AtbFinder Diagnostic Test System Improves Optimal Selection of Antibiotic Therapy in Persons with Cystic Fibrosis.

Cystic fibrosis (CF) is characterized by mutations of CFTR that lead to increased viscous secretions, bacterial colonization, and recurrent infections. Chronic Pseudomonas aeruginosa infection in persons with CF is associated with progressive and accelerated lung function decline despite aggressive antibiotic treatment. We report the management of respiratory infections in persons with CF with antibiotic therapy that was based on the recommendations of AtbFinder, a novel, rapid, culture-based diagnostic test system that employs a novel paradigm of antibiotic selection. AtbFinder mimics bacterial interactions with antibiotics at concentrations that can be achieved in affected tissues or organs and models conditions of interbacterial interactions within polymicrobial biofilms. This open-label, single-arm, investigator-initiated clinical study was designed to identify the efficacy of antibiotics selected using AtbFinder in persons with CF. Microbiological and clinical parameters were assessed following the change of antibiotic therapy to antibiotics selected with AtbFinder between January 2016 and December 2018 and retrospectively compared with clinical data collected between January 2013 and December 2015. We enrolled 35 persons with CF (33 with chronic P. aeruginosa colonization). Antibiotics selected using AtbFinder resulted in clearance of P. aeruginosa in 81.8% of subsequent cultures, decreased pulmonary exacerbations from 1.21 per patient per annum to 0, and an increase in predicted percent predicted forced expiratory volume in 1 s up to 28.4% from baseline. The number of systemic antibiotic courses used in patients after switching to the AtbFinder-selected therapy was reduced from 355 to 178. These findings describe the superiority of antibiotic regimens selected with AtbFinder compared with routine antimicrobial susceptibility testing.

Nonbronchoscopic bronchoalveolar lavage in mechanically ventilated infants: technique, efficacy, and applications.

Bronchoalveolar lavage with the fiberoptic bronchoscope is commonly used for the diagnosis of pulmonary infections in mechanically ventilated adults and children. However, its use for intubated infants is precluded because the small artificial airway does not permit the passage of the bronchoscope. We have developed a technique for nonbronchoscopic bronchoalveolar lavage, performed via a sterile, disposable feeding tube. We have used this technique in 15 infants with diffuse interstitial disease and/or atelectasis, while they were intubated and mechanically ventilated. The volume of the lavage effluent averaged 70.3% of the volume instilled. Specific diagnosis on the basis of the cytologic evaluation and/or culture of the lavage fluid was possible in 9 (60%) patients. Two patients with atelectasis showed radiographic evidence of improvement following the procedure. There were no complications. We conclude that nonbronchoscopic bronchoalveolar lavage is well tolerated, and clinically useful in small, mechanically ventilated infants with respiratory failure due to diffuse pulmonary disease. This technique provides a lower risk alternative to more invasive, and costly procedures.

Lung function in infants with sickle cell disease.

We performed pulmonary function testing in 20 infants (11 male and 9 female; ages 3-30 months) with sickle cell disease to assess whether abnormal lung function develops early in life. Respiratory system compliance (Crs) and resistance (Rrs) were measured by the passive occlusion technique, functional residual capacity (FRC) was measured by the nitrogen washout technique, and tidal flow-volume loops and partial expiratory flow-volume curves were obtained by the thoracoabdominal compression technique to detect airway obstruction. Patients with Hb SS (Group I, n = 12) had significantly lower hemoglobin levels and a higher (but not significant) incidence of acute chest syndrome (ACS), vasoocclusive crisis (VOC), splenic sequestration, transfusions, and history of intermittent bronchospasm compared to with patients with hemoglobinopathies Hb SC, Hb Sbt and Hb SF (Group II; n = 8). Both groups had elevated FRC, decreased maximum expiratory flows at FRC (V'max,FRC), and decreased time needed to reach peak expiratory flow (tme/tE), suggesting lower airway obstruction (LAO) and hyperinflation. Restrictive disease was found in only three patients of Group I. Our findings suggest that in sickle cell disease (especially among patients with Hb SS), abnormal lung function (predominantly LAO) may be present in early infancy. Airway reactivity may play a role in the pathogenesis, but the relation to VOC or ACS remains unclear.

