Telemedicine Chapter 6: Telemedicine and Cystic Fibrosis

This chapter is part of Literature reviews carried out for the Heath Service Executive National Telehealth Steering Group April – July 2020

Randomised Controlled Trials

Lechtzin, Noah et al (2017) [Randomised Controlled Trial] Home Monitoring of Patients With Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study Results[1]

Rationale: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life. Objectives: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects. Methods: We conducted a multi-center, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms. Measurements and main results: The primary outcome was the 52-week change in FEV1. Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms. Conclusions: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with (NCT01104402).

Lechtzin, Noah et al (2013) [Randomised Controlled Trial] Rationale and Design of a Randomized Trial of Home Electronic Symptom and Lung Function Monitoring to Detect Cystic Fibrosis Pulmonary Exacerbations: The Early Intervention in Cystic Fibrosis Exacerbation (eICE)Trial[2]

Background: Acute pulmonary exacerbations are central events in the lives of individuals with cystic fibrosis (CF). Pulmonary exacerbations lead to impaired lung function, worse quality of life, and shorter survival. We hypothesized that aggressive early treatment of acute pulmonary exacerbation may improve clinical outcomes. Purpose: Describe the rationale of an ongoing trial designed to determine the efficacy of home monitoring of both lung function measurements and symptoms for early detection and subsequent early treatment of acute CF pulmonary exacerbations. Study Design: A randomized, non-blinded, multi-center trial in 320 individuals with CF aged 14 years and older. The study compares usual care to a twice a week assessment of home spirometry and CF respiratory symptoms using an electronic device with data transmission to the research personnel to identify and trigger early treatment of CF pulmonary exacerbation. Participants will be enrolled in the study for 12 months. The primary endpoint is change in FEV1 (L)from baseline to 12 months determined by a linear mixed effects model incorporating all quarterly FEV1 measurements. Secondary endpoints include time to first acute protocol-defined pulmonary exacerbation, number of acute pulmonary exacerbations, number of hospitalization days for acute pulmonary exacerbation, time from the end of acute pulmonary exacerbation to onset of subsequent pulmonary exacerbation, change in health related quality of life, change in treatment burden, change in CF respiratory symptoms, and adherence to the study protocol. Conclusions: This study is a first step in establishing alternative approaches to the care of CF pulmonary exacerbations. We hypothesize that early treatment of pulmonary exacerbations has the potential to slow lung function decline, reduce respiratory symptoms and improve the quality of life for individuals with CF.

Murgia, F et al (2015) [Randomised Controlled Trial] Telemedicine home program in patients with cystic fibrosis: Results after 10 years[3]

Objectives: We studied the effect of telehomecare (THC)in a group of cystic fibrosis (CF) patients. Materials and Methods: Forced Expiratory Volume in the first second (FEV1) was monitored at home, with the aim of an early recognition of the relapses of pulmonary infections. FEV1 was monitored for 4.5 years, using THC as a tool, in addition to the standard therapeutic protocol. 16 CF patients were followed by doctors experts in the treatment of CF, over a period of 4.5 years. We compared a control group among patients seen in the past for an identical period, matching for number, age, sex, respiratory function, bacterial colonization, O2 dependency, and complications. 16 CF patients with similar characteristics of age, degree of pulmonary involvement, bacterial colonization and O2 dependency. We calculated the annual mean values of FEV1 in both groups. Results: Spirometry data showed a significant improvement in annual Fev1 mean values for the THC patients as compared to the control group. Discussion: The data are encouraging for a possible role of Telemedicine as a tool for domestic assistance of patients affected by chronic diseases, such as CF. However, reliable data on the long-term effectiveness of the use of THC in the treatment of CF patients is still lacking. The time has come to obtain reliable data through a multi-center collaboration study, also in order to standardize the international Telemedicine protocols.


Calthorpe, Rebecca Jane et al (2020) [Review] Using Digital Technology for Home Monitoring, Adherence and Self-Management in Cystic Fibrosis: A State-Of-The-Art Review[4]

Digital healthcare is a rapidly growing healthcare sector. Its importance has been recognised at both national and international level, with the WHO recently publishing its first global strategy for digital health. The use of digital technology within cystic fibrosis (CF) has also increased. CF is a chronic, life-limiting condition, in which the treatment burden is high and treatment regimens are not static. Digital technologies present an opportunity to support the lives of people with CF. We included 59 articles and protocols in this state-of-the-art review, relating to 48 studies from 1999 until 2019. This provides a comprehensive overview of the expansion and evolution of the use of digital technology. Technology has been used with the aim of increasing accessibility to healthcare, earlier detection of pulmonary exacerbations and objective electronic adherence monitoring. It may also be used to promote adherence and self-management through education, treatment management Apps and social media. Competing interests: ARS has provided consultancy for Vertex and holds a current unrestricted research grant from Vertex. He has taken part in clinical trials sponsored by Vertex, Raptor and Insmed. He has given lectures at meetings sponsored by Teva and Vertex.

