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Comprehensive Cystic Fibrosis Care Provides Lifetime of Personalized Care

For more than 40 years, MassGeneral Hospital for Children (MGHfC) has provided compassionate care for patients with cystic fibrosis. Today teams of specialists at the Joey O’Donnell Cystic Fibrosis Center at MGHfC provide preventive care, active management and nutrition support for patients across their lifetime, as well as psychological support for parents, family members and patients. The MGHfC program is one of only a handful of cystic fibrosis (CF) programs nationwide that includes a psychiatrist as a member of the care team. It also offers seamless care and support as children with CF mature, including the ability to transition patients from pediatric to adult providers within one setting, organ transplant programs which include the patient’s established care team and active involvement in clinical research. In addition to participating in clinical trials of Kalydeco™ (ivacaftor), says Allen Lapey, MD, a principal investigator in the Massachusetts General Hospital Cystic Fibrosis Therapeutic Development Center, MGHfC continues to partner with the drug’s developer, Vertex Pharmaceuticals, and the Cystic Fibrosis Foundation to develop new drugs for a variety of CF-related genetic mutations.

Multidisciplinary support for patients and families MGHfC’s team of CF specialists provides quality, personalized care in a safe and supportive environment, beginning at diagnosis and spanning the lifetime. CF is a challenging disease for patients, parents and siblings, according to Anna Maria Georgiopoulos, MD,

consulting child psychiatrist for the MGHfC Cystic Fibrosis Program. Patients and caregivers are prone to depression and anxiety, and easy access to a psychiatrist with expertise in the emotional repercussions of CF helps improve coping skills. Dr. Georgiopoulos has also noted the impact of attention deficit-hyperactivity disorder (ADHD) in CF and its potential to affect medical adherence and outcomes.1 These and other studies on the relationship between CF and psychological conditions will help mitigate “adolescent slide” and stresses on family members.

Parents whose child has had a preliminary diagnosis of CF based on chorionic testing or newborn screening are seen within weeks of birth for confirmatory diagnosis using a state-of-

the-art sweat chloride testing system. Genetic counselors and physicians from the CF team are immediately available to meet with parents in the event of a positive diagnosis. The CF team includes physicians certified in pediatric pulmonololgy, pulmonary nurse coordinator, nutritionists, respiratory therapists, social workers and psychiatrist. These experts all have specialized training in the care of patients with CF. Experts in pediatric surgery, endocrinology and hepatology are readily available if needed, as are ear, nose and throat specialists from the adjoining Massachusetts Eye and Ear Infirmary. As patients mature, MGHfC providers partner with families to encourage responsible self-care, including transition to adult providers within Mass General at a time that is comfortable to both families and patients.

The hybrid video scope in use at MassGeneral Hospital for Children provides a clearer image (right) than older fiberoptic technology (left) and allows for many of the diagnostic and therapeutic capabilities previously available in the pediatric population.

In This Issue: Advancements in Pulmonary Care

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Safety protocols and state-of-the-art testing enhance pathogen identification and controlBacterial respiratory infections are a significant source of concern in patients with CF, with some strains capable of epidemic spread through local, regional, national or even international CF patient populations. At MGHfC, prevention protocols protect patients from infection while advanced imaging and therapeutic instruments, cutting-edge whole-genome sequencing technologies, a full-service microbiology laboratory, collaboration with other laboratories and CF centers and access to multidisciplinary specialists across the biomedical sciences help insure rapid identification of bacterium for appropriate antibiotic treatment regimens. These resources can also be used to identify the evolution of infections within individuals and across patient populations, helping clinicians proactively develop treatment strategies for bacterial mutations.

According to Benjamin Nelson, MD, director of pediatric bronchoscopy and associate director of the Pediatric Pulmonary Fellowship Program, the new pediatric hybrid fibervideoscopic bronchoscope is small enough to reach peripheral bronchi in patients as young as one year of age, yet has the same capabilities of the larger adult scopes. The adult-size working channel in this pediatric bronchoscope increases diagnostic yield for bronchial washings and trans-bronchial biopsies and allows for endobronchial brushings and improves suctioning capabilities. These procedures help gather cells for pathology assessment and remove secretions from the airway that are causing lung collapse or infection, especially in the CF population. In a recent case, for example, Dr. Nelson was only able to grow Staph aureus from a sample obtained

with older technology. With the hybrid scope, however, Dr. Nelson found evidence of other pathogens, allowing him to target antibiotics more appropriately and achieve a better outcome for the patient. The technology uses advantages of both video and fiberoptic technologies to produce clear, high-quality images that aid in proper diagnosis (see images). In some cases, the precision of this imaging modality can confirm that the child’s airways are healthy, thus eliminating the need for further work up. Pediatric pulmonologists no longer need to sacrifice the diagnostic and therapeutic advantages of an adult bronchoscope while performing the procedure in a child.

