Received: 12 July 2019 Revised: 8 December 2019 Accepted: 16 December 2019 DOI: 10.1002/ajmg.a.61481 ORIGINAL ARTICLE Airway abnormalities in very early treated infantile-onset Pompe disease: A large-scale survey by flexible bronchoscopy Chia-Feng Yang1,2 | Dau-Ming Niu1,2 | Shyh-Kuan Tai2,3 | Ting-Hao Wang1,2 | Hsiao-Ting Su4 | Ling-Yi Huang1 | Wen-Jue Soong1,2,5 1Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan Abstract 2School of Medicine, National Yang-Ming Early enzyme replacement therapy (ERT) improve long-term outcomes in patients University, Taipei, Taiwan with infantile-onset Pompe disease (IOPD). Our cohort of patients with IOPD at Tai- 3Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan pei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening pro- 4Department of Audiology and Speech gram from 2008, testing more than one million newborns until 2018. By 2010, we Language Pathology, Mackay Medical College, had established rapid diagnostic strategies. Now, the average age of ERT initiation Taipei, Taiwan starts at an average age of <10 days-old, the earliest group in the world. However, 5Children's Hospital, China Medical University, Taichung, Taiwan they still presented some airway problems. We present a retrospective study focused on airway abnormalities in these patients along 8 years of observation. Fifteen Correspondence Wen-Jue Soong, Department of Pediatrics, patients with IOPD, who received very early treatment at a mean age of 8.94 Taipei Veterans General Hospital, No.201, Sec. ± 3.75 days, underwent flexible bronchoscopy (FB) for dynamic assessment of the 2, Shipai Rd., Beitou District, Taipei City, Taiwan 11217, China. whole airway. Long-term clinical outcomes and relevant symptoms of the upper air- Email: [email protected], way were assessed. All patients in the study had varying degrees of severity of upper [email protected] airway abnormalities and speech disorders. The three oldest children (Age 94, 93, Funding information and 88 months, respectively) had poor movement of the vocal cords with reduced Ministry of Science and Technology, Taiwan, Grant/Award Number: MOST 108-2635-B- abduction and adduction and had silent aspiration of saliva through the glottis during 075-004; Taipei Veterans General Hospital, respiration. This is the largest cohort study presented to date about airway abnormal- Grant/Award Number: VGH-108-B-005 ities in very early treated patients with IOPD patients by FB. Despite very early treat- ment, we observed upper airway abnormalities in these IOPD patients. In IOPD, upper airway abnormalities seem inevitable over time. We suggest early and continu- ous monitoring for all IOPD patients, even with early and regular treatment. KEYWORDS airway abnormalities, flexible bronchoscopy, Pompe disease 1 | INTRODUCTION involvement to the attenuated, late-onset Pompe disease (LOPD). Early enzyme replacement therapy (ERT) with recombinant human Pompe disease (Glycogen Storage Disease type II, OMIM # 232300) is alglucosidase alfa (Myozyme®; Sanofi Genzyme, Boston, MA) can pro- an autosomal recessive lysosomal storage disorder characterized by long the survival and improve the long-term outcome of patients with the deficiency of acid α-glucosidase (GAA; Banugaria et al., 2011). Pompe disease. Newborn screening have been proved that it was an Deficiency of this enzyme leads to a progressive accumulation of gly- effective way to initiate early diagnosis and treatment (Chien et al., cogen in many types of cells and tissues. A broad spectrum of clinical 2015). Our series at the Taipei Veterans General Hospital (TVGH) phenotypes is observed, ranging from severe, rapidly progressive began with the Pompe newborn screening program in 2008, testing infantile-onset Pompe disease (IOPD) characterized by cardiac approximately two-thirds of the newborn population in Taiwan until Am J Med Genet. 2020;1–9. wileyonlinelibrary.com/journal/ajmga © 2020 Wiley Periodicals, Inc. 1 2 YANG ET AL. 2018. More than 1 million newborns were screened during that time. from the parents. The study protocol was approved by the Institu- By 2010, we had established an effective newborn screening program tional Review Board of the TVGH (TVGH-2017-07-035C). with rapid clinical diagnostic strategies. Almost all of the suspected IOPD infants could be diagnosed correctly within 2 hr and receive ERT with Myozyme within 4 hr of admission (Chien et al., 2015). With 2.2 | FB examination such an effective system, we were able to initiate treatment with Myozyme in patients with IOPD at an average age of around 8 days, FB was performed at a mean age of around 22 months (range 1 day to which is the earliest age reported globally. Comparison of prognostic 51 months). The diameter of