Respiratory Care in Familial Dysautonomia: Systematic Review and Expert Consensus Recommendations

Abstract

Background

Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia.

Methods

We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system.

Results

Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, noninvasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy.

Conclusions

Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

INTRODUCTION

Familial dysautonomia (FD, Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III, OMIM 223900) is a rare autosomal recessive disease, present at birth, first described in 1949 in children of Central European (Ashkenazi) Jewish ancestry [1]. The disorder is caused by a founder mutation in the IkB kinase-associated protein gene (IKBKAP) [2]. This produces a deficiency of the protein IKAP (ELP-1), causing impaired development of sensory and afferent autonomic nerves [3].

Hallmarks of FD include impaired pain and temperature sensation, reduced basal tear production [4], absent deep tendon reflexes, optic neuropathy [5], gait ataxia [6], blood pressure instability owing to afferent baroreflex failure [7-9], neurogenic dysphagia [10], chemoreflex failure [11, 12], sleep-disordered breathing [13-15], and chronic lung disease [16], all which contribute to morbidity and mortality [3, 13]. Respiratory disease remains one of the leading causes of death in patients with FD [3].

Due to the rarity of the disease, the management of its respiratory aspects has been based on empirical decisions without controlled clinical trials [17]. Until now, there were no guidelines for the management of respiratory disease in children or adults with FD. The purpose of this document is to: (a) describe the multiple aspects of airway disease in FD; (b) provide a practical standardized framework for the assessment and management of respiratory disease in this fragile patient population; and (c) identify areas for future research. These recommendations are for both children and adults, with differences in the groups acknowledged when necessary.

METHODS

In January 2016, a task force met to discuss and develop expert-based consensus recommendations. The members of the task force were selected based on their experience with patients with FD and their broad-based expertise to cover multiple aspects of the disease. A literature review committee (J.A.P, C.L.S., E.P.B., L.N.K.) performed a literature search using PubMed, EMBASE, and Google Scholar including articles published from 1949 to 2017. Search terms included combinations of “familial dysautonomia”, “Riley-Day syndrome”, “hereditary sensory and autonomic neuropathy type III”, and “respiratory”, “pneumonia”, “sleep”, “fundoplication”, “ventilation”, “apnea”, “oxygen”, “infections”, “chest”, “dysphagia”, “therapy”. Only English-language publications were considered. This initial search yielded sixty-one articles. Three authors (CLS, JAP and LNK) independently screened all titles and abstracts generated by the search. The full texts of screened articles were independently assessed for inclusion. Original research that reported data relevant to the assessment or management of respiratory disorders in patients with FD was included. To identify additional studies, reference lists of included articles and review papers were screened, and relevant journals and proceedings of key scientific meetings were hand searched. Consensus was required for final exclusion of screened articles and disagreements were resolved through involvement of a third author (HK). Abstracted data included: study methodology (design, number of subjects), and outcomes. Due to the rarity of the disease, case reports were included in the final list of included articles.

Twenty-five full text articles were included in the final search with emphasis given to articles published after 1990. This information was subsequently presented to the full task force, after which there was discussion and drafting of the recommendations. The task force acknowledged that certain existing principles on diagnosis and management of respiratory disease in other disorders would be applicable to FD. Thus, the expert panel reviewed and referenced the additional body of literature related to aspiration-related diseases and non-cystic fibrosis bronchiectasis when appropriate.

The level of evidence and strength of the recommendation was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system [18]. The GRADE system classifies recommendations as strong (grade 1) or weak (grade 2), either for or against a specific recommendation [18]. Factors determining the strength of recommendation include a balance between desirable and undesirable effects, quality of evidence, the values and preferences of the experts, and the costs of the intervention. The task force acknowledged i) the potential limitations of making recommendations in the presence of low-quality evidence, and ii) the fact that the strength of the recommendation was defined taking into consideration the paucity of research data available related to this rare genetic disease.

A strong recommendation is worded as “we recommend” and a weak recommendation is worded as “we suggest.” The quality of evidence is an estimate of the certainty of the estimated treatment effect. An (A) rating conveys that the data were derived from multiple randomized clinical trials or meta-analyses; a (B) rating indicates that data were derived from a one randomized clinical trial or high-quality observational studies; a (C) rating indicates that that data were derived from observational studies; and a (D) rating indicates that recommendations are based on low-quality observational studies, case reports, or expert clinical experience.

Because of the limited number of published reports in patients with FD, prospective clinical data from the NYU Familial Dysautonomia Patient Registry was reviewed to address knowledge gaps. The NYU FD Registry is an ongoing, prospective registry of patient with FD that tracks the natural history of the disease with standardized clinical data collected annually. The Registry started in 1970 and contains clinical and diagnostic data, including cause of death, on 670 patients at the time of writing this document. Patients are followed closely and seen at least once a year.

A writing committee prepared the initial draft and then incorporated comments from all remaining coauthors. While recognizing the small number of published studies on the respiratory aspects of FD, the task force agreed to develop practical expert consensus guidelines that reflected the current state of the art. It is acknowledged that in the vast majority of cases, recommendations are based on the consensus of non-systematic clinical observations [i.e., quality of evidence (D)], rather than the results of randomized clinical trials. These guidelines are intended to assist health care providers in clinical decision making by describing generally acceptable approaches to the diagnosis and management of respiratory disorders in patients with FD.