Research targets resistance mechanisms and novel therapeutics Clinical and basic science research efforts focus on chronic airway infection and host-pathogen interactions in CF. One study in the laboratory of Sam Moskowitz, MD, director of the Mass General CF Center, the Pediatric CF Clinical Program and of the CF Basic Science Program, is devoted to understanding the mechanisms involved in antibiotic resistance in patients infected with Pseudomonas aeruginosa (P. aeruginosa), the most common airway pathogen in CF patients.2 Many CF strains of P. aeruginosa

Comprehensive Cystic Fibrosis Care continued from page one

Sisters Cate and Laura Cheevers received the experimental drug Kalydeco™ (ivacaftor) at MassGeneral Hospital for Children (MGHfC). The drug, developed by Vertex Pharmaceuticals, counters the effect of one specific mutation that accounts for about four percent of cystic fibrosis cases in the United States. MGHfC maintains a close relationship with Vertex and other industry partners to offer promising new protocols to patients with other CF-related gene mutations.


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develop resistance to front-line therapies, causing clinicians to turn to the polymyxin family of antibiotics as a second-line of defense. However, strains of P. aeruginosa are now showing resistance to polymyxins. The Moskowitz lab concentrates on delineating the pathways involved in polymyxin resistance in CF with the goal of developing therapeutic strategies that may overcome or minimize resistance. Polymyxin resistance is emerging as an important problem in critical care medicine as well, where P. aeruginosa is associated with ventilator-assisted pneumonia. The Moskowitz lab is pursuing other projects to define how antibiotics such as azithromycin, tobramycin and ceftazidime, which are used to treat CF patients infected with P. aeruginosa, interact with organized communities of bacteria termed “biofilms.” These studies have been funded from a variety of sources, including the National Institutes of Health (NIH), and are carried out in collaboration with scientists at other US and European CF centers.

Efforts in the laboratories of Laurence Rahme, PhD, director of the molecular surgical laboratory

at Mass General, and Fred Ausubel, PhD, of the Department of Molecular Biology at Mass General, are also aimed at understanding the mechanisms of resistance and susceptibility in P. aeruginosa and other CF-related bacterial pathogens. Dr. Rahme’s group develops drugs that target virulence functions in infectious bacteria and not cell viability, thus disarming the infectious properties of the pathogen while avoiding selective pressure on pathogenic bacteria to evolve mechanisms of resistance. This approach also potentially preserves beneficial flora. To date, the Rahme lab has identified a series of compounds that are highly effective against P. aeruginosa infection in mice. Dr. Laurent is scientific founder of Spero Therapeutics, which is developing these new drugs.

Experienced evaluation and treatment of chest wall defects The Pediatric Surgery Service at MGHfC brings together a multidisciplinary team of experts in the care of infants, children and adolescents to

evaluate and repair all forms of chest defects. These defects include more common conditions such as pectus excavatum—or funnel chest—and pectus carinatum—or pigeon breast—as well as more rare or complex abnormalities of the sternum, ribs or cartilage. The team works closely with plastic and reconstructive surgeons to ensure the most normal post-surgical appearance possible.

Currently, thoracic and pediatric surgeons employ either the modified Ravitch technique or the Nuss procedure to repair pectus excavatum. They may also differ in their recommendations on the proper age for a surgical correction. MGHfC surgeons were early adopters of the Nuss procedure, a minimally invasive approach that involves two small incisions on the lateral chest and insertion of a curved metal bar under the sternum. This bar, which is custom-shaped for the patient’s chest wall, is then rotated so that the convexity is upward to correct the depression, secured to

Multidisciplinary pediatric and surgical specialists utilize the Nuss procedure to correct pectus excavatum (left) in order to achieve a more normal appearance (right) with fewer recurrences.

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Laboratory-grown Human Lung Tissue Speeds Search For New Treatments

Ivacaftor (Kalydeco), approved by the FDA in January 2012 for the treatment of cystic fibrosis (CF), targets the G551D mutation that occurs in about two percent of patients with CF. Efforts to find molecules that target other, more common, mutations associated with CF, however, have been hampered by difficulties in obtaining differentiated lung epithelium for disease modeling. Murine models of lung disease often do not phenocopy human lung disease, and access to human bronchial epithelial tissue appropriate for testing is limited.

