Voluntary Field Recall of Advanced Bionics HiRes Cochlear Implants: A Single-Institution Experience.

OBJECTIVES: In 2020, Advanced Bionics (AB) announced a recall of two cochlear implant (CI) models, the "HiRes Ultra" and "HiRes Ultra 3D", because of reports of hearing degradation. The present study examines clinical parameters and patient features in cases of device failure and evaluates outcomes after reimplantation. MATERIALS AND METHODS: A series of 52 patients implanted with the recalled devices experienced suspected device failure and subsequently underwent revision CI placement at a tertiary academic medical center between December 2019 and November 2021. RESULTS: Consonant-nucleus-consonant scores and individual phonemes increased significantly between patients' preoperative evaluation and primary cochlear implantation. Performance declined significantly before revision and recovered after revision CI placement. Similarly, pure-tone average thresholds improved between preoperative and primary CI, fell before revision surgery, and were corrected with revision implantation. As a group, patients reached their peak hearing performance significantly faster after revision CI (mean ± standard deviation, 53.4 ± 51.8 d) compared with their primary CI (mean ± standard deviation, 260.6 ± 245.9 d). Electrical field imaging performed by AB and device impedance measurements were found to be abnormal in the basally positioned electrodes (electrodes 9-16). CONCLUSION: Hearing performance degradation is significant in AB Ultra device failures and seems to be linked to the basal-most electrodes in the array. Revision outcomes have been robust, necessitating continued monitoring of affected patients and support for reimplantation procedures. LEVEL OF EVIDENCE: IV.

Hearing Stability in Patients With Unilateral Hearing Loss Due to Congenital CMV.

OBJECTIVE: To determine the incidence and severity of progressive hearing loss in both ears in a population of longitudinally-tracked patients with unilateral hearing loss due to congenital cytomegalovirus (cCMV). By determining the natural history of unilateral hearing loss due to cCMV infection, we aim to facilitate therapeutic recommendations. STUDY DESIGN: Retrospective chart review. SETTING: Two tertiary care hospitals. METHODS: Pure-tone averages (PTAs) based on yearly audiograms were calculated for each patient for both ears, and changes were assessed using a linear mixed-effects model. RESULTS: A total of 32 patients with cCMV with congenital, unilateral hearing loss were enrolled. Of these, 4 (12.5%) had progressive losses ≥10 dB by PTA in the initially normal-hearing ear. For the hearing-impaired side, the mean (SD) PTA at initial presentation was 67.9 (29.2) dB. Eight patients initially in this cohort had profound hearing impairment, and of the other 24 patients, 17 (70.8%) had hearing loss progression. Hearing levels stabilized in the initially normal-hearing and hearing-impaired ear when patients were approximately 10 and 2 years old, respectively. CONCLUSION: In 32 patients with unilateral hearing loss related to cCMV, 4 (12.5%) exhibited a shift in hearing levels in the normal-hearing ear that progressively stabilized by age 10 years. For ears with congenital hearing loss, progressive stabilization of hearing occurred by age 2 years.

Otoendoscopes to Enhance Telemedicine During the COVID-19 Pandemic.

OBJECTIVES: As telemedicine has become increasingly utilized during the COVID-19 pandemic, portable otoendoscopy offers a method to perform an ear examination at home. The objective of this pilot study was to assess the quality of otoendoscopic images obtained by non-medical individuals and to determine the effect of a simple training protocol on image quality. METHODS: Non-medical participants were recruited and asked to capture images of the tympanic membrane before and after completion of a training module, as well as complete a survey about their experience using the otoendoscope. Images were de-identified, randomized, and evaluated by 6 otolaryngologists who were blinded as to whether training had been performed prior to the image capture. Images were rated using a 5-point Likert scale. RESULTS: Completion of a training module resulted in a significantly higher percentage of tympanic membrane visible on otoendoscopic images, as well as increased physician confidence in identifying middle ear effusion/infection, cholesteatoma, and deferring an in-person otoscopy (P < .0001). However, even with improved image quality, in most cases, physicians reported that they would not feel comfortable using the images to for diagnosis or to defer an in-person examination. Most participants reported that the otoendoscope was simple to use and that they would feel comfortable paying for the device. CONCLUSIONS: At-home otoendoscopes can offer a sufficient view of the tympanic membrane in select cases. The use of a simple training tool can significantly improve image quality, though often not enough to replace an in-person otoscopic exam.