EPIDEMIOLOGY OF RESPIRATORY DISORDERS IN FD

Respiratory abnormalities are a prominent feature of FD. Patients have varying degrees of upper airway obstruction (83%), lower airway disease (85%), and restrictive lung disease (94%) (NYU FD Registry 2016). Approximately 85% of adults and 91% of pediatric patients [15] have some degree of sleep-disordered breathing which, when untreated, is a risk factor for sudden unexpected death during sleep (SUDS), a leading cause of death in FD [13].

Neurogenic dysphagia occurs in all patients and is usually the presenting neonatal feature [3, 19]. Most patients with FD will develop chronic lung disease, due, in large part, to recurrent aspiration. Currently, 85% of patients have a gastrostomy tube placed for hydration and feeding to reduce the overall risk of aspiration. To prevent gastro-esophageal reflux, another potential source of aspiration, most patients had a Nissen fundoplication at the time of gastrostomy [20, 21](NYU FD Registry 2016). Despite these procedures, recurrent lower airway infections are common with an average of 10 pneumonias per lifetime (FD Registry 2016). Computerized tomographic (CT) imaging of the chest shows bronchial wall thickening in 94% and bronchiectasis in 26% of patients [22]. Chronic hypoxemia (PaO₂ < 80 mmHg) is present in 40% of patients and 16% have daytime hypercapnia (PaCO₂ ≥ 50 mmHg) (NYU FD Registry 2016).

MECHANISMS OF RESPIRATORY DISORDERS IN FD

Several mechanisms contribute to the development and progressive worsening of chronic respiratory disease in FD:

1. Neurogenic dysphagia: Because mutations in IKBKAP result in impaired development of sensory neurons [6], patients present at birth with neurogenic dysphagia and poor suck, as well as hypotonia and indifference to pain. Oropharyngeal and esophageal swallowing mechanisms are variably impaired and most infants aspirate before leaving the nursery [23]. Protective airway reflexes mediated by the vagus and glossopharyngeal nerves and orofacial sensation mediated by the trigeminal nerve, are decreased or lacking, and food and liquids are easily aspirated into the lungs [10, 24, 25]. The cough reflex may be completely absent in some cases.

2. Chemoreflex failure: Lack of information from the carotid body chemoreceptors caused by mutations in IKBKAP results in chemoreflex failure. Ventilatory responses to hypercapnia and to metabolic acidosis -mediated by central chemoreceptors- are partially preserved, whereas to hypoxia –mediated by peripheral chemoreceptors- are almost absent, in all patients with FD [11, 12, 26]. In response to hypoxia, patients may develop paradoxical hypotension, hypoventilation, bradycardia, and potentially, death [11, 12, 26-29]. Rapid correction of hypoxemia with 100% inspired O₂ leads to prolonged apnea [12]. Breath-holding spells potentially causing hypotension and syncope occur in 53% of children with FD [30].

3. Impaired proprioception: Muscle strength is preserved in FD, but proprioceptive afferent information is impaired [6] causing sensory ataxia. Absent or reduced proprioceptive input from pulmonary stretch receptors is likely to contribute to poor coordination of respiratory chest movements.

4. Abnormal spinal and craniofacial development: Up to 90% of patients develop scoliosis causing restrictive lung disease [31-35]. Scoliosis in FD is typically hyperkyphotic, and usually occurs in the upper thoracic spine. The lack of proprioceptive afferents from muscle spindles, a characteristic deficit of FD [6], likely contributes to spinal deformities, similarly to what has been reported in idiopathic scoliosis [36]. The spinal curve worsens in adolescence and then stabilizes. Abnormal craniofacial development also occurs, leading to a distinct facial morphology [37-40], which can hinder the positioning of the tongue and contribute to upper airway obstruction and sleep apnea.

The long-term outlook for patients with FD has improved in the last decades. Mortality before age 5 is now < 12% [3, 41]. While survival has improved, patients remain severely debilitated. Acute pulmonary exacerbations accounted for 54% of hospital admissions in 2016 (NYU FD Registry 2016). Aspiration pneumonia (24%), SUDS (23%), non-aspiration pneumonia (17%), and respiratory failure (5%) are the leading causes of death [3]. Overall, respiratory and sleep-related events account for 53% of deaths.

CHRONIC RESPIRATORY DISORDERS IN FD

Aspiration into the airway

Aspiration in patients with FD is a consequence of neurogenic dysphagia which affect both oropharyngeal and esophageal mechanism of swallowing and causes recurrent misdirection of swallowed or stomach material into the airway. The severity of neurogenic dysphagia varies among patients and on a day-to-day basis, and is worsened by sedative medication [24]. Because of their severe sensory deficits, patients fail to properly sense the presence of food and therefore do not clear the upper airway [25, 42]. Saliva carrying a heavy bacterial pathogen load is an important component of the aspirated material [23, 43, 44]. Recurrent aspiration results in constant irritation of the airway mucosa and an influx of pathogens and is the main contributor to lower airway disease in patients with FD [44]. Gastroesophageal content is another potential source of aspirated material and can result in asthma-like symptoms in these patients [45, 46]. Impaired esophageal motility combined with abnormal tone or abnormal relaxation of the lower esophageal sphincter are common [24]. Peristalsis and propulsion abnormalities can cause megaesophagus [10, 47], food impaction [10], and overflow aspiration [24]. Sometimes, this is aggravated by a tight Nissen fundoplication wrap, a procedure frequently performed in patients at the time of their gastrostomy placement [21]. Some patients develop achalasia and worsening dysphagia [48].

