1 INTRODUCTION

Asthma is the most common chronic disease of childhood, resulting in substantial morbidity, loss of quality of life and healthcare expenditure.¹ The “asthma epidemic” is still evolving, though demonstrating large geographical variation, in prevalence and severity. Urbanization and increased awareness may explain the continuing rise in asthma diagnosis in low- and middle-income countries, whereas a plateau in prevalence is observed in most high-income countries.² Severe asthma affects <10% of children with asthma, but disproportionally impacts health systems and society through both direct and indirect costs.³ Missed days from school and lower educational attainment may incur long-term consequences for the individual child and the society.⁴

Asthma management entails minimization of symptoms and reduction in exacerbation risk. However, despite recent advances in treatment options, hospital admissions and deaths remain unacceptably high.⁵ Unequivocally, regular asthma monitoring has been recognized as a crucial determinant in achieving and maintaining asthma control and decreasing the overall burden of the disease.⁶ However, the operationalization of the respective techniques and procedures has attracted less attention in the literature. Successful asthma monitoring requires a long-term commitment to ensure not only cautious assessment of asthma control and timely treatment modifications but also potential re-evaluation of the initial diagnosis and comorbidities. Consideration of the child's age, variability of disease course and severity as well as socioeconomic, psychosocial, and practical factors specifically pertinent to childhood, are of paramount importance.⁷ A variety of monitoring domains (i.e., lung function, airway inflammation, comorbidities, adherence to treatment, psychosocial factors, and exposures) are highlighted by international guidelines and their respective tools (e.g., spirometry, validated symptom scores, and FeNO) have been employed in clinical practice.⁸ Although the value of each domain is appreciated, only a limited number of studies have directly assessed the effectiveness of different monitoring strategies or tools in improving asthma control and reducing exacerbations, and these have had conflicting results across different asthma-related outcomes.^9-11 Therefore, it is evident that prioritization of monitoring approaches, determination of frequency and intensity of implementation, and recommendations for incorporation into care pathways in different populations and healthcare levels are essential.

In the absence of compelling evidence regarding the optimal monitoring pathway in childhood asthma, the Pediatric Asthma in Real Life (PeARL) group,¹² a think tank consisting of international health professionals and clinical academics with expertise in asthma, initiated a process to develop recommendations toward harmonizing and improving standards for pediatric asthma monitoring. Following a needs assessment, through an international survey identifying gaps and unmet needs concerning monitoring practices,⁸ we applied an evidence appraisal followed by a Delphi consensus exercise to reach recommendation statements that are presented below. The activity developed in collaboration with major professional organizations (Asia Pacific Academy of Pediatric Allergy Respirology and Immunology [APAPARI], European Academy of Allergy & Clinical Immunology [EAACI], Global Asthma Association-INTERASMA, Respiratory Effectiveness Group [REG], World Allergy Organization [WAO]) and the input of patient organizations (European Federation of Allergy and Airways Diseases Patients' Associations [EFA], Global Allergy & Airways Patients Platform [GAAPP)).

2 METHODS

The process was initiated through a needs assessment exercise previously reported.⁸ Briefly, we conducted an international survey involving physicians across a wide range of specializations, levels of care, socioeconomic status, and geography, including over 1300 participants. We surveyed both the actual status of pediatric asthma monitoring and the perceived optimum and analyzed the disparities. Furthermore, monitoring domains were prioritized.⁸

We then searched Pubmed/MEDLINE as well as the Cochrane Database of Systematic Reviews, from 2007 through August 2022, for systematic reviews and/or meta-analyses in children with asthma assessing any of the following prioritized domains: frequency and duration of monitoring, symptom control, lung function, airway inflammation and hyperresponsiveness, biomarkers, treatment adherence, lifestyle and environmental exposures, and adverse events monitoring (Appendix Sx). English-language publications were only considered. We have also included the most recently published international guidelines.^{6, 13-16} The search strategy is described in the Appendix Sx. The titles and abstracts of the citations were reviewed (MM, NGP), and the full-text publications of potentially relevant articles were retrieved. Pertinent data from each publication were extracted by the PeARL steering group members (AC, AD, JG, AN, NGP, WP, GW, and VX) to draft statements regarding asthma monitoring in children.