Association of perioperative ibuprofen exposure with post-tonsillectomy bleeding requiring operative management.

INTRODUCTION: Pediatric tonsillectomy is one of the most common surgical procedures performed in the United States. The safety of ibuprofen use after surgery is debated given concern for increased bleeding. The primary objective of this study was to compare the rate of post-tonsillectomy hemorrhage requiring operative management in patients who received ibuprofen perioperatively vs. patients who did not. METHODS: Retrospective cohort study of patients 0-18 years old who underwent tonsillectomy with or without adenoidectomy (T&A) with recorded inpatient medication administration data at a single tertiary care institution from 1/2005-1/2019. The association between perioperative medication administration and return to operating room (OR) for control was evaluated using multivariable logistic regression adjusted for patient demographics and operative indication. Secondary outcomes evaluated included the time to operative bleed when it occurred. RESULTS: A total of 4098 patients with a median age of 6 years old (IQR 4-10) underwent T&A over the study period. The overall rate of post-tonsillectomy hemorrhage requiring OR was 3.37% (n = 138/4098). After adjustment for confounders, the odds of bleeding requiring OR did not differ significantly between the ibuprofen (OR 1.16, 95% CI (0.76, 1.74), 3.55%, n = 41/1,156, p = 0.47) and non-ibuprofen groups (3.30%, n = 97/2942). The median time to bleeding requiring OR was postoperative day 6.5 (IQR6-8) in the ibuprofen group and day 6 (IQR 3-8) in the non-ibuprofen group. CONCLUSIONS: No difference in post-tonsillectomy hemorrhage requiring OR was observed between patients receiving perioperative ibuprofen versus those patients not receiving this medication. Additional research is required to definitively determine a safe dose and interval for ibuprofen administration following tonsillectomy.

Assessment of Pain and Analgesic Use in Children Following Otologic Surgery.

OBJECTIVE: To compare postoperative pain and analgesic use in children following transcanal endoscopic ear surgery (TEES) vs non-transcanal endoscopic ear surgery (non-TEES). STUDY DESIGN: Prospective case series. SETTING: Tertiary care center. METHODS: Surveys using the Wong-Baker FACES Pain Rating Scale and recording the frequency and dosage of consumed analgesics were administered prospectively to caregivers of children undergoing otologic surgery between May 2018 to February 2020. Pain intensity and medication use were recorded twice daily for 6 days, starting on postoperative day 0. Mean pain scores and mean number of consumed analgesic doses were compared between groups. RESULTS: Survey response rate was 57.9%. Among 53 patients who completed the survey, 35 (66.0%) underwent TEES and 18 (34.0%) underwent non-TEES. Mean pain ratings on postoperative days 0 and 1 were significantly lower among children undergoing TEES (2.2 and 2.1) vs non-TEES (4.0 and 4.1), P = .045 and P = .008, respectively (Mann-Whitney U test). The mean pain ratings across the 6 days were similar in TEES (1.7) and non-TEES (2.6) (P = .140, Mann-Whitney U test). The mean number of analgesic doses consumed per half-day over the 6 days was significantly lower among children undergoing TEES (0.3) vs non-TEES (0.6; P = .049, Mann-Whitney U test). CONCLUSION: Postoperative pain following TEES and non-TEES in children was overall low. Children undergoing TEES had a small but statistically significant decrease in pain on postoperative days 0 and 1 and decreased use of pain medications compared to non-TEES.

Pediatric, Family-Centered, "At-Home" Otologic Physical Examination in the COVID-19 Era.

SARS-CoV-2, the novel coronavirus resulting in the present COVID-19 pandemic, has increased the otolaryngologist's reliance on telemedicine to manage outpatient pathology. The nature of telemedicine, however, limits a provider's ability to obtain a comprehensive physical examination, specifically of the tympanic membrane. Various smartphone-based otoscopic attachments are now available that facilitate patient-obtained otoscopic image capture of the tympanic membrane. Here, we present 3 cases in which a patient-purchased, over-the-counter otoscope was utilized to alter otologic management during the time of social distancing. Further research is necessary to improve our understanding the safety and efficacy of patient-based "at-home" otoscopic examination and to optimize the use of these devices.

