Toward a Core Outcome Set for Head, Neck, and Respiratory Disease in Mucopolysaccharidosis Type II: Systematic Literature Review and Assessment of Heterogeneity in Outcome Reporting

Abstract

The mucopolysaccharidoses (MPS) are a relatively uncommon group of inherited metabolic disorders, with significant negative implications for life span and aspects of quality of life. Their rarity means that producing evidence to guide best practice has often entailed assimilating findings from multiple studies. Core outcome sets (COS) are being increasingly used across medicine as a potential solution to the problems arising from heterogeneous reporting of outcomes in effectiveness studies. A COS is a recommended minimum set of outcomes that should be measured for a given condition in an effectiveness study, with the ultimate aim of increasing the value of clinical information by enabling meaningful comparison and combination of data from various sources. A systematic review identified 41 outcomes measured in published studies and ongoing and completed clinical trials, with individual outcomes being measured using a variety of measurement instruments/tools. This work represents the important initial steps in the development of COS for head, neck, and respiratory disorders in MPS type II, raising awareness of the extent of heterogeneity in outcome reporting and determining the scope of outcomes and corresponding instruments currently used. The next step will be to use the generated “longlist” of outcomes to develop an electronic Delphi prioritization exercise with the intention of reaching a consensus regarding the most important outcomes to measure in effectiveness studies for head, neck, and respiratory disease in MPS type II.

Keywords:
core outcome set; systematic review; mucopolysaccharidosis; outcome domain; outcome measure instrument

Background

The mucopolysaccharidoses (MPS) are a family of inherited metabolic disorders, caused by specific lysosomal enzyme deficiencies, with resultant accumulation of partially degraded glycosaminoglycans (GAG) within tissues.¹ The ubiquitous nature of GAG within the body means that a number of different organ systems can be affected. Eleven distinct types of MPS disorders have been classified, according to the particular enzyme that is deficient.¹–³

Involvement of the upper and lower respiratory tract in MPS type II results in significant airway compromise, with progressive airway obstruction being responsible for a significant proportion of the morbidity and mortality associated with this condition.⁴ Airway disease is characterized by adenotonsillar hypertrophy, macroglossia, recurrent upper respiratory tract infections, thickened nasal mucosa, airway deposits, and tracheomalacia.⁵–⁷ These changes within the airway are considered to result from GAG accumulation in soft tissues.⁵ Sleep disordered breathing, or obstructive sleep apnoea, has been reported in 90% (27/30 patients) of patients with MPS type II when tested using polysomnography.⁸ Obstructive events during sleep can lead to learning impairment, behavioral problems, developmental, and learning delay as well as cardiovascular disease (pulmonary hypertension and right ventricular hypertrophy).⁹ Skeletal abnormalities (eg, small ribs and short neck), enlarged internal organs, restrictive lung disease, neurocognitive impairment, and cardiac disease may further compound multilevel upper airway involvement, leading to respiratory compromise that may significantly restrict lifestyle and ultimately lead to death.⁵,⁶

Hearing loss is a universal finding in MPS, with a third of patients having severe profound hearing loss.¹⁰ More is understood about the hearing loss in MPS type II in comparison with the other subtypes, due to the publication of hearing data from an international observational study (The Hunter outcome survey [HOS]).¹¹ At the time of reporting, 84% (70/83) of the children surveyed had a hearing loss; 24% (20/83) had a mild hearing loss, 31% (26/83) a moderate loss, 22% (18/83) a severe loss, and 7% (6/83) a profound loss (WHO-ICIDH criteria). The conductive component of the hearing loss in MPS type II is predominantly related to an increased tendency toward the development and persistence of otitis media with effusion (OME, glue ear) and recurrent acute otitis media (rAOM). In MPS type II, GAG deposits are believed to accumulate within the nasopharynx contributing to Eustachian tube dysfunction (ETD) and the development and persistence of OME. The increased tendency toward upper respiratory tract infections in MPS may manifest as chronic adenoiditis, further contributing to ETD and AOM. The tendency toward OME may last into adolescence and adulthood in MPS. Long- and short-term ventilation tubes and hearing aids have been used in the management of persistent OME with hearing loss,¹⁰,¹²,¹³ with greater emphasis now being placed on hearing aids due to the anticipated longevity of OME and the attendant risk of recurrent general anaesthesia.

