Adrienne Prestridge

EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-α-induced pulmonary fibrosis

Transforming growth factor-alpha (TGF-alpha) is a ligand for the EGF receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. We determined the effects of EGFR tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) on the development and progression of TGF-alpha-induced pulmonary fibrosis. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-alpha expression, we determined effects of treatment with gefitinib and erlotinib on changes in lung histology, total lung collagen, pulmonary mechanics, pulmonary hypertension, and expression of genes associated with synthesis of ECM and vascular remodeling. Induction in the lung of TGF-alpha caused progressive pulmonary fibrosis over an 8-wk period. Daily administration of gefitinib or erlotinib prevented development of fibrosis, reduced accumulation of total lung collagen, prevented weight loss, and prevented changes in pulmonary mechanics. Treatment of mice with gefitinib 4 wk after the induction of TGF-alpha prevented further increases in and partially reversed total collagen levels and changes in pulmonary mechanics and pulmonary hypertension. Increases in expression of genes associated with synthesis of ECM as well as decreases of genes associated with vascular remodeling were also prevented or partially reversed. Administration of gefitinib or erlotinib did not cause interstitial fibrosis or increases in lavage cell counts. Administration of small molecule EGFR tyrosine kinase inhibitors prevented further increases in and partially reversed pulmonary fibrosis induced directly by EGFR activation without inducing inflammatory cell influx or additional lung injury.

Tricuspid regurgitant jet velocity elevation and its relationship to lung function in pediatric sickle cell disease.

Concerns about the morbidity and mortality associated with tricuspid regurgitant jet velocity (TRJV) elevation, which may indicate pulmonary hypertension (PHT), in adults with sickle cell disease (SCD) have prompted growing interest in screening the pediatric sickle cell population. The goals of our study were to estimate the prevalence of TRJV elevation and determine its relationship to pulmonary function in children and young adults with SCD at baseline. Seventy‐eight subjects (10–24 years old) with SCD underwent prospective screening by Doppler echocardiogram (ECHO), complete lung function evaluation, and laboratory testing as part of standard care at steady state. Tricuspid regurgitation was quantifiable in 68/78 (87%) subjects and peak TRJV was ≥2.5 m/sec in 26/78 (33.3%) evaluated. The frequency of obstruction, restriction, or abnormal gas exchange found on lung function evaluation was not significantly different in subjects with and without TRJV elevation. However, significant inverse correlations were observed between TRJV and both % predicted forced vital capacity (FVC) (r = −0.29, P = 0.022) and oxygen saturation (r = −0.26, P = 0.036). When compared to subjects without TRJV elevation, subjects with TRJV elevation had significantly lower % predicted forced expiratory volume in 1 sec (FEV1) (78.9 ± 14.4 vs. 86.6 ± 13.0%, P = 0.023), FVC (82.8 ± 14.1 vs. 90.7 ± 12.9%, P = 0.017), and oxygen saturation (95.8 ± 3.2 vs. 97.5 ± 2.4%, P = 0.016). We found that the combination of low hemoglobin and low % predicted FVC best predicted TRJV elevation (χ2 = 17.05, P = 0.001) in our cohort, correctly identifying 70% of cases and resulting in positive and negative predictive values of 60 and 74%, respectively. We conclude that in this young population with SCD, TRJV elevation that is not significantly associated with abnormal lung function is common at baseline. Pediatr Pulmonol. 2009; 44:281–289.

Functional capacity in children and young adults with sickle cell disease undergoing evaluation for cardiopulmonary disease

Although cardiopulmonary disease is associated with decreased functional capacity among adults with sickle cell disease (SCD), its impact on functional capacity in children with SCD is unknown. We evaluated 6‐min walk (6MW) distance in 77 children and young adults with SCD undergoing screening for cardiopulmonary disease. Of 30 subjects who also underwent cardiopulmonary exercise testing, we found evidence for decreased exercise capacity in a significant proportion. Exercise capacity was related to baseline degree of anemia and was significantly lower in subjects with a history of recurrent acute chest syndrome. We found that 6MW distance adjusted for weight and body surface area was shorter in subjects with restrictive lung disease but that only 6MW adjusted for weight remained significantly shorter when we controlled for baseline hemoglobin. Exercise capacity was not significantly different in subjects with and without cardiopulmonary disease. We conclude that restrictive lung disease is associated with shorter 6MW distances in children and young adults with SCD, but that variables associated with decreased exercise capacity, other than anemia, remain unclear. Our study underscores the importance of further delineating the direct pathophysiologic processes that contribute to decreased exercise capacity observed among individuals with SCD and cardiopulmonary disease. Am. J. Hematol., 2009.