Cognitive and Behavioral Functioning in Hearing-Impaired Children with and without Language Delay.

Poor language development in patients with sensorineural hearing loss (SNHL) may be related to an auditory deficit and/or other neurologic condition that influences the ability to communicate. A retrospective chart review of children (mean age = 4.0 years) with congenital, bilateral SNHL was performed to assess for linguistic and nonlinguistic neurodevelopmental differences between those who were language-impaired (LI) versus non-language-impaired (NLI). Language, neurodevelopmental functioning, and behavior were assessed. Twenty-two patients were identified: 12 were LI and 10 were NLI. Average pure-tone thresholds and nonverbal intelligence were not different between the language groups, but the LI group demonstrated significantly lower median overall adaptive skills, personal living skills, and motor skills. Behavioral dysregulation was significantly higher in the LI versus NLI group (58% vs 10%; P = .031), although the median neurodevelopmental scores did not differ significantly. These findings introduce the possibility that nonlinguistic processing deficit(s) may be confounding the ability to develop language.

Leveraging Existing Tools in Electronic Health Record Systems to Automate Clinical Registry Compilation.

Clinical registries have proven beneficial by providing a resource to address research questions, monitor care, and identify suitable subjects for clinical studies. Despite a well-organized registry, population is often low because of the human capital required. The increasing prevalence of electronic medical health records provides the opportunity to integrate registry compilation into routine patient encounters. Here we describe how one tool existing within the Epic Medical Record software suite, Smart Phrases, can be adapted to automate population of a hearing loss patient registry. The usage rate of Smart Phrases was high and resulted in a significant reduction in the time burden associated with registry population. Use of Smart Phrases could become an important factor in the design of future registries that allow broad uptake and convenient data input.

Immunoglobulin A defines secretions from salivary tissue in post-Sistrunk procedure drainage.

OBJECTIVES: This was a pilot study to establish a protein difference between thyroglossal duct cyst fluid relative to oral saliva, in order to differentiate patients with residual thyroglossal cyst from those with salivary fistula in the case of post-Sistrunk procedure incisional drainage. Past immunohistochemistry studies on archived tissue blocks from post-Sistrunk procedure patients have shown MUC5AC to have elevated concentrations in thyroglossal duct relative to salivary tissue; secretory immunoglobulin A (IgA) was also chosen as a candidate protein based on previously published reports of its increased concentration in saliva relative to respiratory secretions. DESIGN: Diagnostic tests were assessed. Thyroglossal duct cyst fluid and oral saliva were obtained from 12 patients. Enzyme-linked immunosorbent assay (ELISA) was then performed on the samples to identify the presence of MUC5AC and IgA. SETTING: Tertiary care hospital. SUBJECTS: Patient fluid samples were taken immediately postoperatively for patients undergoing Sistrunk procedure at one institution. Presence of thyroglossal duct cyst was confirmed in all cases by pathology. RESULTS: Seven of 12 thyroglossal duct cyst fluid samples were shown to have elevated absorbance with ELISA for MUC5AC. In experiments for IgA, 10 of the 12 saliva samples had elevated absorbance compared with thyroglossal duct fluid samples obtained from the same patient. CONCLUSIONS: IgA is an accurate identifier of saliva compared with thyroglossal duct fluid in secreted samples obtained from the same patient.

Craniofacial and upper airway development.

Development of the craniofacial and upper airway structures is a complex choreography of mesenchymal and epithelial tissues responding to soluble growth factors and transcription factors in a tightly regulated sequence. Interruption of the development process or mutation of required transcription or growth factors leads to congenital anomalies of the facial and airway structures. Oftentimes, these patients suffer life-long consequences, require multiple medical and surgical interventions, and have significant associated morbidity and mortality. Furthering our understanding of the basic developmental mechanisms of craniofacial and upper airway development will lead to improved diagnostic and treatment strategies to improve the care of these patients.

Matrix metalloproteinase inhibition causes luminal narrowing and ring thickening in the cricoid cartilage.