Compton, Martina et al (2020) [Feasibility Study] A Feasibility Study of Urgent Implementation of Cystic Fibrosis Multidisciplinary Telemedicine Clinic in the Face of COVID-19 Pandemic: Single-Center Experience[5]

Introduction: The coronavirus 2019 (COVID-19) pandemic has become a major world health problem. All US states have advised their cystic fibrosis (CF) populations to socially isolate. Major health care payors such as Medicare and most private insurance companies have agreed to reimburse health care providers for telemedicine and telephone visits. Methods: The CF adult team at the University of Virginia (UVA)transitioned from face-to-face clinics to multidisciplinary telemedicine clinics by using WebEx®, a Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliant platform. Interventions: Patients were contacted before scheduled visits and triaged into: 1. patients eligible for the multidisciplinary telemedicine clinic; 2. patients to be seen in clinic urgently due to acute needs; and 3. stable patients who can be rescheduled at a later time. Ineligible patients for the telemedicine clinic due to lack of access to technology were followed up via telephone. Results: A total of 63 patients were scheduled to be seen in the UVA clinic over 4 weeks, 10 clinic days. Of these patients, 20 (32%) rescheduled their appointment. In addition, 2 patients (3%) were seen in clinic for acute needs and 38 (60%) were seen by the multidisciplinary team through telemedicine. Conclusions: In the context of the COVID-19 pandemic, implementing a telemedicine clinic process that serves the needs of a multidisciplinary care team is paramount to preserving the CF care model. Through a systematic design and test process, a feasible and sustainable program was created that can be utilized by other multidisciplinary programs to adapt to their context.

Cuartero, Maria et al (2019) Wearable Potentiometric Sensors for Medical Applications[6]

Wearable potentiometric sensors have received considerable attention owing to their great potential in a wide range of physiological and clinical applications, particularly involving ion detection in sweat. Despite the significant progress in the manner that potentiometric sensors are integrated in wearable devices, in terms of materials and fabrication approaches, there is yet plenty of room for improvement in the strategy adopted for the sample collection. Essentially, this involves a fluidic sampling cell for continuous sweat analysis during sport performance or sweat accumulation via iontophoresis induction for one-spot measurements in medical settings. Even though the majority of the reported papers from the last five years describe on-body tests of wearable potentiometric sensors while the individual is practicing a physical activity, the medical utilization of these devices has been demonstrated on very few occasions and only in the context of cystic fibrosis diagnosis. In this sense, it may be important to explore the implementation of wearable potentiometric sensors into the analysis of other biofluids, such as saliva, tears and urine, as herein discussed. While the fabrication and uses of wearable potentiometric sensors vary widely, there are many common issues related to the analytical characterization of such devices that must be consciously addressed, especially in terms of sensor calibration and the validation of on-body measurements. After the assessment of key wearable potentiometric sensors reported over the last five years, with particular attention paid to those for medical applications, the present review offers tentative guidance regarding the characterization of analytical performance as well as analytical and clinical validations, thereby aiming at generating debate in the scientific community to allow for the establishment of well-conceived protocols.

Gao, Wei et al (2019) Flexible Electronics Toward Wearable Sensing[7]