There is an unmet need for strong clinical evidence to guide treatment of head, neck, and respiratory disease in MPS disorders, with much of the published evidence reflecting the experience of larger centres based on the retrospective analysis of patient outcomes.

A Core Outcome Set (COS) describes the minimum outcome data that should be measured in a clinical study for a particular condition.¹⁴ The lack of an agreed COS for MPS type II in general, and specifically respiratory/head and neck disease, crucially hinders comparison between studies. In addition, purchasers and regulatory bodies are likely to prefer evidence from clinical studies that adhere to an agreed set of outcome measures. There is also a paucity of information detailing patient and parent perspectives on the symptomatology of MPS disorders. The ideal COS for respiratory/head and neck disease associated with MPS type II would combine both patient/parent and clinician opinion and could be used in the design of all subsequent clinical studies. Currently, the tendency to only report those findings that researchers consider to be significant or positive can lead to outcome reporting bias (ORB).¹⁵ The development of a COS can help to negate the effect of ORB in future study designs and limit heterogeneity of chosen outcomes in studies investigating different interventions in the same organ system.

The aim of this systematic literature review was to generate a “long list” of outcome measures and corresponding list of outcome measurement instruments reported in the MPS type II literature for respiratory/head and neck disease. This information would help to determine the extent of heterogeneity of outcome reporting in this MPS subtype and enable the subsequent development of a COS specific for respiratory/head and neck disease.

Methods

Literature Search

Studies were identified using a systematic search strategy applied to EMBASE, MEDLINE, and CINAHL (using http://www.library.nhs.uk/hdas) over the 24-year period (1990-2014). The time period selected represents contemporary practice and current understanding of the disease, reflecting the introduction of disease-modifying therapies, along with centralized, coordinated, and multidisciplinary care.

Multiple databases were used to maximize the sensitivity of the search. Within EMBASE, MEDLINE, and CINAHL a Medical Subject Headings (MeSH) search (mapped to the Thesaurus) was performed. Within the Thesaurus, the subject heading was “exploded” and the “OR” setting applied. The general MeSH headings (Table 1) was subsequently combined with the mucopolysaccharidosis (MPS) II MeSH heading using the “AND” option.

Table 1
MeSH headings for systematic review search.

	1. Otolaryngology
2. Otorhinolaryngologic Disease	3. Adenoidectomy
4. Positive pressure respiration OR continuous positive airway pressure (CPAP) OR sleep apnoea syndrome OR sleep apnoea or obstructive or polysomnography or airway obstruction or pharynx/or apnoea	5. Deafness
6. Positive pressure respiration	7. Conductive hearing loss
8. Continuous positive airway pressure	9. Sensorineural hearing loss
10. Sleep apnoea syndrome	11. Hearing aids
12. Sleep apnoea	13. Bone conduction/cochlear implant
14. Obstructive	15. Cochlear implant
16. Polysomnography	17. Bone conduction
18. Airway obstruction	19. Chronic disease/psychology
20. Pharynx	21. Psychology
22. Apnoea	23. Health service research
24. Snoring	25. Qualitative research
26. Tracheostomy	27. Questionnaire
28. Respiratory sounds	29. Value of life
30. Rhinitis	31. Health Care surveys
32. Sinusitis	33. Empirical research
34. Nasal polyps	35. Quality of Life
36. Chronic Disease	37. Enzyme replacement therapy (ERT)
38. Otitis media with effusion or otitis media or child or child preschool or middle ear ventilation or ear middle or adenoidectomy	39. Hematopoietic stem cell therapy (HSCT) Or bone marrow replacement or cord blood stem cell transplantation
40. Otitis media with effusion	41. Hematopoietic stem cell therapy
42. Otitis media	43. Bone marrow replacement
44. Child	45. Cord blood stem cell transplantation
46. Child preschool	47. Quality of life OR quality-adjusted life years
48. Middle ear ventilation	49. Quality-adjusted life years

• Abbreviation: MESH, Medical Subject Headings.

