Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19–Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity — Nine States, January–September 2021

What is already known about this topic? Previous infection with SARS-CoV-2 or COVID-19 vaccination can provide immunity and protection against subsequent SARS-CoV-2 infection and illness. What is added by this report? Among COVID-19–like illness hospitalizations among adults aged ≥18 years whose previous infection or vaccination occurred 90–179 days earlier, the adjusted odds of laboratory-confirmed COVID-19 among unvaccinated adults with previous SARS-CoV-2 infection were 5.49-fold higher than the odds among fully vaccinated recipients of an mRNA COVID-19 vaccine who had no previous documented infection (95% confidence interval = 2.75–10.99). What are the implications for public health practice? All eligible persons should be vaccinated against COVID-19 as soon as possible, including unvaccinated persons previously infected with SARS-CoV-2

Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19–Associated Hospitalizations Among Immunocompromised Adults — Nine States, January–September 2021

What is already known about this topic? Studies suggest that immunocompromised persons who receive COVID-19 vaccination might not develop high neutralizing antibody titers or be as protected against severe COVID-19 outcomes as are immunocompetent persons. What is added by this report? Effectiveness of mRNA vaccination against laboratory-confirmed COVID-19–associated hospitalization was lower (77%) among immunocompromised adults than among immunocompetent adults (90%). Vaccine effectiveness varied considerably among immunocompromised patient subgroups. What are the implications for public health practice? Immunocompromised persons benefit from COVID-19 mRNA vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive 3 doses and a booster, consistent with CDC recommendations, practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes

Accuracy of COVID-19–Like Illness Diagnoses in Electronic Health Record Data: Retrospective Cohort Study

BackgroundElectronic health record (EHR) data provide a unique opportunity to study the epidemiology of COVID-19, clinical outcomes of the infection, comparative effectiveness of therapies, and vaccine effectiveness but require a well-defined computable phenotype of COVID-19–like illness (CLI). ObjectiveThe objective of this study was to evaluate the performance of pathogen-specific and other acute respiratory illness (ARI) International Statistical Classification of Diseases-9 and -10 codes in identifying COVID-19 cases in emergency department (ED) or urgent care (UC) and inpatient settings. MethodsWe conducted a retrospective observational cohort study using EHR, claims, and laboratory information system data of ED or UC and inpatient encounters from 4 health systems in the United States. Patients who were aged ≥18 years, had an ED or UC or inpatient encounter for an ARI, and underwent a SARS-CoV-2 polymerase chain reaction test between March 1, 2020, and March 31, 2021, were included. We evaluated various CLI definitions using combinations of International Statistical Classification of Diseases-10 codes as follows: COVID-19–specific codes; CLI definition used in VISION network studies; ARI signs, symptoms, and diagnosis codes only; signs and symptoms of ARI only; and random forest model definitions. We evaluated the sensitivity, specificity, positive predictive value, and negative predictive value of each CLI definition using a positive SARS-CoV-2 polymerase chain reaction test as the reference standard. We evaluated the performance of each CLI definition for distinct hospitalization and ED or UC cohorts. ResultsAmong 90,952 hospitalizations and 137,067 ED or UC visits, 5627 (6.19%) and 9866 (7.20%) were positive for SARS-CoV-2, respectively. COVID-19–specific codes had high sensitivity (91.6%) and specificity (99.6%) in identifying patients with SARS-CoV-2 positivity among hospitalized patients. The VISION CLI definition maintained high sensitivity (95.8%) but lowered specificity (45.5%). By contrast, signs and symptoms of ARI had low sensitivity and positive predictive value (28.9% and 11.8%, respectively) but higher specificity and negative predictive value (85.3% and 94.7%, respectively). ARI diagnoses, signs, and symptoms alone had low predictive performance. All CLI definitions had lower sensitivity for ED or UC encounters. Random forest approaches identified distinct CLI definitions with high performance for hospital encounters and moderate performance for ED or UC encounters. ConclusionsCOVID-19–specific codes have high sensitivity and specificity in identifying adults with positive SARS-CoV-2 test results. Separate combinations of COVID-19-specific codes and ARI codes enhance the utility of CLI definitions in studies using EHR data in hospital and ED or UC settings

Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma: A Multicenter, Randomized, Double-Blind, Sham-Controlled Clinical Trial

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle

Long-term Comparative Immunogenicity of Protein Conjugate and Free Polysaccharide Pneumococcal Vaccines in Chronic Obstructive Pulmonary Disease

BackgroundAlthough the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.MethodsOne hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.ResultsRelative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.ConclusionsPCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points.Clinical trials registrationNCT00457977