Bacterial lower airway inflammation, suppurative lung disease and bronchiectasis

Continuing aspiration results in chronic airway infection and bronchiectasis in 26% of patients [22]. Bronchoscopy findings in children with FD show purulent bronchitis and dense mucus plugging consistent with chronic suppurative lung disease [49]. Bacterial pathogens commonly identified in bronchoalveolar lavage include H. influenzae, S. aureus, S. pneumoniae, M. catarrhalis, and, less frequently, P. aeruginosa [50]. Bronchoalveolar lavage cultures are negative in 30% of cases, probably due to difficulties culturing anaerobic bacteria [49].

Restrictive lung disease

Restrictive lung disease occurs in 94% of patients with FD [31-33, 51], reflected by abnormal pulmonary function test results. There is a progressive tidal volume reduction, consistent with neuromuscular disease [52]. Respiratory muscle incoordination and spine deformities (present in 94% of patients) contribute to hypoventilation, reduced maximal inspiratory and expiratory pressures, and reduced minute ventilation [31-35]. Weak cough and poor secretion clearance contribute to the accumulation of lower respiratory secretions and bacterial overload. Plethysmography data are sparse, as the test can be difficult for patients with FD to perform, but typically shows a restrictive pattern with air trapping (NYU FD Registry 2016).

Upper airway obstruction

In the pediatric FD population, adenoid and tonsillar hypertrophy leads to intermittent obstruction of the upper airway. Craniofacial dysmorphism is frequent [37], and can result in glossoptosis, causing tongue pressure against the epiglottis aggravating obstruction of the upper airway [40, 53]. This is also intensified by low muscle tone of pharyngeal muscles. Upper airway obstruction increases the risk of obstructive sleep apnea.

Obstructive lung disease (wheezing and airway hyperreactivity)

Wheezing and rattle in the chest are common on examination and frequently occur in the absence of dyspnea or other symptoms. Bronchiectasis, resulting in retention of respiratory secretions, can also cause wheezing and should be considered in the differential diagnosis [43]. Pulmonary function tests show obstructive changes in 44% of cases, in addition to the restrictive component present in 94 % of the patients (NYU FD Registry 2016, n=52). In a small double-blind, randomized, placebo-controlled clinical trial, 50% of patients with FD had airway obstruction reversible with both β-agonist and anticholinergic agents [54].

Sleep disordered breathing

Overall, 85% of adults and 91% of pediatric patients with FD have some degree of sleep-disordered breathing with sleep apnea (obstructive and central) occurring in ~50% of patients [15]. The nadir oxygen saturation is, on average, 77%. Hypoventilation (defined as maximum EtCO₂ > 50 mmHg in children and > 55 mmHg in adults) occurs in 60% of children and adults, in many cases without accompanying apneas [15]. Sleep-disordered breathing is a consequence of chemoreflex failure causing impaired ventilatory drive, neuromuscular dysfunction causing or aggravating upper airway obstruction, and chronic lung disease [11, 12, 27, 28, 51, 55]. Untreated sleep apnea is a risk factor for sudden unexpected death during sleep (SUDS) in FD [13].

Daytime hypoventilation

Daytime hypoventilation occurs due to chemoreflex failure, which causes impaired ventilatory drive, and restrictive lung disease largely due to kyphoscoliosis and abnormal proprioception. In clinical practice, a lower threshold of pCO₂ ≥ 45 mmHg is used to define daytime hypercapnia in patients with FD [56]. Hypoventilation is exaggerated by the use of sedative medications or drugs that induce metabolic alkalosis (e.g., fludrocortisone, frequently used in this population for the treatment of orthostatic hypotension).

ACUTE RESPIRATORY EXACERBATIONS IN FD

An acute respiratory exacerbation may present with minimal clinical symptoms despite prominent hypoxemia and CO₂ retention. Physical exam often reveals an overall ill appearance and cyanosis; percussion demonstrates high position of the diaphragm, and auscultation reveals crackles. Patchy airspace opacities are often seen on chest x-ray. Due to chemoreflex failure, respiratory drive remains depressed even in the face of severe hypoxemia. Patients have little sensation of dyspnea and may not report shortness of breath [12]. Compensatory tachycardia may not be a feature of the acute exacerbation. Hyperadrenergic vomiting crises (i.e., dysautonomic crises) can occur during acute respiratory exacerbations [57], and may precede obvious respiratory symptoms. Aspiration into the airway must be suspected in all patients with FD presenting with an acute respiratory exacerbation.

RECOMMENDATIONS FOR THE EVALUATION OF RESPIRATORY DISORDERS IN FD

1. Clinical interview and examination

A clinical interview should screen for signs and symptoms of chronic aspiration into the airway and sleep disordered breathing including:

1. Chronic wet cough while awake or sleeping.

2. Coughing or choking when eating or drinking.

3. Lower respiratory infections (frequent or protracted “colds,” bronchitis, bronchiolitis, pneumonias).

4. Wet or “gurgly” voice.

5. Noisy breathing or snoring during sleep.

It is important to take into consideration that patients with FD may have considerable difficulty recognizing and describing symptoms. Patients have impaired visceral sensation and respiratory irritants frequently elicit only minimal coughing. Also, the ability to provide an accurate medical history depends on cognitive capacity, which varies considerably in these patients. Thus, absence of complaints or obvious respiratory signs does not necessarily eliminate the need for further work up.