The COS being developed is specifically for 2 interrelated body systems (respiratory and head and neck) within MPS type II. Reflecting our understanding of the literature, it was considered necessary to include a range of study types in order to achieve a meaningful summary of outcomes used in studies related to these 2 body systems. We were concerned that the information contained in abstracts for less formal study designs might be insufficient to appropriately screen, and formal studies may not include all outcomes in the abstract. As such, a search strategy using additional general MESH headings considered relevant to these body systems was chosen with the aim of limiting reliance upon the quality of abstracts at the screening stage.

The following limits were applied to the search strategy:

• 1990 to 2014

• English language only

• Human only

Clinical Trials Registry Search

The World Health Organization (WHO) International Clinical Trials Registry Portal (http://apps.who.int/trialsearch/, last accessed January 02 2018) and ClinicalTrials.Gov (https://clinicaltrials.gov/, last accessed January 02 2018) were searched for Mucopolysaccharidosis II. This search revealed 45 and 10 results from the ClinicalTrials.gov and WHO databases, respectively. Both open and closed trials were included.

Inclusion Criteria

Any otolaryngology surgical or medical intervention in patients with MPS II was included, along with studies focusing on ERT and HSCT. We also included all systematic reviews with/without meta-analyses, randomized controlled trials, case-controlled trials, case series, prospective cohorts, and review articles.

Exclusion Criteria

We excluded studies that were not specifically related to MPS type II, studies that did not investigate or report respiratory/head and neck disease in patients with MPS type II (the exception to this were papers looking at bone marrow transplant [BMT] and HSCT), case series with fewer than 3 patients, expert opinion papers, discussion papers, and consensus papers.

Study Selection

Two researchers (J.M. and N.B.) independently reviewed the abstracts produced by the above-mentioned literature search strategy, and a comprehensive list of studies was obtained. The full-text articles of studies that appeared to fit the inclusion criteria and those that have insufficient information in the title and abstract were obtained. The articles were assessed independently by the 2 reviewers (J.M. and N.B.). Any disagreement between the reviewers regarding including the inclusion of a paper was resolved through discussion. Where agreement was not reached, a third reviewer was consulted (I.A.B.).

The reference section of each paper was cross-referenced to identify any further relevant papers. Outcomes relevant to respiratory/head and neck disease were identified in published studies involving patients with MPS type II, receiving either medical or surgical interventions. Clinical trials were reviewed by one researcher (A.M.) and were included if they measured outcomes relevant to respiratory/head and neck disease in patients with MPS type II.

Results

The systematic review of relevant literature was performed. Databases EMBASE, MEDLINE, and CINAHL were searched from 1990 to 2014. Literature search yielded 228 results which subsequently were reduced to 90 records following the removal of 138 duplicates. Of 90 publications following the thorough screening process of abstracts against inclusion and exclusion criteria, further 68 results were excluded. Consequently, 22 publications were left. Full-text articles were collected for those 22 results, and they were assessed using the inclusion and exclusion criteria. The total of 10 full-text articles were excluded for the following reasons: 7 results had less than 3 patients, 1 result was a consensus paper, 1 result was a review article, and 1 publication was a duplicate study published in 2 different journals under a different name. Ultimately 12 publications were identified and reviewed for outcomes (Figure 1).

Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flowchart illustrating the review of methodology.

A total of 55 clinical trials were identified following a clinical trials registry search for “Mucopolysaccharidosis II.” Five trials were duplicated between the databases. Of the remaining 50 clinical trials, 7 studies did not investigate MPS type II. Among the remaining 43 trials, 4 studies were already included in the literature search, and 33 studies did not consider any respiratory/head and neck disease outcomes. Following the review process, 6 clinical trials were identified and outcomes measured were included in this review (Figure 1). Of particular note, the clinical trial NCT03292887 reported data from the Hunter Outcome Survey (HOS). The HOS collects a wealth of data on patients with MPS type II who are or have been treated with ERT (Elaprase) or those who receive no treatment at all. Data collection began in 2005, and it is anticipated to continue for a minimum of 17 years. In addition to general outcomes (eg, GAG status and mobility), HOS collects information about respiratory and ENT outcomes. One publication identified during the systematic literature search have reported on HOS findings relating to otological outcomes.¹¹