Pulmonary function in newborns after repair of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia that limits survival, but the nature and extent of pulmonary dysfunction in neonates with CDH have not been studied. We performed pulmonary function tests (PFTs) in eight intubated infants who survived neonatal repair of CDH (wt, 3.33 +/- 0.15 kg; age, 20.1 +/- 2.7 d; mean +/- S.E.M.). PFTs obtained from six full-term infants (wt, 3.56 +/- 0.15 kg; age, 25.0 +/- 3.3 d) with no respiratory illness served as controls. The deflation flow-volume curve technique produced maximum expiratory flow-volume (MEFV) curves, giving reproducible measurements of forced vital capacity (FVC) and maximal expiratory flow at 25% of FVC (MEF25). Respiratory system compliance (Crs) and resistance (Rrs) were obtained with a modified passive mechanics technique. In seven of eight infants PFTs were repeated after nebulized bronchodilator (0.1% isoetharine). In neonates surviving CDH repair, as compared to those with normal lung function, FVC was significantly reduced (20.78 +/- 3.32 vs. 39.83 +/- 3.30 mL.kg-1, P less than 0.05). MEF25 was also markedly reduced (20.78 +/- 3.32 vs. 39.83 +/- 3.30 mL.kg-1.s-1, P less than 0.05), indicating lower airway obstruction. After administration of nebulized bronchodilator, PFTs showed significant increases from control values in both FVC (15.9%) and MEF25 (200%) without changes in Crs and Rrs. These findings indicate that neonates with CDH have restrictive lung defects, reflecting hypoplasia. After surgical repair and mechanical ventilation airway reactivity develops, primarily in smaller airways, and this may complicate the postoperative course.

Bronchial reactivity in infants in acute respiratory failure with viral bronchiolitis.

Airway reactivity and the effects of bronchodilators in infants are controversial. We studied the response to bronchodilator treatment in 14 mechanically ventilated infants (mean age, 2.74 months; range, 0.6-5.9) in respiratory failure caused by respiratory syncytial virus (RSV)-associated bronchiolitis. Sixteen infants without lung disease, undergoing elective surgery, provided normal values. Maximum expiratory deflation flow-volume (DFV) curves were produced by manual inflation of the lungs with an anesthesia bag to a predetermined static airway pressure followed by rapid deflation with a negative airway pressure before and after administration of bronchodilator. At baseline, the bronchiolitis group had a forced vital capacity (FVC) of 34.5 +/- 3.6 ml/kg compared with 41.8 +/- 1.5 ml/kg in the normal group; maximum expiratory flow rate at 25% of FVC (MEF25) was 10.2 +/- 2.0 ml/kg/s compared with 27.3 +/- 2.0 ml/kg/s in the normal group. The clinical and radiologic impression was severe lower airway obstruction and air trapping. After administration of bronchodilator, FVC did not increase significantly, but MEF25isov increased by over 30% in 13 of 14 infants. Mean MEF25 increased by 148 +/- 43.2% to 21.7 +/- 3.9 ml/kg/s (P less than 0.02). These findings indicate that during the acute phase of severe RSV-positive bronchiolitis most infants have airway reactivity that responds positively to bronchodilator treatment.

Longitudinal follow-up of lung function from childhood to adolescence in prematurely born patients with neonatal chronic lung disease.

We investigated whether early lung function abnormalities in prematurely born children with a history of chronic lung disease improve in late childhood and adolescence. We performed a prospective, longitudinal evaluations of pulmonary function over an 8 year period. In seventeen patients from the age (mean +/- SD) of 8.2 +/- 1.2 years to the age of 15.1 +/- 1.6 years. They had been born at 29.1 +/- 1.9 weeks of gestation, with a birthweight of 1120 +/- 190 g, and they had received supplemental oxygen, with or without mechanical ventilation, for 40.4 +/- 23.8 days during the neonatal period. They all had radiographic evidence of chronic lung disease at 4 weeks of age. Annual measurements of lung volumes using the helium dilution technique, and of airway function with spirometry and maximal expiratory flow-volume curves over a 5 to 8 year period, were obtained. The results indicated that total lung capacity (TLC) and vital capacity (VC) were within the predicted normal range in all patients and increased over time. In contrast, the initially abnormal residual volume (RV) and RV/TLC ratio decreased over time, suggesting gradual resolution of air-trapping. The peak expiratory flow rate (PEFR), forced expiratory volume in 1 second (FEV1), and the ratio FEV1/FVC remained at or above the predicted normal range in all patients. FEF25-75, FEF50, and FEF75 were within normal limits in eight patients and abnormally low (more than 2 SD below the predicted normal value) in the remaining nine patients, indicating small airway obstruction. Eight of the nine patients with lower airway obstruction showed significant response to inhaled bronchodilator, and four responded to a histamine challenge. None of the eight patients with normal airway function responded to histamine, but four responded to bronchodilators. The perinatal history, family history of asthma, and exposure to smoking were similar in patients with and without airway obstruction. The height and weight were and remained within the normal range. We conclude that gradual normalization of air-trapping continues well into adolescence in virtually all patients with a history of prematurity and chronic lung disease. in contrast, airflow obstruction may persist but does not get worse later in life. Although chronic airflow obstruction probably is the consequence of injury to the small airways during the neonatal period, it is present in only some of the children, and it does not appear to be directly related to the perinatal history. Finally, there is evidence that airway hyperresponsiveness may be a contributing factor to the development and/or persistence of airflow obstruction in chronic lung disease of prematurity.