To assess and reach consensus toward the final set of recommendations, an online Delphi procedure was used. The list of draft statements was anonymously circulated via SurveyMonkey to the extended membership of the PeARL think tank (including 74 specialists from 41 countries) who were asked to declare their level of agreement or disagreement for each statement in a 5-point Likert scale. The predefined level of agreement (Strongly Agree or Agree) was set to 75% and up to three iterative rounds were foreseen. Comments from the first round were utilized to reformulate statements in case consensus was not reached. Twenty-four statements were put forward for evaluation. Out of the 74 invited experts, 52 (70%) responded to the first round and 49 to the second. Among 24 statements, 21 (87.5%) reached consensus (range 79–100%) on the first round, while three (12.5%) statements were reformulated and reached consensus (76–84%) in the second round. The median level of consensus was 88%. The detailed results of the Delphi process are shown in the Appendix S1.

The process was appraised using the AGREE II criteria (Appendix S2). The text drafted following the Delphi was subjected to public commentary and external reviewing from experts not involved in the process; comments are also included in the Appendix S3.

To describe the frequency of interventions, we used the scale of our survey: “During every visit,” “Regularly” (every 1–2 visits), “Occasionally” (once to twice a year), “Upon indication” (in the judgment of the treating physician).

3 RECOMMENDATION STATEMENTS

4 COMMENTARY—DISCUSSION

The objective of PeARL Pediatric Asthma Monitoring recommendation statements is to help systematize and harmonize asthma monitoring in children worldwide, including both traditional physician visit-based monitoring as well as the currently developing between-visit monitoring with the use of eHealth and mHealth. The recommendations were prepared with both primary and specialist care in mind. As there are major differences between healthcare systems across the world, we did not attempt to suggest thresholds for referral; these will depend upon the availability of the suggested tools in primary care as well as the availability of specialist services.

While considerable knowledge has been generated on the value of individual monitoring tools, their operationalization in the context of different care pathways is an unmet need. The intention and focus of the PeARL statements is in the pediatric population with a diagnosis of asthma; nevertheless, it is possible that the approach may prove useful in adult asthma as well. The target audience are healthcare professionals looking after children with asthma, particularly those with a responsibility of designing and implementing local care pathways. The statements can also serve as a reference on—and a reminder of—aspects whose monitoring may affect asthma outcomes. Clearly, as our recent survey has shown,⁸ few centers actually perform the full range of available evaluations, either due to lack of time, resources or know-how. A simple monitoring plan based on all 24 recommendations is shown in Table 1.

It is emphasized that a prerequisite for asthma monitoring is asthma diagnosis, for which there are several national and international guidelines available.^{6, 13-16, 42} Nevertheless, effective monitoring allows for diagnosis re-evaluation, in case expected outcomes are not achieved.

Of note, the provided recommendations are overall strongly aligned with preferences and perceived optimal practices of physicians across the globe,⁸ as well as with evidence-based guidance.⁶ There are some notable exceptions: the use of PEFR (Statement 8), FeNO (Statement 13) and QoL (Statement 16), which all required a second round of Delphi to achieve consensus. In all cases, the apparent initial discrepancy was a factor of differential weighing of efficacy against feasibility (including accessibility, affordability, and time constraints). Local variations can be captured through needs assessment evaluation, which are often secondary in evidence-based international guidelines, highlighting the value of our approach.

PeARL recommendations have several important strengths: They were based on the declared needs of their target users, considering the wide variation of practices at the global level and factoring in efficacy evidence with user preferences. Patient representatives have contributed to the whole process, while the Delphi panel was large and inclusive of all subspecialties treating children with asthma. We present not only the final consensus but also the distribution of any contrasting views.