A total of 41 outcomes were extracted (Table 2). The HOS collects 26 outcomes, and the remaining studies reported between 1 and 8 outcomes. The most frequently reported outcome was exercise tolerance, which was reported by 9 out of 17 studies, followed by pulmonary function, which was reported by 8 of the 16 reviewed studies, while sleep apnoea and hearing were assessed in 4 and 5 research studies, respectively (see Table 2 for references). Identified outcomes were subsequently organized according to the most recent COS taxonomy (Table 3).¹⁶ Such classification of outcomes will be presented to stakeholders in the next stage of this project of COS identification, the electronic Delphi (eDelphi) exercise.

Table 2
Long-list of outcome measures and corresponding outcome measurement instruments (OMI).

Outcome		Paper/Clinical Trial Using the Outcome		Outcome Measurement Instrument		Time Point		Study Type
Pulmonary		Muenzer J, et al.		Forced Expiratory Volume in the first		Baseline and 53 weeks		Prospective
	function		Molecular Genetics and		seconda (FEV1), Forced vital		posttreatment
			Metabolism.		capacitya (FVC)
			2007;90:329-33717
		Muenzer J, et al. Genetics		FVCa		Baseline and 18, 36, and 53 weeks		Prospective
			in Medicine August.				posttreatment
			2006;8(8)18
		Sohn, et al. Orphanet		FVCa		Baseline and 12 and 24 weeks		Prospective
			Journal of Rare				posttreatment
			Diseases. 2013;8:4219
		da Silva EMK, et al.		FEV1a, FVCa		Baseline and 18, 36 and 53 weeks		Retrospective
			Cochrane Database Syst				posttreatment
			Rev. 201120
		Glamuzina E, et al. J.		FVCa		Baseline and yearly thereafter		Retrospective
			Inher. Metab. Dis.
			2011;34(3):749-75421
		Wooten W, et al. The		FEV1a, FVCa; Total lung capacityb		1 measurement time pointc		Prospective
			Journal of Paediatrics.		(TLC), Ratio of residual volume to
			162(6):1210-12158		TLCb (RV/TLC)
		NCT02663024		FVCc		Baseline and 25 weeks		Prospective
							posttreatment
		NCT03292887d		FEV1c, FVCc, TLCc		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Dyspnoea		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Chronic Cough		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Bronchitis		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Pneumonia		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Prevalence of		NCT03292887d		Occurrence of hospitalization due to		At time of entry into HOS database.		Prospective
	pulmonary-				pulmonary symptoms		No set points for data collection
	related						thereafter
	hospitalizations
Blood Gas		Muenzer J, et al.		O2 desaturation eventse		Baseline and 53 weeks		Prospective
			Molecular Genetics and				posttreatment
			Metabolism.
			2007;90:329-33717
		Wooten W, et al. The		Minimum SpO2e, mean sleep SpO2e,		1 measurement time pointc		Prospective
			Journal of Paediatrics.		Oxygen desaturation indexe,
			162(6):1210-1215		ETCO2e
		NCT03292887d		Respiratory rate, SpO2		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Need for oxygen		NCT03292887d		Diagnosed Y/N		At time of entry into HOS database.		Prospective and
	therapy						No set points for data collection		Retrospective
							thereafter
Sleep apnoea		Muenzer J, et al.		Apnoea-hypopnoea index (AHI)ef		Baseline and 53 weeks		Prospective
			Molecular Genetics and				posttreatment
			Metabolism.
			2007;90:329-337
		da Silva EMK, et al.		Overnight AHIe		Not reported		Retrospective
			Cochrane Database Syst
			Rev. 2011
		Wooten W, et al. The		AHIef		1 measurement time pointc		Prospective
			Journal Of Paediatrics.
			162(6):1210-1215
		NCT03292887d		Diagnosed Y/N		At time of entry into HOS database.		Prospective and
							No set points for data collection		retrospective
							thereafter
Exercise tolerance		Muenzer J, et al.		6-minute walk test (6MWT)		Baseline and 53 weeks		Prospective
			Molecular Genetics and				posttreatment
			Metabolism.
			2007;90:329-337
		Muenzer J, et al. Genetics		6MWT		Baseline and 18, 36 and 53 weeks		Prospective
			in Medicine. 2006;8(8)				posttreatment
		Sohn, et al. Orphanet		6MWT		Baseline and I2 and 24 weeks		Prospective
			Journal of Rare				posttreatment
			Diseases. 2013;8:42
		da Silva EMK, et al.		6MWT		Baseline and I8, 36 and 53 weeks		Retrospective
			Cochrane Database Syst				posttreatment
			Rev. 2011
		Glamuzina E, et al. J.		6MWT		Baseline and yearly thereafter		Retrospective
			Inher. Metab. Dis.
			2011;34(3):749-754
		NCT02663024		6MWT		Baseline and 25 weeks		Prospective
							posttreatment