Contribution of airway hyperresponsiveness to lower airway obstruction after extracorporeal membrane oxygenation for meconium aspiration syndrome.

OBJECTIVE: To determine whether airway hyperresponsiveness contributes to the development of lower airway obstruction in infants recovering from severe meconium aspiration syndrome treated with extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective comparison study of the response to bronchodilator during the acute and convalescent phase of severe meconium aspiration. SETTING: Pediatric/neonatal intensive care unit in a tertiary care hospital. PATIENTS: Seven neonates with severe meconium aspiration syndrome that was refractory to conventional mechanical ventilation, requiring ECMO treatment. INTERVENTIONS: Evaluation of the effect of bronchodilator treatment on the airway function at a postnatal age of 14 +/- 2.7 (SEM) days, after the patients had been off ECMO for 4.6 +/- 1.4 days, and comparison with the response the same patients had shown at a postnatal age of 2.7 +/- 0.6 days, when they had been on ECMO for 1.3 +/- 0.6 days. Lung mechanics and lower airway function were measured and compared before and after administration of aerosolized isoetharine early in the course of ECMO and again several days after ECMO. Maximum expiratory flow-volume curves produced by the deflation flow-volume curve technique were used for evaluating the lower airway function, and partial passive flow-volume curves were used for measuring respiratory system compliance and resistance. MEASUREMENTS AND MAIN RESULTS: During the first test, isoetharine produced a mild increase in maximum expiratory flows at 25% (MEF25) of forced vital capacity (FVC) (48 +/- 27% compared with baseline values), without significant change in the MEF25 to FVC ratio. During the second test approximately 2 wks later (post-ECMO), isoetharine increased MEF25 by 123 +/- 29% and increased the MEF25/FVC by 40 +/- 13% compared with baseline values. The percent change in both indices was significantly higher during the second test (p < .05) than in the first test. CONCLUSIONS: Airway obstruction in infants recovering from severe meconium aspiration syndrome is partially reversible with aerosolized isoetharine, indicating that airway hyperresponsiveness contributes to the pathogenesis of airway obstruction.

Prevalence and reversibility of lower airway obstruction in children with sickle cell disease.

OBJECTIVE: To determine the prevalence and reversibility of lower airway obstruction (LAO) in children and adolescents with hemoglobin SS sickle cell disease (HbSS SCD). STUDY DESIGN: Retrospective evaluation of lung function in a cross-section of 35 African American and 28 Hispanic children and adolescents with HbSS SCD. Lung function was evaluated with maximal respiratory flow-volume curves and body plethysmography. Each patient was assigned to 1 of 3 patterns of lung function (normal, obstructive, or restrictive). Airway hyperresponsiveness was assessed by means of a trial with bronchodilator. RESULTS: Normal pattern was detected in 57% of the patients, LAO in 35%, and restrictive lung disease in 8%. Positive response to bronchodilator was documented in 30% of those with normal pattern of lung function, 78% in those with LAO, and 67% of those with restrictive lung disease. The pattern of lung function was not associated with race or with history of vaso-occlusive crises, acute chest syndrome, reactive airways disease/asthma, or long-term transfusion therapy. CONCLUSION: Obstructive lung disease possibly precedes the development of restrictive lung disease, and airway reactivity may be part of the pathogenic mechanism.

Lung mechanics during and after extracorporeal membrane oxygenation for meconium aspiration syndrome.