OBJECTIVE: Luminal expansion of the cricoid cartilage appears to be stunted by loss of luminal epithelium (LE) and can be enhanced by transforming growth factor-beta3 (TGF-beta3). When both the LE and perichondrium are disrupted, matrix metalloproteinase (MMP) levels within adjacent chondrocytes are diminished but can be restored by exogenous TGF-beta3. Cricoid growth stunting and luminal expansion that occur in the absence and presence of MMP activity, respectively, suggest that MMPs play an important role in normal subglottal development. The study objective was to determine if MMP inhibition affects cricoid expansion and by what mechanism, which will in turn help to define the mechanism of action of TGF-beta3-induced luminal expansion. STUDY DESIGN: Ex vivo, in vitro whole organ culture of subglottises grown with and without the presence of an MMP inhibitor. SETTING: Tertiary care facility. SUBJECTS AND METHODS: Subglottises from 20 neonatal mice were divided into 10 grown with an MMP inhibitor, GM6001, and 10 grown in basic medium alone. The luminal cross-sectional area, apoptosis levels, cell proliferation rates, and presence or absence of cleaved aggrecan fragments were determined. RESULTS: Subglottises that were exposed to the MMP inhibitor displayed statistically significant luminal narrowing, accompanied by apparent circumferential thickening of the cricoid ring, relatively decreased apoptosis, increased chondrocyte proliferation, and decreased amounts of aggrecan cleavage fragments in the extracellular matrix. CONCLUSION: Matrix metalloproteinases likely play a significant role in growth of the cricoid cartilage such that their inhibition leads to marked changes in the shape of the ring.

Cochlear implantation in children with congenital X-linked deafness due to novel mutations in POU3F4 gene.

OBJECTIVES: We report novel mutations in the POU3F4 gene resulting in congenital X-linked deafness DFN3, and describe the results of cochlear implantation in 4 boys (3 siblings) followed for an average of 3.5 years. METHODS: The diagnosis of DFN3 was made in infant boys on the basis of the radiologic criteria of an underdeveloped modiolus, a wide cochlear fossette, and the presence of all cochlear turns. The POU3F4 gene was sequenced. A standard, transmastoid, facial recess approach was used for cochlear implantation. A lumbar drain was placed before the operation. RESULTS: The identified mutations in the POU3F4 gene were novel (p.R167X in the 3 siblings) or recently reported (p.S310del). A high-flow cerebrospinal fluid leak through the cochleostomy was encountered in each patient and was ultimately controlled. Although the implants functioned properly, the auditory perceptual abilities did not progress past sound detection in the 3 siblings, or past closed-set word identification in the non-sibling, who achieved better speech perception with contralateral amplification. Three boys (2 siblings) show signs of other learning disorders; 1 boy was too young for a complete assessment. CONCLUSIONS: Preoperative gene mutation analysis in DFN3 patients who are considering cochlear implantation may help in long-term counseling and in avoidance of postoperative complications. Limited auditory perception and language acquisition may result. Amplification may sometimes be a better alternative than cochlear implantation, despite the severity of the hearing loss.

Developmental aspects of the upper airway: report from an NHLBI Workshop, March 5-6, 2009.

The upper airway serves three important functions: respiration, swallowing, and speech. During development it undergoes significant structural and functional changes that affect its size, shape, and mechanical properties. Abnormalities of the upper airway require prompt attention, because these often alter ventilatory patterns and gas exchange, particularly during sleep when upper airway motor tone and ventilatory drive are diminished. Recognizing the relationship of early life events to lung health and disease, the National Heart, Lung, and Blood Institute (NHLBI), with cofunding from the Office of Rare Diseases (ORD), convened a workshop of extramural experts, from many disciplines. The objective of the workshop was: (1) to review the state of science in pediatric upper airway disorders; (2) to make recommendations to the Institute to fill knowledge gaps; (3) to prioritize new research directions; and (4) to capitalize on scientific opportunities. This report provides recommendations that could facilitate translation of basic research findings into practice to better diagnose, treat, and prevent airway compromise in children.

Drainage post-thyroglossal duct remnant surgery: possible source and analysis.