		NCT02455622		6MWT		Baseline to minimum 5 years post		Prospective
							enrolment
		NCT03292887d		6MWT		At time of entry into HOS database.		Prospective and
							No set points for data collection		retrospective
							thereafter
		NCT02044692		6MWT		Baseline and every 6 months up to 5		Prospective
							years
Hearing		da Silva EMK, et al.		Audiologic assessment, details not		Not reported		Retrospective
			Cochrane Database Syst		provided
			Rev. 2011
		Vellodi A, et al. J. Inher.		Griffiths Mental Development Scales		Pre (2 weeks to several months		Prospective
			Metab. Dis.		(GMDS)		prior) and posttransplant (6-12
			1999;22:638-64822				months)
		Keilmann A, et al. J Inherit		Database review- Hunter Outcome		From registration to the last follow-		Retrospective
			Metab Dis.		Survey (HOS):		up
			2012;35:343-35311		1. PTA air conduction thresholds
					at 250, 500, I000, 2000, 4000,
					8000 Hz
					2. PTAs bone conduction 250,
					500, 1000, 2000, 4000 and 8000
					Hz
					3. Auditory brainstem response
					(ABR)g
		Cho Y, et al. Audiol			Click-evoked ABR, Pure tone	1 measurement time pointc		Prospective
			Neurotol. 2008;I3:206-		audiogram (PTA)
			2I223
		NCT03292887d			Word recognition testc, Bone	From registration to the last follow-		Prospective
					conductionα		up
QOL		da Silva EMK, et al.		Not reported		Not reported		Retrospective
			Cochrane Database Syst
			Rev. 2011
		Raluy-Callado, et al.			1. The Hunter Syndrome-	At the time of enrolment to a		Retrospective
			Orphanet Journal of		Functional Outcomes for		clinical trial
			Rare Diseases.		Clinical
			2013;8:10124		2. Understanding Scale (HS-
					FOCUS)
					3. The Childhood Health
					Assessment Questionnaire
					(CHAQ)
					4. The Child Health Questionnaire
					(CHQ)
					5. The Health Utilities Index (HUI)
		NCT02455622		HS-FOCUS		Baseline to minimum 5 years post		Prospective
							enrolment
		NCT03292887d		Hunter Syndrome on Health-related		At time of entry into HOS database.		Prospective and
					Quality of Life HS-FOCUS		No set points for data collection		retrospective
							thereafter
Intelligence		Vellodi A, et al. J. Inher.		The Wechsler Intelligence Scale for		Pre (2 weeks to several months		Prospective
			Metab. Dis.		Childrenh, Third Edition UK (W		prior) and posttransplant (6-12
			1999;22:638-648		PPSI-R)		months)
		Cho Y, et al. Audiol		Korean Educational Development		1 measurement time pointα		Prospective
			Neurotol 2008;13:206-		Institute-Wechsler Intelligence Scale
			212		or Developmental Test of
					Visuomotor
					Integration and the Picture
					Vocabulary Test or Social
					Maturation Test
		NCT01870375		Depending on age:		1 measurement time pointc		Prospective
					1. Mullen Scales of Early Learning
					2. Wechsler Preschool and
					Primary Scale of Intelligence III
					3. Wechsler Abbreviated Scale of
					Intelligence
					4. Wechsler Intelligence Scale for
					Children IV (controls)
					5. Wechsler Adult Intelligence
					Scale III (controls)
Psycho-social		Vellodi A, et al. J. Inher.		GMDS1		Pre- (2 weeks to several months		Prospective
	development		Metab. Dis.				prior) and posttransplant (6-12
			1999;22:638-648				months)
Need for surgical		VellodiI A, et al. J. Inher.		Ventilation tubes insertion		Any time after treatment		Prospective
	intervention to		Metab. Dis.
	ears		1999;22:638-648
		Keilmann A, et al. J Inherit		Database review—Hunter Outcome		From registration to the last follow		Retrospective
			Metab Dis.		Survey: Ventilation tubes insertion		up
			2012;35:343-353
		Cho Y, et al. Audiol		Ventilation tubes insertion		1 measurement time pointc		Prospective
			Neurotol 2008;13:206-
			212
		NCT03292887d		Ventilation tubes insertion		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Chronic nasal		Malik V, et al. Int J Pediatr		Instrument not reported/retrospective		Any time during disease		Retrospective
	discharge		Otorhinolaryngol.		case note review
			2013;77(7):1204-1208
Airway		Malik V, et al. Int J Pediatr		Instrument not reported/retrospective		Any time during disease		Retrospective
	obstruction		Otorhinolaryngol.		case note review
			2013;77(7):1204-1208
Voice quality		Malik V, et al. Int J Pediatr		Instrument not reported /		Any time during disease		Retrospective
			Otorhinolaryngol.		retrospective case note review
			20I3;77(7):I204-I208
Complication of		Malik V, et al. Int J Pediatr		Instrument not reported /retrospective		Any time after treatment		Retrospective