Respiratory physical examination should include:

1. Chest morphology with special attention to spinal curvature.

2. Observation of the breathing pattern to identify shallow breathing.

3. Examination of the nail beds to reveal clubbing, common in patients with suppurative lung disease and chronic hypoxemia.

4. Palpation of the chest to reveal “rattle”, frequently associated with the accumulation of secretions in the lower airway.

5. Percussion of the diaphragm to identify small lung volumes or asymmetrical lung sizes due to scoliosis, or hyperresonant sounds due to air trapping.

6. Auscultation to detect crackles or wheezing or decreased air entry to a lung area.

7. Examination of pharynx to detect tonsillar hypertrophy.

8. A prominent second heart sound can indicate pulmonary hypertension.

Expert recommendation

We recommend that clinical encounters to evaluate respiratory disease in patients with FD include a focused interview and physical respiratory examination with particular focus on chest examination. Patients with FD may under-recognize respiratory symptoms and signs thus masking the actual severity of the underlying lung disease (Level of evidence 1D).

2. Radiological evaluation of respiratory disease

Chest x-ray: Typical findings in patients with FD include small lung volumes and chronic atelectatic changes in patients with advanced lung disease [58]. Chest x-ray is indicated during acute exacerbations of respiratory status (e.g., pneumonia, atelectasis) and for monitoring of treatment efficacy.

Expert recommendation

We recommend obtaining a chest x-ray during acute deteriorations of respiratory status and for monitoring treatment efficacy (Level of evidence 1C).

Chest CT

High resolution CT scan of the chest can identify bronchiectasis and should be performed in all patients suspected to have suppurative lung disease/bronchiectasis. Chest CT should be repeated every 3-5 years to follow disease progression. Most adults with FD have short stature and low body mass, allowing pediatric imaging protocols to be used to reduce radiation exposure, particularly if repeat imaging is necessary. Contrast is not usually required.

Expert recommendation

We recommend performing a chest CT when there is unexplained deterioration of respiratory status or suspicion of bronchiectasis. Due to small stature, pediatric doses of radiation can often be used (Level of evidence 1C).

3. Dysphagia evaluation

Videofluoroscopic swallow study, i.e., modified barium swallow study (MBSS), should be performed in all patients with FD and suspected aspiration. Signs may include coughing when eating, wet voice, “chest congestion,” and frequent respiratory infections. The possibility of silent aspiration, i.e. with no symptoms, should be considered as it is common in patients with FD [59]. A MBSS must be performed when recurrent respiratory symptoms (chronic cough, recurrent lower airway infections) are present. If results are normal, close observation is required. When the degree of swallowing impairment does not correlate with the severity of lower airway disease in a patient with FD, the possibility of aspiration of saliva or gastric content should be considered [60]. The MBSS should be repeated if there is suspicion of aspiration or worsening of lung disease. During an acute illness, patients may require enteral nutrition. Before the patient resumes eating, bedside swallow evaluation is recommended.

Expert recommendation

We recommend performing a videofluoroscopic swallow study, i.e., modified barium swallow study if there is suspicion of aspiration-related pulmonary disease (Level of evidence 1C).

4. Gastroesophageal reflux evaluation

Gastroesophageal reflux may be a source of aspiration into the airway in patients with FD [61]. Esophageal impedance with manometry to ascertain the presence of gastro-esophageal reflux is recommended in children and adults with FD [24] with worsening lung disease, refractory wheezing and cough, or chest pain -which can be poorly localized- [62]. The presence of pepsin in the lung is a marker of aspirated gastric content, but the sensitivity and specificity of this technique remains to be determined [63].

Expert recommendation

We recommend performing esophageal impedance with manometry in patients with FD with poorly explained respiratory symptoms, which could be due to gastro-esophageal reflux and secondary aspiration (Level of evidence 1D).

5. Sputum cultures, bronchoscopy, and bronchoalveolar lavage

Sputum cultures are difficult to obtain due to weak cough. Deep pharyngeal “gag” cultures with swab can be obtained in most patients with FD. Bronchoscopy and bronchoalveolar lavage may be required to obtain material for culture. There are no data comparing sputum cultures and pharyngeal “gag” cultures with bronchoalveolar lavage cultures in patients with FD. Indications for bronchoscopy in patients with FD include: chronic wet cough, chronic “chest congestion,” recurrent lower airway infections, presence of wheezes and crackles in the absence of signs of acute respiratory disease, aspiration proven by MBSS even in the absence of major clinical symptoms, and clubbing [64]. Bronchoscopy should be performed with the goals of (a) assessing the extent of lower airway inflammation; (b) obtaining reliable lower airway cultures; and (c) performing bronchial toilette for cases with severe suppurative lung disease, purulent bronchitis and mucus plugging.

Expert recommendation

We recommend performing bronchoscopy with bronchoalveolar lavage to quantify airway inflammation, obtain lower airway cultures and perform bronchial toilette in patients with purulent disease and to aid in the diagnosis of respiratory clinical deterioration (Level of evidence 1D).