Recently Jayaraj (Jay) Rajagopal, MD, a pulmonologist and researcher in the Massachusetts General Hospital Center for Regenerative Medicine, announced a significant step toward eliminating this problem: the ability to produce human disease-specific functioning airway epithelium from human CF induced pluripotent stem cells (iPSCs).1 This new platform, says Rajagopal, will allow scientists to study the patient-specific genetic variations that produce variability in the clinic and will also support investigations of the molecular underpinnings of other diseases, including asthma, bronchitis and brochogenic carcinoma.

Earlier efforts to create human lung disease models using iPSCs from patients with lung diseases have been hampered by the inability to convert the cells into differentiated cell types. Rajagopal and his co-investigators mimicked the timing and coordination of the signaling events at play during mouse lung development to produce multipotent embryonic lung progenitor cells and airway cells from mouse embryonic stem cells. Following the success of this experiment, they adopted the approach for human cell lines and used the cells to create functioning lung epithelium.

1Mou H, Zhao R, Sherwood R, Ahfeldt T, Lapey A, Wain J, Sicilian L, Izvolsky K, Musunuru K, Cowan C, Rajagopal J. Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem Cell. 2012 Apr 6:10(4):385-97.

1Georgiopoulos AM, Hua LL. The diagnosis and treatment of attention deficit-hyperactivity disorder in children and adolescents with cystic fibrosis: a retrospective study. Psychosomatics. 2011 Mar-Apr;52(2):160-6. 2Gutu AD, Sgambati N, Strasbourger P, Brannon MK, Jacobs MA, Haugen E, Kaul RK, Johansen HK, Høiby N, Moskowitz SM. Polymyxin resistance of Pseudomas aeruginosa phoQ mutants is dependent on additional two-component regulatory systems. Antimicrob Agents Chemother. 2013 May;57(5)2204-15. 3Lesic B, Lépine F, Déziel E, Zhang J, Zhang Q, Padfield K, Castonguay MH, Milot S, Stachel S,Tzika AA, Tompkins RG, Rahme LG. Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLos Pathog. 2007 Sep 14;3(9):1229-39.

the chest wall and/or ribs and stabilized with a lateral bar. This approach is preferred at MGHfC, according to Daniel Doody, MD, a pediatric surgeon at Mass General, because the incision is less visible than in the Ravitch technique, the surgery time is substantially shorter and patients experience reduced blood loss. In addition, the Nuss procedure results in a more normal looking chest wall than the Ravitch technique and in fewer recurrences. MGHfC has had only one retrusion in 14 years of performing the Nuss procedure.

While some surgeons recommend postponing surgery until after the adolescent growth spurt, MGHfC surgeons more frequently recommend correction for pectus excavatum earlier in adolescence, when the chest wall is more flexible. Earlier correction seems to lessen post-operative discomfort and the length of time the bar needs to remain in place, says Dr. Doody. It also helps obviate self-esteem issues related to the sunken appearance of the chest. MGHfC surgeons have also performed the Nuss procedure on older adolescents and young adults with excellent results. Close cooperation with breast

reconstruction experts ensures that young women with breast hypoplasia resulting from pectus excavatum or pectus carinatum achieve a more normal appearance.

Comprehensive Cystic Fibrosis Care continued from page three

Researcher and pulmonologist Jayaraj Rajagopal, MD, and co-investigator Hongmei Mou, PhD, produced disease-specific, functioning human airway epithelium from induced pluripotent stem cells.



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With asthma on the rise in the United States, pediatric pulmonologists at MassGeneral Hospital for Children (MGHfC) are exploring new ways to treat difficult-to-control asthma; help adolescents with asthma achieve a healthy transition to self-care; and educate patients, families and the next generation of physicians about asthma diagnosis and management. Care for infants, children and adolescents is provided by multidisciplinary teams of experts who work together to provide seamless, comprehensive testing, medication management, education and psychosocial support. Because MGHfC is fully integrated within Massachusetts General Hospital, patients can easily transition to adult care providers.