	surgical		Otorhinolaryngol.		case note review
	treatment		2013;77(7):1204-1208
		Jeong H, et al. Int J Pediatr		Review in clinic: complication present/		Up to 12 months following the		Retrospective
			Otorhinolaryngol.		absent		procedure
			2006;70(10):1765-
			176925
Need for		Malik V, et al. Int J Pediatr		Use of CPAP (prior to insertion of		Any time during disease		Retrospective
	noninvasive		Otorhinolaryngol.		tracheostomy tube)
	ventilatory		2013;77(7):1204-1208
	support	Wooten W, et al. The		Use of CPAP		Any time during disease		Prospective
			journal of pediatrics.
			162(6):1210-1215
		Muenzer j, et al;		Use of CPAP		At baseline		Prospective
			Molecular Genetics and
			Metabolism.
			2007;90:329-337I7
		NCT03292887d		Use of CPAP, BIPAP		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Enlarged tonsils		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Tosillectomy		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Enlarged Adenoids		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Adenoidectomy		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Swallowing		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
	difficulties						No set points for data collection		Retrospective
							thereafter
Tracheotomy		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Survival		Malik V, et al. Int J Pediatr		Age at death		In the event		Retrospective
			Otorhinolaryngol.
			2013;77(7):1204-1208
			NCT03292887d	Age at death		In the event		Prospective and
									Retrospective
Acute Otitis		Keilmann A, et al. J Inherit		Database review—HOS: present/		At time of entry into HOS database.		Retrospective
	Media (AOM)		Metab Dis.		absent		No set points for data collection
			2012;35:343-353				thereafter
Tinnitus		Keilmann A, et al. J Inherit		Database review—HOS: present/		At time of entry into HOS database.		Retrospective
			Metab Dis.		absent		No set points for data collection
			2012;35:343-353				thereafter
Tympanic		Keilmann A, et al. J Inherit		Database review—HOS: present/		At time of entry into HOS database.		Retrospective
	membrane		Metab Dis.		absent		No set points for data collection
	perforation		2012;35:343-353				thereafter
		Cho Y, et al. Audiol		Otoscopy		1 measurement time pointc		Prospective
			Neurotol. 2008;13:206-
			2I2
Vertigo		Keilmann A, et al. J Inherit		Database review—HOS: present/		At time of entry into HOS database.		Retrospective
			Metab Dis.		absent		No set points for data collection
			2012;35:343-353				thereafter
Chronic Otitis		Keilmann A, et al. J Inherit		Database review—HOS: present/		At time of entry into HOS database.		Retrospective
	Media (COM)		Metab Dis.		absent		No set points for data collection
			2012;35:343-353				thereafter
Turbulent Ear		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
	Discharge						No set points for data collection		Retrospective
							thereafter
Middle ear		Cho Y, et al. Audiol		Impedance audiometry		I measurement time pointa		Prospective
	function		Neurotol 2008;I3:206-
			212
Language		Cho Y, et al. Audiol			1. Preschool Language Scale,	I measurement time pointc		Prospective
	development		Neurotol. 2008;13:206-		Picture Vocabulary Test, Test of
	and		2I2		Language Development
	communication				- Primary
	skills				2. Evaluating Acquired Skills in
					Communication
					- Revised
		NCT02455622		Vineland Adaptive Behaviour Scales		Baseline to minimum 5 years post		Prospective
					(domain: communication)		enrolment
		NCT03333200		No details available on ClinicalTrials.		15 years total: 3 months the first		Prospective
					gov		year, every 6 months the second
							year and once a year thereafter
Nonsurgical		Cho Y, et al. Audiol		Hearing aid: present/absent		I measurement time pointa		Prospective
	intervention to		Neurotol. 2008;13:206-
	ears		2I2
		NCT03292887d		Hearing aid: present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Temporal Bone		Cho Y, et al. Audiol		CT		I measurement time pointa		Prospective
	status		Neurotol. 2008;13:206-
			2I2
Nasal congestion/		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
	obstruction						No set points for data collection		Retrospective
							thereafter
Rhinorrhea		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Nasal polyps		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter
Sinus involvement		NCT03292887d		Present/absent		At time of entry into HOS database.		Prospective and
							No set points for data collection		Retrospective
							thereafter