Wearable sensors play a crucial role in realizing personalized medicine, as they can continuously collect data from the human body to capture meaningful health status changes in time for preventive intervention. However, motion artifacts and mechanical mismatches between conventional rigid electronic materials and soft skin often lead to substantial sensor errors during epidermal measurement. Because of its unique properties such as high flexibility and conformability, flexible electronics enables a natural interaction between electronics and the human body. In this Account, we summarize our recent studies on the design of flexible electronic devices and systems for physical and chemical monitoring. Material innovation, sensor design, device fabrication, system integration, and human studies employed toward continuous and noninvasive wearable sensing are discussed. A flexible electronic device typically contains several key components, including the substrate, the active layer, and the interface layer. The inorganic-nanomaterials-based active layer prepared by a physical transfer or solution process is shown to have good physicochemical properties, electron/hole mobility, and mechanical strength. Flexible electronics based on the printed and transferred active materials has shown great promise for physical sensing. For example, integrating a nanowire transistor array for the active matrix and a conductive pressure-sensitive rubber enables tactile pressure mapping; tactile-pressure-sensitive e-skin and organic light-emitting diodes can be integrated for instantaneous pressure visualization. Such printed sensors have been applied as wearable patches to monitor skin temperature, electrocardiograms, and human activities. In addition, liquid metals could serve as an attractive candidate for flexible electronics because of their excellent conductivity, flexibility, and stretchability. Liquid-metal-enabled electronics based on liquid-liquid heterojunctions and embedded microchannels have been utilized to monitor a wide range of physiological parameters: eg pulse and temperature. Despite the rapid growth in wearable sensing technologies, there is an urgent need for the development of flexible devices that can capture molecular data from the human body to retrieve more insightful health information.

We have developed a wearable and flexible sweat-sensing platform toward real-time multiplexed perspiration analysis. An integrated iontophoresis module on a wearable sweat sensor could enable autonomous and programmed sweat extraction. A microfluidics-based sensing system was demonstrated for sweat sampling, sensing, and sweat rate analysis. Roll-to-roll gravure printing allows for mass production of high-performance flexible chemical sensors at low cost. These wearable and flexible sweat sensors have shown great promise in dehydration monitoring, cystic fibrosis diagnosis, drug monitoring, and noninvasive glucose monitoring. Future work in this field should focus on designing robust wearable sensing systems to accurately collect data from the human body and on large-scale human studies to determine how the measured physical and chemical information relates to the individual’s specific health conditions. Further research in these directions, along with the large sets of data collected via these wearable and flexible sensing technologies, will have a significant impact on future personalized healthcare.

Lee, Eun Kwang et al (2019) [Review] Skin-Mountable Biosensors and Therapeutics: A Review[8]

Miniaturization of electronic components and advances in flexible and stretchable materials have stimulated the development of wearable health care systems that can reflect and monitor personal health status by health care professionals. New skin-mountable devices that offer seamless contact onto the human skin, even under large deformations by natural motions of the wearer, provide a route for both high-fidelity monitoring and patient-controlled therapy. This article provides an overview of several important aspects of skin-mountable devices and their applications in many medical settings and clinical practices. We comprehensively describe various transdermal sensors and therapeutic systems that are capable of detecting physical, electrophysiological, and electrochemical responses and/or providing electrical and thermal therapies and drug delivery services, and we discuss the current challenges, opportunities, and future perspectives in the field. Finally, we present ways to protect the embedded electronic components of skin-mountable devices from the environment by use of mechanically soft packaging materials.

Martinez-Millana, Antonio et al (2019)[Mixed-Methods Study] The Potential of Self-Management mHealth for Pediatric Cystic Fibrosis: Mixed-Methods Study for Health Care and App Assessment[9]

Background: Remote care services and patient empowerment have boosted mobile health. A study of user needs related to mHealth for pediatric cystic fibrosis (PCF)identified the set of preferred features mobile apps should support; however, the potential use of PCF apps and their suitability to fit into PCF clinical management remains unexplored. Objective: We examine whether PCF holds potential for the implementation of mHealth care. Methods: The study is based on a literature review and qualitative analysis of content and was conducted in two parts: 1. we reviewed scientific and gray literature to explore how European countries manage PCF and conducted a qualitative study of 6 PCF units; and 2. we performed a systematic review of apps available in the repository searching for cystic fibrosis (CF) management and nutrition apps, which we analyzed for characteristics, business models, number of downloads, and usability. Results: European CF routine care guidelines are acknowledged in most European countries, and treatments are fully covered in almost all countries. The majority of teams in CF units are interdisciplinary. With respect to the systematic review of apps, we reviewed 12 apps for CF management and 9 for general nutrition management in the directory. All analyzed apps provided functionalities for recording aspects related to the disease and nutrition such as medication, meals, measurements, reminders, and educational material. None of the apps reviewed in this study supported pancreatic enzyme replacement therapy. CF apps proved to be less appealing and usable than nutrition apps (2.66 [SD 1.15] vs 4.01 [SD 0.90]; P<.001, z-value: -2.6). User needs detected in previous research are partially matched by current apps for CF management. Conclusions: The health care context for PCF is a unique opportunity for the adoption of mHealth. Well-established clinical guidelines, heterogeneous clinical teams, and coverage by national health care systems provide a suitable scenario for the use of mHealth solutions. However, available apps for CF self-management do not cover essential aspects such as nutrition and education. To increase the adoption of mHealth for CF self-management, new apps should include these features. International registered report identifier (irrid): RR2-10.1136/bmjopen-2016-014931.