OBJECTIVE: To establish the distance between tongue base salivary tissue and hyoid. Also, to identify protein differences between thyroglossal duct (TGD) remnants and salivary tissue in order to distinguish drainage source post Sistrunk surgery. METHODS/SETTING: The anterior neck block was obtained from 10 adult cadavers with no known neck pathology. The distance between the normal salivary tissue and hyoid was measured histologically. Immunohistochemistry (IHC) was then performed on 20 archived tissue blocks from pediatric patients post Sistrunk surgery to identify the presence of amylase, MUC5AC (tracheobronchial mucin), and MUC7 (salivary mucin) within the excised specimen. RESULTS: Average distance between salivary tissue and the hyoid within adult human cadavers was 3.3 mm (range, 1.0-4.2 mm). IHC revealed all excised TGD remnants contained amylase and MUC5AC but none contained MUC7. Both amylase and MUC7 were present within adjacent salivary tissues. CONCLUSIONS: Salivary tissue of the tongue base normally resides an average of 3.3 mm from the hyoid within the adult population. Biochemical analysis showed MUC5AC was specific for TGD remnants while MUC7 was specific for salivary tissue. Amylase does not distinguish between the two tissues.

Inflammatory cytokine response to injury in the aging rabbit subglottis.

OBJECTIVES: We performed a pilot study to determine whether there is an age-related change in inflammatory expression in the subglottic mucosa of rabbits in response to a one-time injury. METHODS: Twenty-seven rabbits of 3 different ages meant to represent infant, adolescent, and adult stages underwent a unilateral, subglottic soft tissue injury. The animal groups were allowed to heal for 3 different durations to reflect the early, middle, and late stages of inflammation. Animal subglottises were then analyzed for quantitative differences in thickness and expression of multiple inflammatory cytokines within the soft tissue relative to the uninjured side. RESULTS: The animals in the youngest age group demonstrated a thickened-tissue response to injury yet a lower level of inflammatory cytokines than did the older animals at the early and middle stages of healing. CONCLUSIONS: Pronounced tissue thickness was an unanticipated finding in the youngest age groups and suggests better regulatory control by older animals. Also, a developmental difference in the inflammatory response to injury is suggested by the data.

Transforming growth factor beta3 increases chondrocyte proliferation and decreases apoptosis in murine cricoid cartilage in vitro.

OBJECTIVE: To determine if the luminal epithelium and/or exogenous transforming growth factor beta (TGFbeta) affects growth of the cricoid. DESIGN: Subglottises from 20 neonatal mice were subdivided into four groups: A, five subglottises with luminal epithelium grown in basic medium; B, five epithelium-free subglottises in basic medium; C, five epithelium-free subglottises in basic medium with supplemental TGFbeta1, and D, five epithelium-free subglottises in basic medium with supplemental TGFbeta3. RESULTS: Groups A and D demonstrated the greatest luminal area expansion. Group A rings demonstrated statistically higher chondrocyte proliferation than Groups B and C and lesser amounts of luminal apoptosis. Groups B and C rings demonstrated the least amount of cell proliferation, and greater luminal apoptosis relative to Group A. Groups A and D rings had similar apoptotic and proliferative results. CONCLUSIONS: Luminal epithelium exerts influence over the cricoid by increasing chondrocyte proliferation and decreasing the relative proportion of luminal chondrocytes that undergo apoptosis. Exogenous TGFbeta3, not TGFbeta1, also increases chondrocyte proliferation within the cricoid and appears to influence apoptosis as well.

Matrix metalloproteinases 2 and 9 are concentrated in the luminal aspect of the cricoid cartilage, diminish with loss of perichondrium, and are reinstated by transforming growth factor beta 3.

OBJECTIVES: We determined the location of matrix metalloproteinases (MMP) 2 and 9, and whether the luminal perichondrium or transforming growth factor (TGF) beta3 influences the presence of MMP-2 and/or -9 within the chondrocytes of the cricoid cartilage. METHODS: Subglottises from 15 neonatal mice were divided into group A (N = 5; luminal epithelium intact, grown in basic medium), group B (N = 5; epithelium-free, with sections of luminal perichondrium removed, grown in basic medium), and group C (N = 5; epithelium-free, with sections of luminal perichondrium removed, grown in basic medium with supplemental TGF-beta3). Immunohistochemical analysis was done to identify MMP-2 and -9 distributions. RESULTS: Group A demonstrated concentrations of MMP-2 and -9 in the luminal perichondrial and adjacent chondrocytes with a gradual decrease in signal intensity toward the outer perichondrium. Group B showed findings similar to those in group A, but in the region of removed perichondrium, the adjacent chondrocytes lost MMP-2 and -9 signal. The group C rings demonstrated reestablishment of MMP-2 and -9 signal in regions of luminal perichondrial loss. CONCLUSIONS: Localization of MMP-2 and -9 is predominantly in the luminal perichondrium and gradually decreases toward the outer perichondrium. The luminal perichondrium maintains expression of MMP-2 and -9 within the adjacent chondrocytes. Exogenous TGF-beta3 reestablishes production of at least MMP-9, and probably MMP-2, in cricoid cartilages missing luminal perichondrium.