New clinic focuses on link between obesity and pulmonary conditionsObesity has long been thought to cause restrictive lung disease, but recent evidence indicates that the relationship between obesity and pulmonary function is, in fact, highly complex and goes well beyond changes in lung volumes. Three years ago, researchers established the existence of a link between asthma and obesity: not only are obese individuals more likely to have asthma than non-obese individuals, but their asthma also tends to be less responsive to standard asthma medications, particularly steroids. Moreover, obese children with asthma have more emergency department visits and longer, more frequent hospitalizations than their non-obese peers. Obesity contributes to other respiratory conditions as well, most notably sleep-disordered breathing. Rates of obesity, asthma and obstructive sleep apnea have all risen in recent years; in fact, pediatric pulmonologists at MGHfC have noted that nearly half of new patients referred for asthma are overweight or obese.

Pediatric Asthma Program Pioneers Clinical and Educational Offerings

Integrated pulmonary and weight loss program provides comprehensive clinical care and supports studies of the complex relationships between obesity and respiratory conditions.

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To help treat these patients and to shed new light on the complex relationship between obesity and the respiratory system, the Division of Pediatric Pulmonary Medicine at MGHfC has launched a specialty program for children with obesity-related pulmonary conditions. The program, called Inspired Health, was initially launched in January 2013 with an emphasis on asthma, but has recently expanded to include patients with other obesity-related conditions including sleep-disordered breathing, exercise intolerance and other causes of dyspnea. Patients may also be referred for management of obesity related to underlying respiratory conditions, medication used to treat such conditions and neuromuscular diseases. MGHfC is one of only a handful of centers nationwide with a program geared to this population. The clinic sees children of any age.

According to Christina Scirica, MD, MPH, Inspired Health director, the mission of the program is to provide coordinated, expert and individualized evaluation and management of both respiratory disorders and weight. Each patient undergoes an initial evaluation to assess current health, respiratory status, asthma control (if relevant), weight, level of conditioning and other factors that might impact care. Diagnostic testing is individualized for each patient and may include pulmonary function and cardiopulmonary exercise testing as well as other specialty diagnostic tests when indicated, including testing in the newly reopened Mass General Sleep Laboratory. Patients and families receive personalized action plans and close follow up from a physician, registered dietician and social worker with expertise in the management of obesity and pulmonary

conditions. For more information or to refer a patient, please call 617-726-8707 or email Dr. Scirica at [email protected].

“Like” asthma controlAsthma control is typically most challenging during the patient’s teenage years. These young people are just learning to take responsibility for their own health, and the influence of peers and the desire to fit in tends to replace parents as the center of influence. Two years ago, T. Bernard Kinane, MD, chief of the Pediatric Pulmonary Unit at MGHfC, decided to capitalize on adolescent peer interaction and interest in social media. Together with the Partners Center for Connected Health—a division of Partners HealthCare that uses consumer technologies to enhance the patient-physician relationship and to deliver quality care—he launched a study

Pediatric Asthma Program continued from page five

Taking tutorials to TwitterSocial media is an integral part of today’s communication. To Dr. Kinane, incorporating these modalities into teaching seemed as obvious as adding the use of telephone conversations and emails in prior decades. In addition, medical students are constantly on the move, making mobile education modules more practical than assigning a book chapter. To help determine the utility of social media in medical education, Dr. Kinane and his colleagues created a Twitter site that is only visible to tutorial coordinators and medical students. Dr. Kinane posts a case study and

picture or video every evening; students have 24 hours in which to reach a diagnosis. During the course of the day, Dr. Kinane may prompt students to consider aspects of the case they have overlooked or may suggest that they consult residents or other clinicians they interact with in the course of the day. The learning modules are easily adaptable as social media sites evolve.

MGHfC is viewed as a national leader in this new approach to education, and a recent presentation at the Council on Medical Student Education in Pediatrics (COMSEP) meeting generated significant enthusiasm.

However, cautions Dr. Kinane, educators need to consider the challenges in this educational approach as well as the opportunities. Complex problems need to be reduced to binary tasks, for example, and students must still learn to relate the small lessons learned through Twitter to the complexities of patient care. The MGHfC team will study these issues as they continue introducing new ways to use social media in medical care and education.