There are certain limitations. Declared priorities are not necessarily objective or evidence-based and may be subject to bias. Nevertheless, evidence cross-checking as well as external reviewing can address this issue. It is clearly not possible to cover the totality of global complexity. “Extremes” or outliers may not be necessarily wrong. In principle, all care pathways are only starting points for reference and can be adapted for local needs. Finally, our evidence-based appraisal was based on existing systematic reviews and meta-analyses.

The variability and complexity of health systems poses a challenge to the applicability of the PeARL monitoring recommendations on a global scale and particularly in low-middle income countries (LMIC).¹²² Health system parameters, including available time, specialist access, infrastructure and cost issues, all place the practicing physician under a tight frame for using a certain monitoring framework. On the other hand, considerable effort was put into making the recommendations flexible enough and defining ranges according to current best practices, which we envision will make the recommendations adaptable to different systems. Adoption by several international societies may help dissemination.

The statements need to be updated at regular intervals; this is particularly true when it comes to between-visit monitoring and eHealth. It is foreseen to review and expand the content, following 3 years of implementation.

In conclusion, the PeARL statements are compatible but go beyond the scope and expand the efforts of currently available international pediatric asthma recommendations. We hope that they will add value toward harmonizing and bringing best practices to children with asthma around the world.

AUTHOR CONTRIBUTIONS

Nikolaos G. Papadopoulos: Conceptualization; methodology; project administration; supervision; writing – review and editing; writing – original draft. Adnan Custovic: Writing – review and editing. Antoine Deschildre: Writing – review and editing. James E. Gern: Writing – review and editing. Antonio Nieto Garcia: Writing – review and editing. Michael Miligkos: Writing – review and editing. Wanda Phipatanakul: Writing – review and editing. Gary Wong: Writing – review and editing. Paraskevi Xepapadaki: Writing – review and editing. Ioana Agache: Writing – review and editing. Stefania Arasi: Writing – review and editing. Zeinab Awad El-Sayed: Writing – review and editing. Leonard B. Bacharier: Writing – review and editing. Matteo Bonini: Writing – review and editing. Fulvio Braido: Writing – review and editing. Davide Caimmi: Writing – review and editing. Jose A. Castro-Rodriguez: Writing – review and editing. Zhimin Chen: Writing – review and editing. Michael Clausen: Writing – review and editing. Timothy Craig: Writing – review and editing. Zuzana Diamant: Writing – review and editing. Francine M. Ducharme: Writing – review and editing. Motohiro Ebisawa: Writing – review and editing. Philippe Eigenmann: Writing – review and editing. Wojciech Feleszko: Writing – review and editing. Vincezo Fierro: Writing – review and editing. Alessandro Fiocchi: Writing – review and editing. Luis Garcia-Marcos: Writing – review and editing. Anne Goh: Writing – review and editing. René Maximiliano Gómez: Writing – review and editing. Maia Gotua: Writing – review and editing. Eckard Hamelmann: Writing – review and editing. Gunilla Hedlin: Writing – review and editing. Elham M. Hossny: Writing – review and editing. Zhanat Ispayeva: Writing – review and editing. Daniel J. Jackson: Writing – review and editing. Tuomas Jartti: Writing – review and editing. Miloš Jeseňák: Writing – review and editing. Omer Kalayci: Writing – review and editing. Alan Kaplan: Writing – review and editing. Jon R. Konradsen: Writing – review and editing. Piotr Kuna: Writing – review and editing. Susanne Lau: Writing – review and editing. Peter Le Souef: Writing – review and editing. Robert F. Lemanske: Writing – review and editing. Michael Levin: Writing – review and editing. Mika J. Makela: Writing – review and editing. Alexander G. Mathioudakis: Writing – review and editing. Oleksandr Mazulov: Writing – review and editing. Mário Morais-Almeida: Writing – review and editing. Clare Murray: Writing – review and editing. Karthik Nagaraju: Writing – review and editing. Zoltan Novak: Writing – review and editing. Ruby Pawankar: Writing – review and editing. Marielle W. Pijnenburg: Writing – review and editing. Helena Pite: Writing – review and editing. Paulo M. Pitrez: Writing – review and editing. Petr Pohunek: Writing – review and editing. David Price: Writing – review and editing. Alfred Priftanji: Writing – review and editing. Valeria Ramiconi: Writing – review and editing. Daniela Rivero Yeverino: Writing – review and editing. Graham Roberts: Writing – review and editing. Aziz Sheikh: Writing – review and editing. Kun-Ling Shen: Writing – review and editing. Zsolt Szepfalusi: Writing – review and editing. Ioanna Tsiligianni: Writing – review and editing. Mirjana Turkalj: Writing – review and editing. Steve Turner: Writing – review and editing. Tetiana Umanets: Writing – review and editing. Arunas Valiulis: Writing – review and editing. Susanne Vijveberg: Writing – review and editing. Jiu-Yao Wang: Writing – review and editing. Tonya Winders: Writing – review and editing. Dong Keon Yon: Writing – review and editing. Osman M. Yusuf: Writing – review and editing. Heather J. Zar: Writing – review and editing.