Wood, Jamie et al (2019)High Usability of a Smartphone Application for Reporting Symptoms in Adults With Cystic Fibrosis[10]

Introduction: In cystic fibrosis, exacerbations impair lung function and health-related quality of life, increase healthcare costs and reduce survival. Delayed reporting of worsening symptoms can result in more severe exacerbations and worse clinical outcomes; therefore, there is a need for a novel approach to facilitate the early identification and treatment of exacerbations in this population. This study investigated the usability of a smartphone application to report symptoms in adults with cystic fibrosis, and the observer agreement in clinical decision-making between senior clinicians interpreting smartphone application responses. Methods: Adults with cystic fibrosis used the smartphone application weekly for four weeks. The application comprised 10 yes/no questions regarding respiratory symptoms and two regarding emotional well-being. Usability was measured with the System Usability Scale; observer agreement was tested by providing a cystic fibrosis physician and a nurse practitioner with 45 clinical scenarios. For each scenario the clinicians, who were blinded to each other’s responses, were asked to indicate whether or not they would: 1. initiate telephone contact; and/or 2. request a clinic visit for the individual. Results: 10 participants (5 female), aged mean (SD) 33 (11) years, FEV1 49 (27)% predicted completed the study. The mean (SD) System Usability Scale score was 94 6.. There was perfect agreement between clinicians for initiating contact with the participant (κ = 1.0, p < 0.001), and near-perfect for requesting a clinic visit (κ = 0.86, p < 0.001). Discussion The use of a smartphone application for reporting symptoms in adults with cystic fibrosis has excellent usability and near-perfect agreement between senior clinicians when interpreting the application responses.

Calvo-Lerma, Joaquim et al (2017) Innovative approach for selfmanagement and social welfare of children with cystic fibrosis in Europe: Development, validation and implementation of an mHealth tool (MyCyFAPP)[11]

Introduction: For the optimal management of children with cystic fibrosis, there are currently no efficient tools for the precise adjustment of pancreatic enzyme replacement therapy, either for advice on appropriate dietary intake or for achieving an optimal nutrition status. Therefore, we aim to develop a mobile application that ensures a successful nutritional therapy in children with cystic fibrosis. Methods and analysis: A multidisciplinary team of 12 partners coordinate their efforts in 9 work packages that cover the entire so-called ‘from laboratory to market’ approach by means of an original and innovative co-design process. A cohort of 200 patients with cystic fibrosis aged 1-17 years are enrolled. We will develop an innovative, clinically tested mobile health application for patients and health professionals involved in cystic fibrosis management. The mobile application integrates the research knowledge and innovative tools for maximising self-management with the aim of leading to a better nutritional status, quality of life and disease prognosis. Bringing together different and complementary areas of knowledge is fundamental for tackling complex challenges in disease treatment, such as optimal nutrition and pancreatic enzyme replacement therapy in cystic fibrosis. Patients are expected to benefit the most from the outcomes of this innovative project. Ethics and dissemination: The project is approved by the Ethics Committee of the coordinating organisation, Hospital Universitari La Fe (Ref: 2014/0484). Scientific findings will be disseminated via journals and conferences addressed to clinicians, food scientists, information and communications technology experts and patients. The specific dissemination working group within the project will address the wide audience communication through the website (, the social networks and the newsletter.

Emaminejad, Sam et al (2017) Autonomous Sweat Extraction and Analysis Applied to Cystic Fibrosis and Glucose Monitoring Using a Fully Integrated Wearable Platform[12]

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals’ health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL)for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications.

