diagnosis of cancer. Follow-up began at time of sarcoidosis diagnosis and continued for up to 10 years. We calculated hazard ratios (HRs) as estimates of the cancer risk among the sarcoidosis patients relative to that among the population-controls and used cumulative incidence functions to calculate absolute 10-year risk estimates. Results We observed an increased long-term risk of hematologic cancers (HR during the first 2 years of follow-up: 2.71 (95% CI: 1.18-6.25); HR after >2 years of follow-up: 2.12 (95% CI: 1.29-3.47)) and NMSC (HR after >2 years of follow-up: 1.82 (95% CI: 1.43-2.32)) among the sarcoidosis patients. An increased risk of invasive solid tumors was only observed during the first 2 years (HR: 1.55 (95% CI: 1.18-2.04)). Compared with the population-controls, the sarcoidosis patients had an increased absolute 10-year risk of hematologic cancers (risk difference: 0.56% (95% CI: 0.11%-1.01%)) and NMSC (risk difference: 1.58% (95% CI: 0.70%-2.47%)). Conclusion Sarcoidosis patients with biopsy-verified non-necrotizing granulomatous inflammation have an increased long-term risk of hematologic cancers and NMSC compared with the general population.

Rates and Predictors of Visits to Primary Care Physicians during and after Treatment of Childhood Acute Lymphoblastic Leukemia: A Population-Based Cohort Study

Introduction: Though ideal models of survivorship care are not definitively established, it has been suggested that childhood acute lymphoblastic leukemia (ALL) survivors can be cared for by properly informed primary care physicians (PCP - e.g. family physicians, community pediatricians) given low risks of late effects. PCP-driven models of care are dependent on the willingness of families to re-engage with their PCPs after a prolonged period of treatment delivered by pediatric oncologists during which PCP involvement may be minimal. We thus aimed to identify rates and predictors of PCP visits both during and after treatment among a population-based cohort of children with ALL. Methods: We identified all children &lt;18 years at diagnosis of ALL at a pediatric center in Ontario, Canada between 2002-2012. Patients were linked to healthcare data and matched to population-controls by age, sex, and geography (1:5 ratio). PCP physicians at the time of diagnosis were identified through validated algorithms using primary care billing codes and patient rosters. PCP visit rates during treatment were determined and compared between cases and controls, with cases censored at the time of relapse, stem cell transplant, or death. Post-treatment PCP visit rates were calculated among those completing frontline therapy until relapse, death, or the end of the study period. Predictors included demographic- (e.g. age, sex, socioeconomic status, distance from treatment center), disease-related (e.g. risk status, lineage), and PCP-related variables (e.g. pediatrician vs. non-pediatrician). Results: Of 801 children with ALL, 751 (93.8%) had an identified PCP at the time of diagnosis. Excluding a further 8 (1.0%) patients who did not have treatment information available resulted in 743 cases and 3,112 controls. The median age of children with ALL was 4.0 years [interquartile range (IQR) 3.0-8.0], 409 (55%) of whom were male. Nearly half of patients (361, 48.6%) did not visit their PCP during treatment. The rate of PCP visits during treatment was 0.64 per person per year (PPPY) compared to 1.4 PPPY among controls. Adjusting for age, sex, and socioeconomic status resulted in an adjusted rate ratio (aRR) of 0.47 [95th confidence interval (95CI) 0.40-0.54; p&lt;0.0001]. In multivariable analyses, no disease-related factors were associated with PCP visit rates. Infants had lower PCP visit rates during treatment (RR 0.09 vs. age 1-4 years, 95CI 0.01-0.6, p=0.01) while patients living at greatest distance from their treatment centre had higher rates (RR 1.6, 95CI 1.1-2.3, p=0.01). PCP type (pediatrician vs. other) did not have an impact on visit rates during treatment. Excluding 32 (4.3%) patients who relapsed, died, or underwent stem cell transplant prior to completing frontline therapy yielded 711 cases (survivors) and 2,973 controls available for analyses of post-treatment PCP visits. The median time of follow up after the end of treatment among survivors was 6.0 years (IQR 4.0-8.5). Though 287 (40.4%) of survivors did not visit their PCP during the post-treatment period, survivors overall still experienced greater post-treatment PCP visit rates compared to controls (aRR 1.4, 95CI 1.2-1.6; p&lt;0.0001). This was true throughout the post treatment period, with the greatest increase in visit rates compared to controls seen 10 years from the end of treatment and beyond (aRR 3.6, 95CI 1.7-7.5, p=0.0007). In multivariable analyses, survivors who had seen their PCP during active treatment had post-treatment visit rates twice as high as those who had not (aRR 2.0, 95CI 1.6-2.5; p&lt;0.0001). Survivors with pediatricians as PCPs also had higher post-treatment visit rates compared to survivors who did not (aRR 1.4, 95CI 1.1-1.8; p=0.003). Conclusions: Only a portion of children with ALL see their PCPs during treatment and return to PCP care following the completion of leukemia treatment, indicating that PCP-led survivorship care is feasible only for a subset of this population. The rate of PCP visits among survivors however continues to increase relative to general-population controls beyond 10 years after end of treatment. Post-treatment engagement with PCPs may be improved by PCP involvement during treatment, as well as in some cases the involvement of community pediatricians. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Mortality and ventricular arrhythmia after acute myocarditis: a nationwide registry-based follow-up study

ObjectiveIncidence and severity of acute myocarditis vary significantly in previous reports and there is a lack of epidemiological studies on the short-term risks of mortality, heart failure and ventricular arrhythmias in patients with acute myocarditis. Therefore, study aims were to examine 90-day risks of mortality, heart failure (HF) and ventricular arrhythmias in patients with acute myocarditis in comparison to age-matched and sex-matched background population controls.MethodsIn this nationwide register-based follow-up study of patients hospitalised with myocarditis between 2002 and 2018 in Denmark, 90-day risks of all-cause mortality, HF, ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation (VF)), cardiac arrest and implantable cardioverter-defibrillator (ICD) implantation were compared with age-matched and sex-matched controls from the background population (1:5 matching). Absolute risks standardised to the age, sex and comorbidity distribution of the entire study population were derived from multivariable Cox regression.ResultsA total of 2523 patients hospitalised with myocarditis were included. Median age was 48 years (Q1–Q3: 30–69) and 67.7% were men. Comorbidity burden was more pronounced among patients with myocarditis relative to controls. Standardised 90-day all-cause mortality risk was 4.9% for patients with acute myocarditis versus 0.3% for controls (p<0.001). Ninety-day standardised risks for other endpoints were 7.5% versus 0.1% for HF, 1.9% versus <0.1% for VF/VF/arrest risk and 1.6% versus <0.1% for ICD implantation (all p<0.001).ConclusionsIn this large nationwide register-based follow-up study, patients hospitalised with myocarditis had significantly higher 90-day risks of all-cause mortality, HF, ventricular arrhythmias, cardiac arrest and ICD implantation compared with background population controls.

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361–0.7719 and OR 0.1522; 95% CI 0.02941–0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.