CONFLICT OF INTEREST STATEMENT

NGP reports grants or contracts from any entity Capricare, Nestle, Numil, Vianex, consulting fees from Abbott, Abbvie, Astra Zeneca, GSK, HAL, Medscape, Menarini/Faes Farma, Mylan, Novartis, Nutricia, OM Pharma, Regeneron/Sanofi, outside the submitted work. AC reports outside the submitted work, research grants from MRC, EPSRC, Wellcome trust, consulting fees from Worg Pharmaceuticals, payment or honoraria for lectures, presentations, speaker bureaus from GSK, AstraZeneca, Stallergens-Greer and fiduciary role in WAO board of officers unpaid. AD reports outside the submitted work consulting fees from Novartis, GSK, Sanofi, Regeneron, AstraZeneca, Aimmune Therapeutics, DBV Technologies, Nestlé Health Science, ALK, Stallergènes-Greer, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, ALK, GSK, Sanofi, AstraZeneca, Aimmune Therapeutics, DBV Technologies, Nestlé Health Science, Support for attending meetings and/or travel ALK, Sanofi, Stallergenes Greer, Novartis, Astra-Zeneca, DBV Technologies, Aimmune, Nutricia, Invitation to congresses (EAACI, AAAAI, ATS, ERS, PAAM, FAAM, CPLF, CFP2A, SFA), Data Safety Monitoring Board (DSMB) for BOOM study. PX reports outside the submitted work Payment or honoraria for lectures, presentations, speakers' bureaus, Galenica, GlaxoSmithkline, Menarini, Novartis, Uriach, Nestle, Nutricia. WP reports outside the submitted work Payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Genentech, Novartis, Sanofi, Teva, GSK, Regeneron, Astra Zeneca, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from ABAI, AAAAI. ANG reports outside the submitted work, payments for Consultant or Advisory Committee: MSD, Novartis, Merck, Inmunotek, Diater and Lecture fees from AstraZeneca, Merck, Novartis, Inmunotek, Diater, Uriach, Menarini. PP reports outside the submitted work, consultation fees from GlaxoSmithKline, AstraZeneca. AS reports outside the submitted work, an institutional research grant from Asthma UK. IT has received grants for research/educational purposes from Chiesi, Astra Zeneca, Menarini, GSK Hellas, outside the submitted work. MWP reports outside the submitted work payment or honoraria for lectures, presentations, DMC board and advisory boards from Sanofi and Novartis. SLS reports honoraria for lectures and advisory boards from Sanofi-Aventis, DBV-technologies, Allergopharma, Lilly, Viatris, GSK, Leo Pharma and Leti, outside the submitted work. OM reports outside the submitted work Payment or honoraria for lectures, presentations, speakers' bureaus from Astra Zeneca, Sanofi. MB reports outside the submitted work: grants or contracts from any entity from AstraZeneca, Chiesi, GSK, Omron and Sanofi; consulting fees from AstraZeneca and GSK; Payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, Grifols, Menarini, Sanofi. GR advisory boards for ALK-Abello, AstraZeneca and Sanofi outside the submitted work. HP reports outside the submitted work grants or honoraria for lectures/educational events from AstraZeneca, FAES Farma, GlaxoSmithKline, JABA Recordati, Leti, Medinfar, Menarini, Organon, Tecnimede, Viatris. LBB reports being a member of the GINA Science Committee; reports