Cox, Narelle S et al (2015) [Feasibility Study] Feasibility and acceptability of an Internet-Based program to promote physical activity in adults with cystic fibrosis[1]

Background: Lifelong physical activity is an important component of the therapeutic management of patients with cystic fibrosis (CF). Use of the Internet to monitor and encourage participation in physical activity has not been assessed in adults with CF. We aimed to establish the feasibility and acceptability of a specifically developed Internet-based program to monitor and encourage physical activity participation in adults with CF. Methods: Subjects were recruited at hospital discharge to trial an Internet-based physical activity program (ActivOnline)for 8 weeks, which incorporated fortnightly telephone consultation to support physical activity behavior change. Acceptability of the program was assessed by semi-structured interview, as well as subject-rated system usability and perceived benefit using Likert scales. Feasibility was assessed by frequency of access of the online site and number of physical activity sessions recorded. Results: Ten subjects were recruited who rated system usability and perceived benefit favorably (median score usability of 89% [interquartile range of 84-95%]; median score of perceived benefit (maximum of 5) of 4 [interquartile range of 3-4.8]). During interviews, subjects described a positive reaction to receiving graphical representation of their activity participation; however, 80% would have preferred a more mobile interface such as an app. Subjects accessed ActivOnline on a mean ± SD of 13 ± 11 occasions over 8 weeks and recorded a mean of 35 (range of 15-57) physical activity sessions. Conclusions: Use of an Internet-based program to encourage participation in physical activity was both feasible and acceptable to adults with CF. Feasibility may be further improved with the ability to access the program through a mobile application.

[1] Lechtzin N, Mayer-Hamblett N, West NE et al Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute
Pulmonary Exacerbations. eICE Study Results. Am J Respir Crit Care Med. 2017;196(9):1144‐1151. doi:10.1164/rccm.201610-

[2] Lechtzin N, West N, Allgood S et al Rationale and design of a randomized trial of home electronic symptom and lung function
monitoring to detect cystic fibrosis pulmonary exacerbations: the early intervention in cystic fibrosis exacerbation (eICE)trial.
Contemp Clin Trials. 2013;362.:460‐469. doi:10.1016/j.cct.2013.09.004

[3] Murgia F, Bianciardi F, Solvoll T et al Telemedicine Home Program in Patients with Cystic Fibrosis: Results after 10 Years. Clin
Ter. 2015;1666.:e384‐e388. doi:10.7417/T.2015.1905

[4] Calthorpe RJ, Smith S, Gathercole K, Smyth AR. Using digital technology for home monitoring, adherence and selfmanagement in cystic fibrosis: a state-of-the-art review. Thorax. 2020;751.:72‐77. doi:10.1136/thoraxjnl-2019-213233

[5] Compton M, Soper M, Reilly B et al A Feasibility Study of Urgent Implementation of Cystic Fibrosis Multidisciplinary
Telemedicine Clinic in the Face of COVID-19 Pandemic: Single-Center Experience [published online ahead of print, 2020 Apr
30]. Telemed J EHealth. 2020;10.1089/tmj.2020.0091.

[6] Cuartero M, Parrilla M, Crespo GA. Wearable Potentiometric Sensors for Medical Applications. Sensors (Basel).2019;192.:363.
Published 2019 Jan 17. doi:10.3390/s19020363

[7] Gao W, Ota H, Kiriya D, Takei K, Javey A. Flexible Electronics toward Wearable Sensing. Acc Chem Res. 2019;523.:523‐533.

[8] Lee EK, Kim MK, Lee CH. Skin-Mountable Biosensors and Therapeutics: A Review. Annu Rev Biomed Eng. 2019;21:299‐323.

[9] Martinez-Millana A, Zettl A, Floch J et al The Potential of Self-Management mHealth for Pediatric Cystic Fibrosis: MixedMethods Study for Health Care and App Assessment. JMIR Mhealth Uhealth. 2019;74.:e13362. Published 2019 Apr 18. doi:10.2196/13362

[10] Wood J, Jenkins S, Putrino D et al High usability of a smartphone application for reporting symptoms in adults with cystic
fibrosis. J Telemed Telecare. 2018;248.:547‐552. doi:10.1177/1357633X17723366

[11] Calvo-Lerma J, Martinez-Jimenez CP, Lázaro-Ramos JP et al Innovative approach for self-management and social welfare of
children with cystic fibrosis in Europe: development, validation and implementation of an mHealth tool (MyCyFAPP). BMJ
Open. 2017;73.:e014931. Published 2017 Mar 16. doi:10.1136/bmjopen-2016-014931

[12] Emaminejad S, Gao W, Wu E et al Autonomous sweat extraction and analysis applied to cystic fibrosis and glucose
monitoring using a fully integrated wearable platform. Proc Natl Acad Sci U S A. 2017;114(18):4625‐4630. doi:10.1073/pnas.1701740114

[13] Cox NS, Alison JA, Button BM, Wilson JW, Holland AE. Feasibility and acceptability of an Internet-based program to promote
physical activity in adults with cystic fibrosis. Respir Care. 2015;603.:422‐429. doi:10.4187/respcare.03165