• ^a
  Measured by spirometry.
• ^b
  Measured by plethysmography.
• ^c
  Not standardized for the group.
• ^d
  Hunter Outcome Survey.
• ^e
  Measured by polysomnography.
• ^f
  No details provided about the test stimulus.
• ^g
  No definition of AHI in the paper.
• ^h
  Verbal IQ, performance IQ and an overall general IQ.
• ⁱ
  Include the following areas: locomotor, personal-social, hearing and language, eye and hand co-ordination, performance, practical reasoning.

Table 3
Long-list of outcome measures organised according to COMET COS taxonomy.

Outcome Area	Outcome Domain	Outcome
Death	1. Mortality/survival	Survival
Physiological/clinical	2. Blood and lymphatic system outcomes	Blood Gas
	6. Ear and labyrinth outcomes	Acute Otitis Media (AOM)
		Tinnitus
		Tympanic membrane perforation
		Vertigo
		Chronic Otitis Media (COM)
		Middle ear function
		Hearing
		Turbulent Ear Discharge
	15. Musculoskeletal and connective tissue outcomes	Temporal Bone status
	22. Respiratory, thoracic, and mediastinal outcomes	Pulmonary function
		Sleep apnoea
		Chronic nasal discharge
		Airway obstruction
		Dyspnoea
		Chronic Cough
		Bronchitis
		Pneumonia
		Enlarged tonsils
		Enlarged adenoids
		Swallowing difficulties
		Nasal Congestion/obstruction
		Rhinorrhoea
		Nasal Polyps
		Sinus involvement
Life impact	25. Physical functioning	Exercise tolerance
	26. Social functioning	language development and communication skills
		Intelligence
		Psycho-social development
	30. Global quality of life	QOL
Resource use	36. Need for intervention	Need for surgical intervention to ears
		Need for noninvasive ventilatory support
		Nonsurgical intervention to ears
		Tonsillectomy
		Adenoidectomy
		Tracheotomy
		Need for oxygen therapy
		Prevalence of pulmonary-related hospitalizations
Adverse events	38. Adverse events/effects	Voice quality
		Complication of surgical treatment

• Abbreviation: QoL, quality of life.