FB was 2.3 mm. All patients received intrave- parameters in our study (collected after 2010) to that of other studies nous sedation, with minimal doses of midazolam (0.05 mg/kg) and keta- of patients with IOPD suggests that patients receiving early Myozyme mine (0.05 mg/kg) for maintaining the patients' spontaneous breathing in our study had better outcomes (Confalonieri et al., 2016; Ebbink ability throughout the procedure. All patients were continuously moni- et al., 2012; Fuller et al., 2013; Jones et al., 2010; Keeler et al., 2017), tored with electrocardiography, pulse oximetry, and noninvasive blood including normal cognitive and motor function. All of our patients with pressure measurements. Pediatric intensivists and anesthesiologists were IOPD survived without mechanical ventilation, walking devices or on standby during the procedure. For delivering oxygen, a nasopharyngeal gastrostomy tube feeding (Lai et al., 2016; Yang et al., 2014, 2016). catheter (NPC; 6F, 8F, or 10F; depending on body weight) was introduced Despite early treatment, we found that even though our patients through one nasal tract and the tip was kept in the oropharynx with its with IOPD had better outcomes, they still developed some airway, position confirmed by FB. Pure, warmed, and humidified oxygen at a flow buccal region, and respiratory problems, including easy choking, recur- rate of 0.3–0.5 L/kg/min was continuously delivered via the nasopharyn- rent otitis media, facial muscle weakness, and articulation disorders. geal catheter throughout the procedure. FB examination was performed Studies suggest that even with regular Myozyme treatment, patients and the abnormalities of the whole airway were diagnosed by a pediatric with IOPD and LOPD still developed respiratory dysfunction that pulmonologist certified to perform pediatric FB. The FB video of FB exam- might be attributed to respiratory muscle weakness or CNS neuropa- ination was recorded and thoroughly analyzed for all patients. thy (Lai et al., 2016; McIntosh et al., 2018; Musumeci et al., 2019; Owens, Wong, Bhattacharya, & Ellaway, 2018). Respiratory dysfunction is a critical prognostic factor for Pompe dis- 2.3 | Associated clinical symptoms surveys ease (Bay et al., 2019; Gupta et al., 2019; McCall & ElMallah, 2019) even with regular treatment with Myozyme. There are limited descriptions of Data regarding relevant outcomes such as growth status at the end of the abnormalities of the whole airway. The purpose of this study was to study; longitudinal change of CK (creatine kinase), LDH (lactate dehydro- evaluate the abnormalities of the whole airway by FB and study the genase), and AST levels (aspartate aminotransferase); and the heart size associated clinical outcomes in very early treated patients with IOPD. (LVMI) were recorded. Associated airway symptoms, including easy chok- ing, recurrent acute otitis media (defined as ≥3 episodes in 6 months, or ≥ 4 episodes in 12 months) and recurrent respiratory tract infections 2 | METHODS (defined as >6 serious diseases in a year) were recorded. Speech disorders were simultaneously tested for patients aged >3 years by the Revised Pre- 2.1 | Study population school Language Impairment Scale. Facial muscle weakness was defined by drooping of the lower lip, absence of the nasolabial folds, or ptosis. Screening for Pompe disease was added to the Taiwan newborn screening program from 2008 nationally. In this nationwide program, dried blood spot (DBS) screening was conducted at Taipei Institute of 2.4 | Data analysis Pathology and Chinese Foundation of Health newborn screening cen- ters using fluorescence (4-MU) assay; this test was changed to the Data are presented as the median with range and mean ± interquartile MS/MS method after 2010 (Chien et al., 2015). At the same time, we range. Wilcoxon rank sum test and Kruskal–Wallis test were used to per- also established the effective clinical diagnostic strategies (Chien form statistical analysis. Analysis of longitudinal data by linear regression et al., 2015). The study population included 14 patients with IOPD of the mean value with the outcome for biochemical parameters yielded who were referred by the newborn screening program to the TVGH a Pearson's product–moment correlation coefficient. All statistical ana- between January 1, 2010 and December 31, 2018. One patient (I-11) lyses were performed using the SPSS 15.0 statistics software (SPSS Inc., was born at our hospital and diagnosed prenatally according to the Chicago, IL) and SigmaStat 3.1 (Jandel Scientific, San Rafael, CA). result of a sibling study in the same period. All included patients were correctly diagnosed by our clinical diagnostic strategies and received ERT on the same day of admission.