6. Pulmonary function tests

Pulmonary function tests should be performed annually in all capable patients. With adequate coaching to promote controlled breathing, overcome poor coordination, and properly seal the mouthpiece most patients with FD are able to perform basic pulmonary function testing. Spirometry before and after bronchodilator challenge is useful to diagnose reversible obstructive disease. Quantitative measurements of peak cough flow with maximal inspiratory (MIP) and expiratory pressures (MEP) are useful for documenting disease progression and individualized management strategies. Lung volume determinations via plethysmography or nitrogen washout test are preferred, but not always available or possible due to cognitive or coordination difficulties. In patients with significant respiratory involvement, pulmonary function tests should be performed more frequently, as indicated by the treating physician. It should be taken into account that many patients with FD are unable to perform pulmonary function testing due to impaired oral coordination, inability to regulate their breathing pattern and severe sialorrhea. Therefore the results may be inaccurate.

Expert recommendation

We recommend annual assessments of pulmonary function in all capable patients, regardless of their respiratory status (Level of evidence 1C).

7. Flexible laryngoscopy

Awake flexible laryngoscopy should be performed to assess the size of the tonsils and adenoid tissue when the patient has noisy breathing, snoring, stridor, or obstructive sleep apnea on polysomnography. When a patient has moderate or severe obstructive sleep apnea and the anatomical reason for upper airway obstruction is not found, sleep laryngoscopy under light sedation may be considered to detect potential pharyngeal collapse, glossoptosis, and sleep laryngomalacia. Sleep laryngoscopy may be coupled with bronchoscopy.

Expert recommendation

We recommend performing awake or sleep laryngoscopy in patients with noisy breathing, snoring, stridor, or obstructive sleep apnea on polysomnography (Level of evidence 1D).

8. In-laboratory polysomnography

Full, in-laboratory attended polysomnography should be performed in all patients with FD at the time of diagnosis regardless of the presence of signs or symptoms of sleep-disordered breathing. Polysomnography should be repeated yearly in all patients with FD regardless of prior negative studies. In patients with sleep disordered breathing on non-invasive ventilation, polysomnopgrahy should be repeated yearly to reassess the parameters of non-invasive ventilation [52]. In patients undergoing tonsillectomy or adenoidectomy, in-lab polysomnography should be repeated 6 weeks to 3 months following surgery [52]. Some children with FD receive growth hormone therapy for short stature [17, 65]. Due to the potential risk of adenoid and tonsil tissue enlargement, in-lab polysomnography should be performed both before, and 6 to 8 weeks after, initiating growth hormone therapy. Because of the high frequency of hypoventilation, the in-lab polysomnography must include CO₂ measurements. Due to impaired autonomic vasomotor control in FD, the reliability of transcutaneous CO₂ in this population is questionable, and end-tidal CO₂ measurement is recommended.

Expert recommendations

We recommend performing an in-lab polysomnography, including end-tidal CO₂ measurements, in all patients at the time of diagnosis and repeated annually if no major deterioration occurs (Level of evidence 1C). Due to the risk of adenoid and tonsil hypertrophy, we recommend that polysomnography be performed before and 6 to 8 weeks after starting growth hormone treatment (Level of evidence 1C).

9. Home polysomnography

Because of the high prevalence of hypoventilation, polysomnography must include CO₂ monitoring in an in-lab setting. This is not available on most home polysomnography equipment, and, therefore, home polysomnography is not recommended.

Expert recommendation

We do not recommend home sleep studies for patients with FD (Level of evidence 1D).

RECOMMENDATIONS FOR THE MANAGEMENT OF RESPIRATORY DISORDERS IN FD

1. Prevention and management of aspiration

Oral hygiene techniques

Volitional cough and clear and cleansing the mouth of debris after eating or drinking are essential techniques that should be performed by patients with FD following each meal to decrease the infectious inoculum of aspirated saliva.

Expert recommendation

We recommend that all patients with FD and their caregivers be educated about oral hygiene techniques to reduce the infectious inoculum of aspirated saliva (Level of evidence 1D).

Speech and swallow therapy

Patient and family education is the cornerstone of prevention and management of aspiration. All patients with FD should have a baseline evaluation by a speech and swallow specialist with video fluoroscopic swallow study. Patients with neurogenic dysphagia and aspiration into the airway should be referred to and managed by speech and swallow specialists. After thorough evaluation of swallowing function some patients with milder dysphagia may maintain the oral route of nutrition. This should be an interdisciplinary decision including the pulmonologist, neurologist, speech and swallow therapist and patient and caregivers. The swallow specialist must instruct the patient and caregivers how to perform safe swallowing techniques based on the individual’s evaluation and video fluoroscopic swallow study. A variety of techniques to improve oral hygiene may improve sequelae of salivary aspiration. The “safe” consistencies of food shall be defined after videofluoroscopic swallow evaluation.

Expert recommendation

We recommend that speech and swallow specialists be involved in the management of neurogenic dysphagia in patients with FD. All patients with FD should have a baseline evaluation and video fluoroscopic swallow study with a speech and swallow specialist. Intermittent swallow therapy is recommended, particularly with a decline in respiratory function or increase in respiratory infections (Level of evidence 1C).

