Browsing by Author "Ferkol, Thomas W."

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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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    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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    Early respiratory viral infections in infants with cystic fibrosis
    (Elsevier, 2019-11) Deschamp, Ashley R.; Hatch, Joseph E.; Slaven, James E.; Gebregziabher, Netsanet; Storch, Gregory; Hall, Graham L.; Stick, Stephen; Ranganathan, Sarath; Ferkol, Thomas W.; Davis, Stephanie D.; Biostatistics, School of Public Health
    Background Viral infections contribute to morbidity in cystic fibrosis (CF), but the impact of respiratory viruses on the development of airway disease is poorly understood. Methods Infants with CF identified by newborn screening were enrolled prior to 4 months of age to participate in a prospective observational study at 4 centers. Clinical data were collected at clinic visits and weekly phone calls. Multiplex PCR assays were performed on nasopharyngeal swabs to detect respiratory viruses during routine visits and when symptomatic. Participants underwent bronchoscopy with bronchoalveolar lavage (BAL) and a subset underwent pulmonary function testing. We present findings through 8.5 months of life. Results Seventy infants were enrolled, mean age 3.1 ± 0.8 months. Rhinovirus was the most prevalent virus (66%), followed by parainfluenza (19%), and coronavirus (16%). Participants had a median of 1.5 viral positive swabs (range 0–10). Past viral infection was associated with elevated neutrophil concentrations and bacterial isolates in BAL fluid, including recovery of classic CF bacterial pathogens. When antibiotics were prescribed for respiratory-related indications, viruses were identified in 52% of those instances. Conclusions Early viral infections were associated with greater neutrophilic inflammation and bacterial pathogens. Early viral infections appear to contribute to initiation of lower airway inflammation in infants with CF. Antibiotics were commonly prescribed in the setting of a viral infection. Future investigations examining longitudinal relationships between viral infections, airway microbiome, and antibiotic use will allow us to elucidate the interplay between these factors in young children with CF.
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    Hyperinflation is Associated with Increased Respiratory Rate and is a More Sensitive Measure of Cystic Fibrosis Lung Disease During Infancy Compared to Forced Expiratory Measures
    (Wiley, 2021-09) Muston, Heather N.; Slaven, James E.; Tiller, Christina; Clem, Charles; Ferkol, Thomas W.; Ranganathan, Sarath; Davis, Stephanie D.; Ren, Clement L.; Pediatrics, School of Medicine
    Background The goal of this study was to identify clinical features associated with abnormal infant pulmonary function tests (iPFTs), specifically functional residual capacity (FRC), in infants with cystic fibrosis (CF) diagnosed via newborn screen (NBS). We hypothesized that poor nutritional status in the first 6-12 months would be associated with increased FRC at 12-24 months. Methods This study utilized a combination of retrospectively and prospectively collected data from ongoing research studies and iPFTs performed for clinical indications. Demographic and clinical features were obtained from the electronic medical record. Forced expiratory flows and volumes were obtained using the raised volume rapid thoracoabdominal technique (RVRTC) and FRC was measured via plethysmography. Results A total of 45 CF NBS infants had iPFTs performed between 12-24 months. Mean forced vital capacity, forced expiratory volume in 0.5 second, and forced expiratory flows were all within normal limits. In contrast, the mean FRC z-score was 2.18 (95%CI=1.48, 2.88) and the mean respiratory rate (RR) z-score was 1.42 (95%CI=0.95, 1.89). There was no significant association between poor nutritional status and abnormal lung function. However, there was a significant association between higher RR and increased FRC, and a RR cutoff of 36 breaths/min resulted in 92% sensitivity to detect hyperinflation with 32% specificity. Conclusions These results suggest that FRC is a more sensitive measure of early CF lung disease than RVRTC measurements and that RR may be a simple, non-invasive clinical marker to identify CF NBS infants with hyperinflation. This article is protected by copyright. All rights reserved.
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    Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype
    (American Thoracic Society, 2019-01-15) Davis, Stephanie D.; Rosenfeld, Margaret; Lee, Hye-Seung; Ferkol, Thomas W.; Sagel, Scott D.; Dell, Sharon D.; Milla, Carlos; Pittman, Jessica E.; Shapiro, Adam J.; Sullivan, Kelli M.; Nykamp, Keith R.; Krischer, Jeffrey P.; Zariwala, Maimoona A.; Knowles, Michael R.; Leigh, Margaret W.; Pediatrics, School of Medicine
    RATIONALE: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood. OBJECTIVES: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype. METHODS: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV1 and weight and height z-scores). MEASUREMENTS AND MAIN RESULTS: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV1 and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV1 and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], -1.11 [0.48] percent predicted/yr; P = 0.02). CONCLUSIONS: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.