Browsing by Author "Davis, Stephanie D."

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    Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis
    (ATS, 2017-07) Shapiro, Adam J.; Josephson, Maureen; Rosenfeld, Margaret; Yilmaz, Ozge; Davis, Stephanie D.; Polineni, Deepika; Guadagno, Elena; Leigh, Margaret W.; Lavergne, Valery; Pediatrics, School of Medicine
    Rationale: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. Objectives: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. Data Sources: Ten databases were searched for reference sources from database inception through July 29, 2016. Data Extraction: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. Synthesis: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7–99.2) and specificity was 96.0% (87.9–98.7), with a positive likelihood ratio of 24.3 (7.6–76.9), a negative likelihood ratio of 0.03 (0.01–0.08), and a diagnostic odds ratio of 956.8 (141.2–6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7–98.9) and specificity of 96.4% (85.1–99.2), with a positive likelihood ratio of 26.5 (5.9–119.1), a negative likelihood ratio of 0.04 (0.01–0.12), and a diagnostic odds ratio of 699.3 (67.4–7256.0). Certainty of the evidence was graded as moderate. Conclusions: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.
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    Accuracy of Nasal Nitric Oxide Measurement as a Diagnostic Test for Primary Ciliary Dyskinesia. A Systematic Review and Meta-analysis
    (American Thoracic Society, 2017-07) Shapiro, Adam J.; Josephson, Maureen; Rosenfeld, Margaret; Yilmaz, Ozge; Davis, Stephanie D.; Polineni, Deepika; Guadagno, Elena; Leigh, Margaret W.; Lavergne, Valery; Pediatrics, School of Medicine
    RATIONALE: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. OBJECTIVES: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. DATA SOURCES: Ten databases were searched for reference sources from database inception through July 29, 2016. DATA EXTRACTION: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. SYNTHESIS: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate. CONCLUSIONS: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.
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    Association between early respiratory viral infections and structural lung disease in infants with cystic fibrosis
    (Elsevier, 2022) Sanders, Don B.; Deschamp, Ashley R.; Hatch, Joseph E.; Slaven, James E.; Gebregziabher, Netsanet; Kemner-van de Corput, Mariette; Tiddens, Harm A. W. M.; Rosenow, Tim; Storch, Gregory A.; Hall, Graham L.; Stick, Stephen M.; Ranganathan, Sarath; Ferkol, Thomas W.; Davis, Stephanie D.; Pediatrics, School of Medicine
    Background: Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF. Methods: Infants with CF were enrolled before 4 months of age. Multiplex PCR assays were performed on nasal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent CT imaging at approximately 12 months of age. Associations between Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) CT scores and respiratory viruses and symptoms were assessed with Spearman correlation coefficients. Results: Sixty infants were included for analysis. Human rhinovirus was the most common virus detected, on 28% of tested nasal swabs and in 85% of participants. The median (IQR) extent of lung fields that was healthy based on PRAGMA-CF was 98.7 (0.8)%. There were no associations between PRAGMA-CF and age at first virus, or detection of any virus, including rhinovirus, respiratory syncytial virus, or parainfluenza. The extent of airway wall thickening was associated with ever having wheezed (ρ = 0.31, p = 0.02) and number of encounters with cough (ρ = 0.25, p = 0.0495). Conclusions: Infants with CF had minimal structural lung disease. We did not find an association between respiratory viruses and CT abnormalities. Wheezing and frequency of cough were associated with early structural changes.
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    Association between early respiratory viral infections and structural lung disease in infants with cystic fibrosis
    (Elsevier, 2022-11) Sander, Don B.; Deschamp, Ashley R.; Hatch, Joseph E.; Slaven, James E.; Gebregziabher, Netsanet; Kemner-van de Corput, Mariette; Tiddens, Harm A. W. M.; Rosenow, Tim; Storch, Gregory A.; Hall, Graham L.; Stick, Stephen M.; Ranganathan, Sarath; Ferkol, Thomas W.; Davis, Stephanie D.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Background: Infants with cystic fibrosis (CF) develop structural lung disease early in life, and viral infections are associated with progressive lung disease. We hypothesized that the presence of respiratory viruses would be associated with structural lung disease on computed tomography (CT) of the chest in infants with CF. Methods: Infants with CF were enrolled before 4 months of age. Multiplex PCR assays were performed on nasal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent CT imaging at approximately 12 months of age. Associations between Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) CT scores and respiratory viruses and symptoms were assessed with Spearman correlation coefficients. Results: Sixty infants were included for analysis. Human rhinovirus was the most common virus detected, on 28% of tested nasal swabs and in 85% of participants. The median (IQR) extent of lung fields that was healthy based on PRAGMA-CF was 98.7 (0.8)%. There were no associations between PRAGMA-CF and age at first virus, or detection of any virus, including rhinovirus, respiratory syncytial virus, or parainfluenza. The extent of airway wall thickening was associated with ever having wheezed (ρ = 0.31, p = 0.02) and number of encounters with cough (ρ = 0.25, p = 0.0495). Conclusions: Infants with CF had minimal structural lung disease. We did not find an association between respiratory viruses and CT abnormalities. Wheezing and frequency of cough were associated with early structural changes.