Sialorrhea

Sialorrhea can be a source of aspiration. Injection of botulinum toxin into the parotid glands is safe and should be considered when sialorrhea is significant [66]. Anticholinergic therapy (e.g., glycopirrolate) may be also used to decrease sialorrhea, with close monitoring for worsening of alacrima and associated corneal injury, as well as urinary symptoms. Surgical interventions, including ligation, transposition, reduction, or removal of the salivary glands are not recommended.

Expert recommendation

We recommend considering botulinum toxin injections (Level of evidence 1C) in patients with FD in whom sialorrhea is disabling or a source of aspiration. Alternatively, we suggest using oral anticholinergic agents (e.g., glycopyrrolate) (Level of evidence 2D). We do not recommend surgical procedures (ligation, transposition, reduction, or removal of the salivary glands) (Level of evidence 1D).

Gastrostomy tube

If non-invasive techniques fail and respiratory disease progresses in patients with neurogenic dysphagia, avoidance of the oral route in favor of gastrostomy tube nutrition should be strongly considered [59, 60]. The decision should be made after careful review of the extent of dysphagia and other sources of aspiration. Partial or complete gastrostomy tube nutrition may be implemented [52]. Oral fluid avoidance may be sufficient in those patients who can still swallow solid or thickened consistencies with less risk of aspiration.

Expert recommendation

We recommend avoidance of the oral route in favor of gastrostomy tube nutrition if respiratory disease progresses after implementation of safe swallowing techniques (Level of evidence 1D).

Gastro-jejunal tube

If gastroesophageal reflux is contributing to respiratory disease, and further supported with impedance and manometry studies, gastro-jejunal tube nutrition should be strongly considered. If there is no clinical improvement, laparoscopic fundoplication surgery to avoid gastroesophageal reflux might be considered [21].

Expert recommendation

We recommend gastro-jejunal tube nutrition in patients with gastroesophageal reflux complicating respiratory disease (Level of evidence 1D).

Fundoplication surgery

A few decades ago, Nissen fundoplication surgery was a first-line treatment for virtually all patients with FD [20, 21, 67]. The goal was to reduce the risk of aspiration pneumonia during paroxysmal vomiting. However, there is no data to support significant benefit of fundoplication surgery in children with FD without proven gastroesophageal reflux-related respiratory disease. The decision to perform fundoplication surgery in a patient with FD requires standardized work up. In the general population, the failure rate of fundoplication is around 16% [68]. The gastric fundoplication wraps around a main branch of the vagus nerve; whether gastric motility worsens post-surgery due to vagal nerve injury is unknown but plausible [24]. Other potential side effects of fundoplication include dumping syndrome, worsening of esophageal motility, and the “gas-bloat syndrome” [69, 70]. There are data to suggest that the presence of a fundoplication may increase the risk of gastrointestinal bleeding [71]. Gastrointestinal bleeding occurred in 10% of patients with FD that had fundoplication surgery, compared to 2% in patients who did not have fundoplication surgery (NYU FD Registry 2016). The mechanism(s) for this increased risk of bleeding remains elusive at this time.

Expert recommendation

We do not recommend performing Nissen fundoplication routinely in patients with FD (Level of evidence 1D).

2. Airway mucus clearance and chest physical therapy

Moderate Chest Physical Therapy

Aggressive airway clearance in patients with FD is of potential therapeutic value and appears to have a very low risk of adverse events. Cough-augmentation is a key component of effective airway mucus clearance therapy. This can be achieved by manually assisted coughing, or with mechanical insufflation/exsufflation methods.

Expert recommendation

We recommend airway mucus clearance with manually assisted coughing or with mechanical insufflation/exsufflation methods for patients with FD with restrictive respiratory disease (Level of evidence 1D).

Aggressive Chest Physical Therapy

For patients with FD with suppurative lung disease, bronchiectasis or chronic cough/respiratory infections, more aggressive chest physical therapy is recommended. These include:

1. Manual chest physical therapy.

2. High-frequency chest wall oscillation (HFCWO) therapy. A 1-month study assessing the impact of oscillating chest vest therapy in 15 patients with FD showed good compliance, an improvement in oxygen saturation, and an increase in both forced vital capacity and peak expiratory flow rate. In the long term, HFCWO was associated with a reduction in pneumonia incidence, hospitalizations and antibiotic use [72].

3. Positive expiratory pressure devices (e.g. Acapella®). These have been successfully used in patients with bronchiectasis [73].

Due to the relatively high incidence of airway hyperreactivity in children with FD [54], the use of bronchodilators is recommended before initiation of any airway clearance routine.

Expert recommendation

We recommend manual chest physical therapy (Level of evidence 1D), HFCWO therapy (Level of evidence 1C), and positive expiratory pressure devices (Level of evidence 1D) for patients with bronchiectasis, chronic cough, or chronic respiratory infections.

3. Home pulse oximetry

Hypoxemia may be the sole presentation of pulmonary exacerbation in patients with FD, thus pulse oximetry, particularly at night or after taking benzodiazepines or similar sedative medications, is recommended. Pulse oximetry should be monitored in patients requiring supplemental oxygen, with advanced lung disease, and/or frequent respiratory exacerbations. The possibility of CO₂ retention while on supplemental oxygen therapy needs to be considered (see section #9).