Autoantibody to PL-12 (Anti-Alanyl-tRNA synthetase) in an African American girl with juvenile dermatomyositis and resolution of interstitial lung disease.

To the Editor: Juvenile dermatomyositis (JDM) is an immune-mediated pediatric idiopathic inflammatory myopathy (IIM) characterized by muscle and skin inflammation1. Anti-PL-12 is a myositis-specific antibody (MSA), directed against alanine-tRNA synthetase2, often with debilitating interstitial lung disease (ILD), that is sporadically reported in childhood3. We describe a child with anti-PL-12 antibody who recovered lung function after therapy. A 14-year-old African American girl developed bilateral ankle stiffness associated with swelling and redness of the upper eyelid. One month later, she noticed proximal weakness of shoulder girdle and pelvic girdle. Four months later, she had fever to 102°F; an erythematous rash over upper chest, arms, and upper eyelids; difficulty walking and getting up from bed, with shortness of breath during exertion. After admission to intensive care unit for suspected aspiration pneumonia, she was diagnosed with JDM on the basis of a muscle biopsy. She received intravenous (IV) steroid (30 mg/kg/dose) for 5 days, followed by oral prednisone (1 mg/kg/day), and was lost to followup. Six months later, she was admitted to Children’s Memorial Hospital with fever, malaise, weakness, worsening rash, and bilateral knee arthritis. Laboratory data were elevated: creatine kinase 12,464 IU/l (normal 29–165 IU/l), aldolase 150 U/l (normal 3.4–8.6 U/l), alanine transaminase 156 IU/l (normal 2–30 IU/l), aspartate transaminase 257 … Address correspondence to Dr. L.M. Pachman, Children’s Memorial Research Center, 2300 Children’s Plaza, Box 212, Chicago, IL 60614. E-mail: pachman{at}northwestern.edu

Pulmonary Function Tests in Idiopathic Inflammatory Myopathy: Association With Clinical Parameters in Children†

To determine the association of decreased lung function in children with idiopathic inflammatory myopathies (IIMs) with specific clinical parameters.

Improving Screening for Cystic Fibrosis–Related Diabetes at a Pediatric Cystic Fibrosis Program

OBJECTIVE: Despite guidelines recommending an annual oral glucose tolerance test (OGTT) for all patients with cystic fibrosis (CF) aged ≥10 years, screening rates for cystic fibrosis–related diabetes (CFRD) remained low at our center. The aim of this project was to implement an outpatient system to provide effective, evidence-based screening for CFRD at a pediatric CF program. METHODS: Development of a system to improve outpatient screening for CFRD included structured education, communication with families, and processes for scheduling laboratory appointments. The primary outcome measure was the proportion of eligible patients seen at the clinic who received an OGTT by the subsequent clinic appointment. The proportion of patients without CFRD in our program who received an OGTT within the previous 12 months was also tracked longitudinally. RESULTS: The outpatient screening rate for CFRD increased from 2% of eligible patients seen at the clinic during the 18 weeks before the start of our initiative to 78% during the 18 weeks after the start of our initiative (P < .001). The screening rate was also increased from the corresponding date range the previous year, when only 35% of eligible patients received an OGTT (P < .001). The overall percentage of patients without CFRD in our program who received an OGTT in the previous 12 months increased from 47% to 71% after implementation of our initiative (P = .003). CONCLUSIONS: A systematic, quality improvement approach effectively increased the rate of outpatient screening for CFRD at a pediatric CF program.

Successful prolonged use of recombinant human insulin-like growth factor-1 in a child with cystic fibrosis.

Growth failure is a common and complicated process in children with cystic fibrosis (CF). Growth hormone, which is becoming a more commonly used agent in such patients, has demonstrated beneficial effects aside from increased growth velocity. Recently, insulin‐like growth factor‐1 has gained significant attention in the understanding of growth failure in children with CF. We report the successful prolonged use of recombinant human insulin‐like growth factor‐1 in an adolescent boy with CF, who demonstrated significant clinical benefits from the therapy. Pediatr. Pulmonol. 2011; 46:1137–1141.

Successful use of plasmapheresis for granulomatosis with polyangiitis presenting as diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is uncommon in pediatric patients and is a rare presenting sign of granulomatosis with polyangiitis (GPA). We present the case a 14‐year‐old girl who presented with respiratory failure secondary to DAH as the initial presenting sign of GPA. Her clinical course improved after initiation of plasmapheresis therapy and she is now in clinical remission. Pediatr Pulmonol. 2013; 48:614–616.