High-Dose Inhaled Nitric Oxide As Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia Multivorans

Hindawi Case Reports in Pediatrics Volume 2020, Article ID 1536714, 6 pages https://doi.org/10.1155/2020/1536714 Case Report High-Dose Inhaled Nitric Oxide as Adjunct Therapy in Cystic Fibrosis Targeting Burkholderia multivorans Bethany L. Bartley ,1 Kelly J. Gardner,1,2 Stefano Spina ,3 Bryan P. Hurley,2,4 David Campeau,3 Lorenzo Berra,3,4 Lael M. Yonker,1,2,4 and Ryan W. Carroll 4,5 1Department of Pediatric Pulmonology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA 2%e Mucosal Immunology and Biology Research Center, Massachusetts General Hospital East, 16th Street, Charlestown, MA 02129, USA 3Department of Anesthesia, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA 4Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA 5Department of Pediatric Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA Correspondence should be addressed to Ryan W. Carroll; [email protected] Received 20 January 2020; Revised 15 April 2020; Accepted 30 April 2020; Published 25 June 2020 Academic Editor: Junji Takaya Copyright © 2020 Bethany L. Bartley et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Individuals with cystic fibrosis (CF) have persistent lung infections, necessitating the frequent use of antibiotics for pulmonary exacerbations. Some respiratory pathogens have intrinsic resistance to the currently available antibiotics, and any pathogen may acquire resistance over time, posing a challenge to CF care. Gaseous nitric oxide has been shown to have antimicrobial activity against a wide variety of microorganisms, including common CF pathogens, and offers a potential inhaled antimicrobial therapy. Case Presentation. Here, we present the case of a 16-year-old female with CF who experienced a precipitous decline in lung function over the prior year in conjunction with worsening antibiotic resistance of her primary pathogen, Burkholderia multivorans. She received 46 intermittent inhalations of 160 parts-per-million nitric oxide over a 28-day period. *e gas was administered via a mechanical ventilator fitted with nitrogen dioxide scavenging chambers. Conclusions. High-dose inhaled nitric oxide was safe, well tolerated, and showed clinical benefit in an adolescent with cystic fibrosis and pulmonary colonization with Burkholderia multivorans. 1. Introduction treatment for pulmonary hypertension in newborns using 20 parts-per-million (ppm) [4]. Off-label applications have Cystic fibrosis (CF) is a genetic disease characterized by been explored, and intermittent high-dose concentrations of recurrent lung infection and inflammation, which leads to 160 ppm have been shown to have antimicrobial activity progressive lung damage and respiratory insufficiency. against CF pathogens in vitro [5] and in an animal model [6]. Burkholderia multivorans (B. multivorans) belongs to a Inhaled intermittent dosing of 160 ppm NO was found to be group of Gram-negative bacteria known as the Burkholderia safe and well tolerated in healthy adult volunteers [7], as well cepacia (B. cepacia) complex. Bacteria from this group infect as in individuals with CF and respiratory colonization with the lungs of only 2.4% of individuals with CF [1], but have common CF pathogens including Pseudomonas aeruginosa inherent resistance to many common antibiotics, and col- (P. aeruginosa) [8] and Mycobacterium abscessus [9]. A onization often leads to a decline in lung function [2]. phase II clinical study is currently underway to evaluate the Nitric oxide (NO) plays a key role in host defense safety and efficacy of high-dose inhaled NO in adults with mechanisms in the lung and endogenous production of NO CF and chronic respiratory colonization with P. aeruginosa, is decreased in CF airways [3]. *e US Food and Drug Staphylococcus aureus, or Stenotrophomonas maltophilia Administration (FDA) initially approved inhaled NO as (ClinicalTrials.gov, Identifier: NCT02498535). Previous to 2 Case Reports in Pediatrics this report, the use of high-dose inhaled NO in an individual *e NO gas source was commercially available as with CF and pulmonary colonization with B. multivorans 850 ppm nitric oxide in nitrogen tanks that meet the En- has not been described. vironmental Protection Agency (EPA) traceability protocol requirements (Airgas Inc., Radnor Township, Pennsylvania, 2. Case Presentation USA). Oxygen, medical air, and NO were blended and in- troduced through a ventilator (Puritan Bennett 980 Series, *e patient is a 16-year-old female with CF (genotype: Medtronic, Minneapolis, Minnesota, USA) (Figure 3). A F508del/W1282X), CF-related diabetes requiring insulin, and target level of 160 ppm inhaled