Expert recommendation

We recommend using home pulse oximetry, particularly at night or following use of sedative medications, to detect hypoxemia and alert caregivers of potential respiratory exacerbations (Level of evidence 1D).

4. Prevention and treatment of respiratory infections including vaccinations

Viral pathogens including influenza A, influenza B, rhinovirus, adenovirus, respiratory syncytial virus, human metapneumovirus, and parainfluenza pose a greater risk in patients with FD with chronic lung disease. In these patients, influenza can be fatal. Annual influenza vaccination is strongly recommended unless contraindicated due to allergy [74]. During the influenza season, oseltamivir (5-day course) should be initiated immediately when there is a reasonable suspicion of influenza infection. If the polymerase chain reaction swab results negative for influenza, oseltamivir must be discontinued. Standard vaccination schedules from the U.S. Centers for Disease Control (CDC) should be followed for pneumococcal and other vaccinations.

Expert recommendation

We recommend annual influenza vaccination for all patients with FD (Level of evidence 1C). Treatment with oseltamivir must be started promptly in patients with high suspicion of influenza infection. Standard vaccination schedules from the U.S. CDC should be followed for pneumococcal and other vaccinations (Level of evidence 1D).

5. Special precautions during high altitude or air-flight travel

Oxygen

Complications of exposure to hypobaric hypoxia at high altitude or during air-flight travel in patients with FD include syncope and fatal cases of pulmonary edema [75]. Supplemental oxygen appears to prevent these complications and is therefore recommended during exposure to hypoxia. The possibility of CO₂ retention while on supplemental oxygen therapy needs to be considered (see section #9).

Expert recommendation

We recommend using supplementary oxygen when at high altitude or during air-flight travel (Level of evidence 1C).

Acetazolamide

Acetazolamide, a carbonic anhydrase inhibitor, has been used in some patients with FD as a respiratory stimulant. The safety and efficacy of acetazolamide in this patient population is unknown.

Expert recommendation

We do not suggest using acetazolamide as respiratory stimulant in FD as its safety and efficacy are unknown (Level of evidence 2D).

6. Empiric anti-acid reflux treatment

Empiric treatment with anti-acid reflux medications in patients with FD is strongly discouraged [62]. Acid suppression increases the risk of bacterial respiratory infections [76]. Inhibition of gastric acid secretion is only indicated for patients with gastrointestinal bleeding and evidence of gastroesophageal acid reflux disease [62].

Expert recommendation

We do not recommend empiric treatment with anti-reflux medications in patients with FD (Level of evidence 1D).

7. Airway specialist referral

Patients with FD with noisy breathing, stridor or snoring, with evidence of upper airway obstruction on laryngoscopy (not resolved by tonsillectomy and adenoidectomy surgery) should be referred for specialist airway management.

Expert recommendation

We recommend that patients with FD with complex obstructive respiratory disease be referred to an airway specialist (Level of evidence 1D).

8. Non-invasive ventilation during sleep

Non-invasive ventilation during sleep (e.g., continuous positive airway pressure [CPAP] or bi-level positive pressure) in patients with FD and sleep-disordered breathing reduces the risk of SUDS [13]. Therefore, patients with sleep-disordered breathing should initiate treatment with non-invasive ventilation. Due to chemoreflex failure [11, 12, 27], non-invasive ventilation should be initiated even in patients with FD with mild sleep-disordered breathing (e.g., apnea hypopnea index between 5-14 events/h in adults or between 1-5 events/h in children; nocturnal pCO₂ between 45-50 mmHg during >30% of sleep time; or nocturnal oxygen saturation of between 90-92% for a duration > 5 min).

Expert recommendation

We recommend using non-invasive ventilation even in cases of mild sleep disordered breathing (Level of evidence 1B).

9. Nocturnal oxygen supplementation

Nocturnal oxygen supplementation alone (i.e., without concurrent non-invasive ventilation) is not recommended due to the risk of further ventilatory depression, apnea and death [11, 12, 27]. In rare cases where nocturnal oxygen supplementation is required, it must be initiated under medical supervision in a sleep center, including CO₂ monitoring.

Expert recommendation

We do not recommend using nocturnal oxygen supplementation without non-invasive ventilation (Level of evidence 1C).

10. Steroid therapy

There is no data to support empirical use of inhaled steroids in patients with FD. Inhaled steroids should be considered in patients with FD with asthma, reversible lower airway obstruction on pulmonary function testing, or eosinophilia during bronchoscopy [77, 78]. Inhaled steroids in patients with suppurative lung disease and bronchiectasis are ineffective [43]. During severe pulmonary exacerbations with lower airway obstruction, a short trial (3-5 days) of oral prednisone 1 mg/kg/day may be considered.

Expert recommendation

We recommend inhaled steroids in patients FD with objective evidence of asthma (Level of evidence 1D).

11. Mucolytic therapy

The effectiveness of mucolytic agents is unclear as there are only a few small trials in patients with non-cystic fibrosis bronchiectasis. Inhaled hypertonic saline is safe and was shown to improve lung function and quality of life in a small study of patients with non-cystic fibrosis bronchiectasis [43, 79-83].

Expert recommendation

We suggest using inhaled hypertonic saline in patients with FD on a case-by-case basis (Level of evidence 2D).