Local control of murine subglottis development.

OBJECTIVE: To determine if subglottic development is at least partially under local control and to determine which tissue layer(s) is predominantly responsible. DESIGN: The suglottises of 12 day-3 CD1 mice were grown in whole organ culture. The 12 subglottises were divided into 3 individual groups: +++, -++, and ---. Group+++ had all tissue layers of the subglottis intact: luminal epithelium, cricoid cartilage, inner and outer perichondrium. Group-++ had all layers intact with the exception of luminal epithelium. Group--- had all layers removed (luminal epithelium, inner and outer perichondrium) resulting in cricoid cartilage-only rings. All rings were grown in basic medium without the use of growth factors or serum for 15 days. Measurements of the rings were taken before and after organ culture growth. RESULTS: Group+++ was the only group that experienced growth. Only luminal growth was statistically significant although all rings experienced growth in both the luminal and external diameter. Group-++ did not experience any growth. Group--- lost structural integrity with collapse of the ring and did not experience growth of any dimension of the cartilage. CONCLUSIONS: Growth of the subglottis is under local control but may have additional influences from the outside that were not investigated here. Removal of just the epithelium stunts growth of the entire ring, but preferentially the lumen more so than the external diameter. Removal of all tissue layers around the cricoid cartilage results in a structural collapse of the ring, suggesting that the cartilage in this age group is dependent on surrounding tissues for structural integrity.

Age-related mechanisms of cricoid cartilage response to injury in the developing rabbit.

OBJECTIVE: To evaluate age-related mechanisms of cricoid cartilage response to injury in an animal model. STUDY DESIGN: A pilot study using monoclonal antibodies to chondrocyte proliferation markers collagen II, aggrecan, and proliferating cell nuclear antigen (PCNA) to evaluate age-related response of injured cricoid cartilage. METHODS: Twenty-seven New Zealand white rabbits aged 4 weeks, 8 weeks, and 1.5 years were studied. Six animals in each age group underwent intracartilaginous injury through cricofissure and tracheofissure. Three animals of each group were used as control subjects. The animals were killed 4 weeks after injury, their cricoid cartilages harvested, and 7-microm sections of tissue obtained. The cricoid tissue sections were stained with immunofluorescent monoclonal antibody markers to collagen II, aggrecan, and PCNA. RESULTS: In all age groups, no control animals had symptoms of airway compromise or immunohistochemical abnormality. For all three markers of chondrocyte proliferation, the 4-week-old animals showed markedly increased staining at the injured edges of cartilage. The 8-week-old animals showed mild increased extracellular staining, and the 1.5-year-old animals showed no increased staining compared with uninjured areas of the cricoid ring and with control animals. CONCLUSION: There was a progressive, age-related attenuation of staining for markers of chondrocyte proliferation in the 8-week and 1.5-year-old rabbits compared with the 4-week-old rabbit cricoids.

Pediatric non-orbital pseudotumor of the head and neck.

OBJECTIVE: To evaluate the incidence, sites of presentation, and treatment outcome of non-orbital pseudotumor of the head and neck in the pediatric population. METHODS: 10-year retrospective case series at a tertiary care center. All patients 18 years of age and younger with non-orbital pseudotumor of the head and neck evaluated and treated at our institution over the study period (1990-2000) were identified through the Systematic Nomenclature of Medicine (SNOMED) database with the keyword 'pseudotumor'. RESULTS: Among 146 patients identified with head and neck pseudotumor at our institution, 15 (10%) were pediatric patients, only three (20%) of whom had pseudotumor in non-orbital sites (the infratemporal and pterygopalatine fossae, submandibular gland, and masseter space). Four (27%) of the 15 had pseudotumor limited to the lacrimal gland, with the remaining eight (53%) being orbital pseudotumor cases. CONCLUSIONS: Similar to cases of orbital pseudotumor, long term systemic steroid therapy proved effective in the management of non-orbital pseudotumor in all three children with eventual disease resolution.