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First-in-Nation Pediatric Pulmonary ClinicMany lung diseases have a genetic component, with interstitial lung disease (ILD) foremost among them. ILD refers to a group of approximately 20 rare lung diseases that affect the pulmonary interstitium, which is the area between the capillaries and the alveolar space. Ordinarily, the interstitium is narrow, allowing for the efficient exchange of gas. In ILD, cells accumulate in the interstitium, increasing the thickness of this space and disrupting gas exchange. Although the disease is more common in adults—where it can be triggered by occupational exposure, drugs, radiation, tobacco exposure (primary or secondary), various connective tissue diseases or for unknown reasons—some children are born with ILD. Children’s ILD usually has a genetic basis, and the most prominent adult ILD is not found in children. Differences also exist between the treatment and prognosis of childhood ILD and adult ILD. However, since the lung tissue of children with ILD is relatively unaffected by environmental exposure or disease, it offers a “clean slate” for gene study, and important insights into adult ILD have arisen from studies in pediatric patients. T. Bernard Kinane, MD, unit chief of pediatric pulmonary and the Cystic Fibrosis Unit at MGHfC, and Daniel Shannon, MD, published some of the early papers about ILD in infants,1 paving the way to a greater understanding of the disease in both adults and children.

In a new, first-in-nation clinic called the Pediatric Pulmonary Genetics Clinic, specialists within MGHfC’s Department of Pediatric Pulmonology will provide comprehensive care for patients and families with ILD and other lung diseases of genetic origin and cost-effective diagnostic gene testing using whole genome sequencing strategies. Clinical researchers will also develop new treatment approaches based on insights developed in the clinic. The group has already created comprehensive and cost-effective genetic test panels in collaboration with the Harvard-affiliated Laboratory for Molecular Medicine at Partners Healthcare. The clinic is co-directed by Dr. Kinane and Lael Yonker, MD. A companion adult clinic is opening at Brigham and Women’s Hospital under the leadership of pulmonologist and genetic epidemiologist Benjamin Raby, MD, MPH.


Taking Tutorials to Twitter

MassGeneral Hospital for Children is a national leader in the use of Twitter tutorials in medical education. Students are given 24 hours to reach a diagnosis on case studies that are posted every evening.

of the value of an asthma Facebook page designed exclusively for individuals between the ages of 13 and 18 who have moderate-to-severe asthma.

The site, which is an actual Facebook page, is private, secured and only visible to group members. Dr. Kinane and his colleagues prompt questions or post games to stimulate interaction among the members, but mostly he says, they observe the asthma-related issues that concern teens and track whether participating on the site improves medication compliance.

The study has demonstrated the ability to engage teens and provided important insights into topics of concern to teenagers with asthma, including questions about the commonality of symptoms and the possibility of an asthma cure. Understanding these concerns will help improve and personalize care; data about the efficacy of the site in improving compliance is not yet available.

Currently more than 60 teenagers are participating in the study, which is still open for enrollment. For more information or to refer a patient, please call, 877-635-0177.

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1Kinane BT, Mansell AL, Zwerdling RG, Lapey A, Shannon DC. Follicular bronchitis in the pediatric population. Chest. 1993 Oct; 104(4):1183-6.


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In this issue:• Comprehensive Cystic Fibrosis

Care Provides Lifetime of Personalized Care

• Pediatric Asthma Program Pioneers Clinical and Educational Offerings

• Outpatient Testing for Primary Ciliary Dyskinesia

In This Issue: Advancements in Pulmonary CareThis issue of Cascades highlights recent progress in research, training and clinical care within the Division of Pediatric Pulmonology at MassGeneral Hospital for Children (MGHfC). MGHfC cystic fibrosis (CF) specialists have developed new approaches to pathogen identification and infection prevention and control, including studies of the pathways involved in P. aeruginosa resistance to polymyxins. Separate investigations have led to the ability to produce functioning, disease-specific airway epithelium from human CF stem cells, a breakthrough that facilitates disease modeling and treatment development by allowing scientists greater access to tissue that mimicks the gene variability seen in the clinic.

MGHfC pulmonologists are among the first in the country to use social networking to reduce “adolescent slide” in teenagers with asthma and to use

Twitter tutorials to educate the next generation of pediatric pulmonologists. The division’s new clinics include a specialty program to study the complex relationships between obesity and pulmonary function and a first-in-nation Pediatric Pulmonary Genetics Clinic that provides comprehensive care and cost-effective diagnostic gene sequencing for patients and families with genetically based lung diseases. Insights into these diseases in the pediatric population may pave the way to better understanding of related diseases in adults as well as produce new treatment options for infants and children.

These new programs exist within a well-established multidisciplinary group of practitioners with a history of comprehensive consultation, diagnostic and management services for a wide array of pulmonary conditions.


Cascades Fall 2013 Newsletter to Physicians

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