12. Antibiotic therapy during acute exacerbations

Antibacterial therapy must be started promptly in patients with FD with acute exacerbation of suppurative lung disease/bronchiectasis. Sputum/gag culture should be obtained prior to initiation of antibacterial therapy in all patients. The appropriate antibiotic should be used in accordance to the bacteriology of lower airway secretions and coverage of aspiration flora [43]. Oral antibiotics should be given for 14 days [43]. The decision to initiate intravenous antibiotics depends on the patient baseline respiratory status. Intravenous antibiotics should be strongly considered in patients with FD who failed to improve after a course of oral antibiotics. Clinical monitoring and follow up pulmonary function testing or arterial blood gas should be performed to monitor recovery. Bronchoscopy with cultures should be considered for patients who fail to improve after appropriate antibacterial therapy.

Expert recommendation

We recommend selecting antibiotic therapy and route based on culture results, coverage of aspiration flora, baseline respiratory status of the patient, and the severity of the exacerbation (Level of evidence 1C).

13. Chronic antibiotic therapy

Azithromycin

Macrolides exert immunomodulatory effects on inflammatory responses, including reduction of mucus production, inhibition of biofilm production, suppression of inflammatory mediators, and modulation of leukocyte recruitment and function. Oral azithromycin 3 times weekly given for 6 months has been shown beneficial in reducing exacerbations of bronchiectasis in patients with non-cystic fibrosis bronchiectasis [43].

Expert recommendation

We recommend chronic oral azithromycin (3 times per week) in patients with FD who have bronchiectasis and frequent pulmonary exacerbations (Level of evidence 1D).

Inhaled tobramycin

Prophylactic antibacterial therapy with inhaled tobramycin is beneficial in patients with non-cystic fibrosis bronchiectasis colonized with P. aeruginosa [84] and may be considered in patients with FD who have suppurative lung disease/bronchiectasis who are colonized with P. aeruginosa [85]. Inhaled gentamicin may also be considered [86, 87].

Expert recommendation

We recommend chronic inhaled tobramycin or gentamicin in patients with FD and suppurative lung disease/bronchiectasis colonized with P. aeruginosa (Level of evidence 1D).

14. Scoliosis surgery

Bracing is not effective in the treatment of scoliosis in patients with FD. Corrective surgery has been performed on 32% patients with FD in the USA (NYU FD Registry 2016). While the aesthetic improvement is evident, solid evidence on its impact on respiratory function is lacking. Vital capacity appears to be similarly reduced in patients that did and did not undergo surgery (NYU FD Registry 2016). Complications of surgery can be severe, and include post-surgical refractory hypertensive-vomiting crisis, pain, pancreatitis, and paraplegia. Some patients with FD have very early-onset scoliosis and kyphosis. When surgery is performed, rather than fusing the spine, adjustable lengthening rods are used so that the chest retains elasticity as the thorax grows. Whether non-surgical approaches (e.g., bracing or physical therapy) can slow the progression of scoliosis and improve functional outcomes in patients with FD is unknown.

Expert recommendation

We suggest considering surgical correction of scoliosis in patients with FD on a case-by-case basis (Level of evidence 2D).

15. Continuous oxygen therapy, lung lobectomy, and tracheostomy

Continuous oxygen therapy

Patients with chronic severe hypoxemia may be considered for chronic oxygen supplementation. Careful monitoring of CO₂ levels is required. During sleep, use of non-invasive ventilation in conjunction with supplemental oxygen is required.

Lung lobectomy

Lung lobectomy for chronic suppurative lung disease should be performed only in patients with FD with severe localized bronchiectasis [88, 89]. Less than 1% of patients with FD require lobectomy (NYU FD Registry 2016). Ventilation-perfusion scan may be useful to assist in the decision of performing a lobectomy [90].

Tracheostomy

Tracheostomy should be considered in patients with FD with: a) severe obstructive sleep apnea refractory to tonsillectomy/adenoidectomy surgery and non-invasive ventilation, or b) chronic daytime respiratory failure with hypoventilation [91].

Expert recommendation

We recommend continuous oxygen, tracheostomy, and lung lobectomy only in patients with FD with chronic, advanced respiratory disease (Level of evidence 1D).

FUTURE DIRECTIONS

With advances in clinical care, life expectancy of patients with FD is increasing. However, respiratory disease remains a significant cause of morbidity and mortality in these patients. Swallow dysfunction and aspiration are not well understood in patients with FD. Improved methods to assess neurogenic dysphagia are required. Robust techniques to characterize the microbiome in the respiratory system will be an important step forward. Developing a standardized rating scale to grade CT scan findings specific for FD will be a future objective. Development of animal models reproducing the respiratory disorders of patients with FD [92, 93] and improved controlled clinical studies to evaluate the response to therapeutic interventions will allow us to understand the actual impact of potential treatments. An international collaborative effort is needed to enable sufficient power to assess the impact of standard treatments.

Highlights.

• Familial dysautonomia (FD) is a rare genetic disease characterized by severe respiratory disorders.

• A task force performed a systematic review to summarize current knowledge and evidence on respiratory disorders in FD.

• Expert recommendations for the diagnosis and management of respiratory disease in patients with FD are provided.

• These recommendations create a milestone in identifying key respiratory issues in patients with FD.

• It also provides a clinical and research framework to further study respiratory problems in FD.