NO and 0.21 FiO2 were CF-related liver disease after liver transplant, who experi- delivered via a tight-fitting noninvasive mask using a enced a precipitous decline in lung function over the prior pressure support mode of 2 cmH2O driving pressure over a year, requiring frequent- near monthly -hospital admissions positive end-expiratory pressure of 5 cmH2O. Because the for intravenous antibiotics targeting her primary respiratory NO source of 850 ppm is mixed with nitrogen, the ventilator pathogen, B. multivorans. *e patient acquired this pathogen was set to a range of 0.25-0.26 FiO2, in order to deliver an in her sputum six years before, and over time, it developed FiO2 of 0.21 to the patient. increasing antibiotic resistance (Figure 1). Notably, the pa- Nitric oxide and nitrogen dioxide (NO2) analyzers were tient required long-term immunosuppressive therapy fol- attached to a sampling port proximal to the facemask and lowing liver transplant 21 months before. Her frequency of provided real-time measurements. Nitrogen dioxide, a po- hospital admission for pulmonary exacerbations remained tentially harmful gas that develops when oxygen and NO are unchanged for the first year after liver transplant but doubled mixed, was scavenged with calcium hydroxide chambers in the succeeding 9 months. Her pulmonary exacerbations (Spherasorb™, Intersurgical Ltd, Berkshire, UK), and levels would only briefly respond to a single antibiotic, intravenous remained less than 1.5 ppm in the circuit. Ambient NO and meropenem-vaborbactam. Furthermore, the patient’s weight NO2 levels were intermittently measured in the patient’s remained stagnant at the 10th percentile. room and consistently remained below EPA recommen- Female sex, body mass index ≤18 kg/m2, CF-related dations [15] at less than 4 parts-per-billion (ppb) and 12 ppb, diabetes requiring insulin, B. cepacia complex infection, and respectively. frequent pulmonary exacerbations have all been identified as *ere were no serious adverse events, and inhalations risk factors for mortality in individuals with CF and low lung were well tolerated. Echocardiograms were performed be- function [10]. Cystic fibrosis transmembrane conductance fore, during, and after the first inhalation and demonstrated regulator (CFTR) modulators have been shown to increase normal estimated pulmonary pressures. Heart rate, respi- lung function and decrease rates of pulmonary exacerbation ratory rate, oxygen saturation, and blood pressure were in individuals with CF [11, 12]; however, the patient’s ge- recorded at 5-minute intervals throughout inhalations and notype and history of liver transplantation precluded her 30 minutes after cessation. *e patient did not experience from qualifying for any CFTR modulators available at the any hemodynamic instability or significant hypoxia with 2+ time or therapeutic trials, respectively. Lung transplantation treatments. Nitric oxide oxidizes ferrous (Fe ) hemoglobin 3+ was discussed though the patient’s colonizing pathogen and into the ferric state (Fe ), known as methemoglobin. adolescent age are controversially associated with poorer Methemoglobin levels were continuously monitored during outcomes [13, 14]. inhalations using a peripheral pulse co-oximeter (Masimo TM High-dose inhaled NO administration via a mechanical Rainbow Set Technology, Irvine, CA) and never surpassed ventilator fitted with scavenging chambers was reviewed and our safety threshold of 5%. Specifically, at the end of the 30- approved under an institutional process called “Innovative minute and 60-minute inhalations, the highest recorded Diagnostics and *erapeutics,” by which independent methemoglobin levels were 3.1% and 4.1%, respectively, and hospital leadership evaluate novel approaches to the care of returned to baseline prior to subsequent treatments (Fig- individual patients. *e patient assented, and her parents ure 4). Additionally, the patient received 125 mg of ascorbic provided consent for this therapy. acid by mouth daily (on treatment days) to enhance methemoglobin reductase activity [16]. Sputum was collected prior to (days 1 and 16), midcycle 2.1. Treatment and Outcome. *e patient received a total of (days 3 and 23), and on completion (days 12 and 28) of each 46 intermittent inhalations of 160 ppm NO over a 28-day NO cycle (Figure 1). Colony forming units (CFU) were period during two separate hospital admissions: days 1–12 calculated using sputum solubilized with Sputolysin® and days 16–28 (Figure 2). During the first admission, in- (MilleporeSigma) and plated on Burkholderia cepacia iso- haled NO was given over 30-minute intervals up to three lation agar. On days 1, 12, 23, and 28, B. multivorans

Load more