OBJECTIVE: To determine whether abnormalities in lung mechanics detected in infants during the acute phase of meconium aspiration syndrome persist after treatment with extracorporeal membrane oxygenation (EMCO). DESIGN: Prospective, descriptive study. Prospective evaluation of airway function and lung mechanics during and after ECMO by pulmonary function testing at 1.8 +/- 0.5 days of EMCO (period 1), follow-up at 1.4 +/- 0.2 days (period 2), and 7.0 +/- 0.9 days (period 3) after decannulation from ECMO. SETTING: Tertiary care neonatal/pediatric ICU. PATIENTS: Twelve neonates undergoing ECMO treatment for severe meconium aspiration syndrome that was refractory to conventional mechanical ventilation. INTERVENTIONS: Maximum expiratory flow-volume curves were studied with the deflation flow-volume curve technique, and compliance and resistance of the respiratory system were studied with partial passive flow-volume curves. MEASUREMENTS AND MAIN RESULTS: Respiratory system compliance was the only index of respiratory mechanics that was significantly (p less than .05) improved (0.96 +/- 0.1 vs. 0.61 +/- 0.1 mL/cm H2O/kg) immediately after decannulation from ECMO compared with period 1. Clinically important (p less than .05) improvement in forced vital capacity (28.0 +/- 5.5 vs. 16.1 +/- 1.9 mL/kg), respiratory system compliance (1.01 +/- 0.2 vs. 0.61 +/- 0.1 mL/cm H2O/kg), and maximum expiratory flow at 25%/forced vital capacity (1.0 +/- 0.3 vs. 2.2 +/- 0.3) was evident only during period 3 compared with period 1. CONCLUSIONS: We conclude that improvements in the clinical condition and oxygenation, permitting successful decannulation from ECMO, are achieved before clinically important improvements in lung mechanics.

Thoracoabdominal compression and respiratory system compliance in HIV-infected infants.

The thoracoabdominal compression technique (TAC) is used to measure expiratory flow in infants. We investigated whether TAC caused a change in total thoracic compliance (Crs), resistance (Rrs), and respiratory system time constant (Trs). We studied 41 infants (mean age, 12.4 mo; SD, 7.5) from five centers studying longitudinal lung and cardiovascular function of infants from HIV-infected mothers. We measured Crs, Rrs, and Trs before and after TAC. Changes in Crs, Rrs, and Trs after TAC were not dependent on the length of time since TAC. Crs and Trs were reduced after TAC, p = 0.013 and p = 0.003, respectively, whereas Rrs did not change. When compared with uninfected infants, HIV-infected infants had a larger post-pre TAC percent decline in Crs (p = 0.003) and a post-pre TAC rise in mean Rrs (p = 0.03). These differences remained significant after adjusting for sex and age. When performing infant pulmonary function testing, TAC itself produces a temporary decrease in Crs and Trs that is more significant in infants at risk for abnormal lung volume or compliance. Therefore, the sequence of performing the infant lung function parameters should be the same each time the testing is repeated with TAC as the last parameter tested at each testing session.

Forced expiratory flow in uninfected infants and children born to HIV-infected mothers.

The Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV (P(2)C(2) HIV) Study is a multicenter study examining pulmonary and cardiac outcomes in offspring of HIV-infected mothers. This portion of the P(2)C(2) study tests the hypothesis that infants exposed to, but uninfected by, maternal HIV have normal maximal expiratory flow at functional residual capacity (V'max,(FRC)). We obtained 500 measurements of V'max,(FRC) by rapid thoracic compression in 285 children ages 6-30 mo in five U.S. centers. The data were compared with those from a healthy cohort of children described elsewhere. V'max,(FRC) rose with height in a linear relationship. The slope of the regression line in the exposed infants did not differ statistically from the slope in the comparison group, but the intercept was about 20% lower (p < 0.001). Height and weight were comparable in the two cohorts, and the differences between intercepts persisted after adjusting for birth weight and gestational age. However, maternal HIV infection cannot be assumed to be the cause as the cohorts may have differed in other variables, such as socioeconomic status and frequency of maternal smoking and drug use. Also, measurements varied substantially within and between our five centers, probably in part because of different racial and ethnic distributions. In summary, maternal HIV infection probably has only a modest effect, if any, on maximal expiratory flow at functional residual capacity in uninfected infants.