Discussion

Mucopolysaccharidosis type II is rare with an incidence of approximately 1 per 100 000 male births. In the period between 1992 and 2002, 52 babies with Hunter syndrome were born in the United Kingdom (http://www.mpssociety.org.uk/diseases/mps-diseases/mps-ii/). The rarity of this condition makes it difficult to obtain sufficient amounts of good-quality data to guide practice and decision-making, both for clinicians and for carers alike. Currently, we are reliant on case series from larger tertiary referral centers to support evidence-based practice, with only limited conformity in choice of outcome reporting. Pathology found in MPS type II may affect both the lower and the upper aerodigestive tract, and we suggest that combining assessments of both has direct clinical application. Mucopolysaccharidosis type II is an expensive disease to treat; ERT has been reported by de Bitencourt to cost over £100 000 per year for a child and twice as much for an adult.²⁶ It is difficult to assess “value for money” when the evidence for efficacy is so limited.

The core outcome measures in effectiveness trials (COMET) initiative (http://www.comet-initiative.org) promotes standardization of outcome reporting in research, supporting researchers in developing COS. A COS is an agreed standardized collection of outcomes, which should, as a minimum, be measured and reported in all trials in a specific clinical area. Core outcome measures in effectiveness trials also provide a database resource for researchers and patients, detailing what COS have been, or are being developed for a particular medical condition or intervention. This study was the first step toward determining a COS for head, neck, and respiratory disease for patients with MPS type II. This systematic literature review highlights the extent of heterogeneity in outcome reporting, in terms of both outcome measures and corresponding outcome measurement instruments.

It is important to note that only 2 publications and 2 clinical trials considered QoL as an outcome.²⁰,²⁴ One of the publications was a systematic review that established QoL as one of its secondary outcomes. However, only 1 publication subsequently fulfilled the criteria to be included in the systematic review¹⁸ and in that study QoL was not measured. The second publication which considered the QoL used 4 different questionnaires of which only 1 was MPS type II specific (HS-FOCUS). Mucopolysaccharidosis type II has been shown to be associated with significant impact on the QoL of both patients and their families.²⁴,²⁷ Raluy-Callado et al used the Health Utility Index (HUI) which specifically investigated the impact of disease on hearing. They have shown that hearing is the biggest deficiency suffered by patients with MPS type II in agreement with previous publications.⁵ Inclusion of hearing in the HUI makes it particularly relevant for studies involving the head and neck. It is difficult to predict why it was not considered in any of the studies reviewed in this work, although the cost of purchasing a license for use may be a barrier.²⁸ Another tool to consider when evaluating head and neck and respiratory-related QoL is HS-FOCUS which measures patient and parental views in 6 areas, including breathing.²⁹ The use of QoL scales in complex diseases such as MPS type II presents additional challenges to clinicians and researchers: (1) generic scales may not be sufficiently sensitive or specific to detect meaningful change in the patient cohort, that is, ask the wrong questions and (2) bespoke disease-specific scales may not be validated and we do not understand their utility.

The next step in this project is to use the outcomes “long list” in an eDelphi prioritization and consensus exercise to reach agreement between clinical stakeholder groups (ear, nose, and throat surgeons, metabolic physicians, clinical geneticists, specialist nurses, physiotherapists, and respiratory pediatricians) and patients and parents/carers regarding the most important outcomes to be measured in clinical studies of MPS type II. Involvement of a variety of stakeholders will help ensure that the resultant COS will be inclusive, helpful, and provide a valuable resource for any future clinical studies investigating the head, neck, and respiratory manifestations of MPS type II. Additionally, this study provides a component of the information needed to develop a “general” COS for studies involving patients with MPS type II. Finally, the prioritization and consensus seeking involved in COS development could be used to inform review of the existing HOS database for MPS type II.

Funding

• The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by an investigator-led research grant from Shire, Zug, Switzerland. IAB and NB are supported by the NIHR Manchester Biomedical Research Centre.

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Publication Dates

• Publication in this collection
  2019

History

• Received
  07 Aug 2018
• Accepted
  04 Sept 2018