grants from NIH/NIAID/NHLBI, personal fees from GlaxoSmithKline, Genentech/Novartis, Merck, Teva, Boehringer Ingelheim, AstraZeneca, Avillion, WebMD/Medscape, Sanofi/Regeneron, Vectura, Circassia, OM Pharma, Recludix and Kinaset; for DSMB activities from AstraZeneca, DBV Technologies, Aravax and Vertex; royalties from Elesvier outside the submitted work; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from ABAI, AAAAI. DP has advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; consultancy agreements with AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Viatris, Teva Pharmaceuticals; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Chiesi, Viatris, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Inside Practice, GlaxoSmithKline, Medscape, Viatris, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme, Teva Pharmaceuticals; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Novartis, Medscape, Teva Pharmaceuticals; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation program, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. TC reports research with GSK, Takeda and Regeneron. Speaking for Takeda, Regeneron and Grifols. Director, Alpha-1 Resource Center, Alpha-1 Foundation. Other conflicts do not apply to this disease space. FM received unrestricted research funds from Jamieson and GlaxoSmithKline; investigator-initiated research funds from Covis Pharma, Banque Scotia Foundation, GlaxoSmithKline and MEDteq in partnership with Thorasys Inc.; honorarium for consultancy work or advisory board from Institut d'excellence en soins et services sociaux du Québec (INESSS), Covis Pharma, Ontario Lung Association, Sanofi, and Teva; and honorarium as an invited speaker from Association des Médecins omnipraticiens du Richelieu Saint-Laurent, Covis Pharma, Fédération des Médecins Omnipraticiens du Québec, the Réseau québécois d'éducation en santé respiratoire (RQESR), Sanofi-Regeneron, Thorasys Inc., and Trudell Medical International. TW received paid speaker & advisor for AstraZeneca, GSK, Merck/MSD, Novartis, and Sanofi Regeneron, outside the submitted work. DJJ Grants from NIH, GlaxoSmithKline, and Regeneron, consulting with Areteia, AstraZeneca, Avillion, Genentech, GlaxoSmithKline, Regeneron, Sanofi, DSMB for Pfizer, Upstream Bio, AstraZeneca, outside the submitted work. DC reports outside the submitted work payments from Stallergenes Greer, ALK, Sanofi, AstraZeneca. PK reports personal fees from Adamed, personal fees from Berlin Chemie Menarini, personal fees from Boehringer Ingelheim, personal fees and other from AstraZeneca, personal fees from Celon Pharma, personal fees from FAES, personal fees from Glenmark, personal fees from Novartis, personal fees from GSK, personal fees from Sanofi, personal fees from Teva, personal fees from Polpharma, outside the submitted work. FB reports grants from GS, Chiesi, Vitalaire, cosulting fees from Astra Zeneca, Glaxo Smith Kline, Chiesi, Menarini group, Zambon, Sanofi Regeneron, Payment or honoraria for lectures from Astra Zeneca, Glaxo Smith Kline, Chiesi, Menarini group, Zambon, Sanofi Regeneron, outside the submitted work. All other authors have nothing to report.