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    Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis
    (American Thoracic Society, 2017-10) Pittman, Jessica E.; Wylie, Kristine M.; Akers, Kathryn; Storch, Gregory A.; Hatch, Joseph; Quante, Jane; Frayman, Katherine B.; Clarke, Nadeene; Davis, Miriam; Stick, Stephen M.; Hall, Graham L.; Montgomery, Gregory; Ranganathan, Sarath; Davis, Stephanie D.; Ferkol, Thomas W.; Pediatrics, School of Medicine
    RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. RESULTS: Thirty-two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.
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    Bronchopulmonary Dysplasia: Executive Summary of a Workshop
    (Elsevier, 2018-06) Higgins, Rosemary D.; Jobe, Alan H.; Koso-Thomas, Marion; Bancalari, Eduardo; Viscardi, Rose M.; Hartert, Tina V.; Ryan, Rita M.; Kallapur, Suhas G.; Steinhorn, Robin H.; Konduri, Girija G.; Davis, Stephanie D.; Thebaud, Bernard; Clyman, Ronald I.; Collaco, Joseph M.; Martin, Camilia R.; Woods, Jason C.; Finer, Neil N.; Raju, Tonse N. K.; Pediatrics, School of Medicine
    Comment in Bronchopulmonary Dysplasia: The Ongoing Search for One Definition to Rule Them All. [J Pediatr. 2018] Midlife crisis? In its 50th year, BPD redefines itself. [J Pediatr. 2018]
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    Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents
    (American Thoracic Society, 2016-08) Leigh, Margaret W.; Ferkol, Thomas W.; Davis, Stephanie D.; Lee, Hye-Seung; Rosenfeld, Margaret; Dell, Sharon D.; Sagel, Scott D.; Milla, Carlos; Olivier, Kenneth N.; Sullivan, Kelli M.; Zariwala, Maimoona A.; Pittman, Jessica E.; Shapiro, Adam J.; Carson, Johnny L.; Krischer, Jeffrey; Hazucha, Milan J.; Knowles, Michael R.; Pediatrics, School of Medicine
    Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations., Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents., Methods: Investigators at seven North American sites in the Genetic Disorders of Mucociliary Clearance Consortium prospectively and systematically assessed individuals (aged 0–18 yr) referred due to high suspicion for PCD. The investigators defined specific clinical questions for the clinical report form based on expert opinion. Diagnostic testing was performed using standardized protocols and included nasal nitric oxide measurement, ciliary biopsy for ultrastructural analysis of cilia, and molecular genetic testing for PCD-associated genes. Final diagnoses were assigned as “definite PCD” (hallmark ultrastructural defects and/or two mutations in a PCD-associated gene), “probable/possible PCD” (no ultrastructural defect or genetic diagnosis, but compatible clinical features and nasal nitric oxide level in PCD range), and “other diagnosis or undefined.” Criteria were developed to define early childhood clinical features on the basis of responses to multiple specific queries. Each defined feature was tested by logistic regression. Sensitivity and specificity analyses were conducted to define the most robust set of clinical features associated with PCD., Measurements and Main Results: From 534 participants 18 years of age and younger, 205 were identified as having “definite PCD” (including 164 with two mutations in a PCD-associated gene), 187 were categorized as “other diagnosis or undefined,” and 142 were defined as having “probable/possible PCD.” Participants with “definite PCD” were compared with the “other diagnosis or undefined” group. Four criteria-defined clinical features were statistically predictive of PCD: laterality defect; unexplained neonatal respiratory distress; early-onset, year-round nasal congestion; and early-onset, year-round wet cough (adjusted odds ratios of 7.7, 6.6, 3.4, and 3.1, respectively). The sensitivity and specificity based on the number of criteria-defined clinical features were four features, 0.21 and 0.99, respectively; three features, 0.50 and 0.96, respectively; and two features, 0.80 and 0.72, respectively., Conclusions: Systematically defined early clinical features could help identify children, including infants, likely to have PCD., Clinical trial registered with ClinicalTrials.gov (NCT00323167).
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    The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials
    (European Respiratory Society, 2018-02-16) Foong, Rachel E.; Harper, Alana J.; Skoric, Billy; King, Louise; Turkovic, Lidija; Davis, Miriam; Clem, Charles C.; Rosenow, Tim; Davis, Stephanie D.; Ranganathan, Sarath; Hall, Graham L.; Ramsey, Kathryn A.; Pediatrics, School of Medicine
    The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3-6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible.
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    Cystic fibrosis: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases
    (American Thoracic Society, 2014-04) Pittman, Jessica E.; Cutting, Garry; Davis, Stephanie D.; Ferkol, Thomas; Boucher, Richard; Pediatrics, School of Medicine
    Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF.
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    Defining and Promoting Pediatric Pulmonary Health: A NHLBI Workshop Executive Summary
    (American Academy of Pediatrics, 2023) Chmiel, James F.; Natarajan, Aruna; Banerjee, Koyeli; Fessel, Josh; Lachowicz-Scroggins, Marrah; Laposky, Aaron; Davis, Stephanie D.; Pediatrics, School of Medicine