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Advances in Otolaryngology

NIH-Funded Research Addresses Today’s Major Issues in Laryngeal Function Research

image of Dr. Michael J. Pitman

Dr. Michael J. Pitman

Michael J. Pitman, MD, Chief of the Division of Laryngology and Director of the Center for Voice and Swallowing in the Department of Otolaryngology – Head and Neck Surgery at NewYork-Presbyterian/Columbia University Irving Medical Center, is a recognized expert in voice restoration, conservation, and care of the professional voice, as well as in the care of swallowing and airway disorders. He has received numerous grants for his pioneering research in the field of laryngology, including most recently two prestigious National Institutes of Health awards to investigate the restoration of laryngeal innervation in recurrent laryngeal nerve injury and vocal fold paralysis and to study the complications of intubation on laryngeal function for patients with COVID-19.

The Impact of COVID-19 on Laryngeal Function

Emerging evidence demonstrates that patients who spend time in an ICU are often left with physiologic impairments that affect their health and overall quality of life. Indeed, it is becoming clear that ICU survivors of COVID-19 who undergo prolonged intubation are at higher than normal risk of laryngeal injuries. In all, 5 to 10 percent of the 1.7 million patients infected in the U.S. to date (85,000 to 170,000) have required intubation for ventilation in an ICU.

“We started to see enormous amounts of laryngeal injury due to long-term intubation in patients who had COVID-19,” says Dr. Pitman. “They are presenting with airway stenosis, vocal fold immobility, difficulty breathing, major voice issues, and even significant swallowing issues. And so we applied for a grant to study these patients to try and quantify these consequences, learn how to best treat them now, and to prevent them in the future.”

According to Dr. Pitman, the laryngeal injury risk in patients with COVID-19 is compounded because tracheotomy is discouraged over concerns of aerosolizing the virus and exposing caregivers, health care workers, and other patients. “Current guidelines recommend delaying tracheotomy for COVID-19 patients until they have been intubated more than 21 days,” says Dr. Pitman, who serves as principal investigator of the one-year NIH study. “This has major implications since most mechanically ventilated COVID-19 patients require prolonged intubation with large endotracheal tubes; both factors that are strongly associated with the development of acute laryngeal injury, unilateral vocal fold immobility, and posterior glottic stenosis.”

Dr. Pitman and the study’s co-investigators, Alexander H. Gelbard, MD, and David O. Francis, MD, experts in airway stenosis and outcomes research, at Vanderbilt University Medical Center and University of Wisconsin School of Medicine and Public Health, respectively, are tapping into the comprehensive database of the North American Airway Collaborative (NoAAC), established by Drs. Gelbard and Francis several years ago. With more than 40 centers, the network comprises laryngologists and speech language pathologists who share their patient data related to laryngeal stenosis. “We’re going to use the power of that collaborative to gather not only NewYork-Presbyterian’s data, but also national data,” says Dr. Pitman. “We plan to tease out comparisons and gain a better understanding of what is occurring nationally and to compare treatments and outcomes in different regions and in different hospital systems.”

The primary goal of the study is to quantify the impact of COVID-19 infection and its treatment on laryngeal function, voice, communication, and quality of life. The long-term goal is to develop interventions to reduce the incidence and impact of post-intubation laryngeal injury.

image of image of vocal folds in the throat

A 40-year-old-female was evaluated for dyspnea and dysphonia following a hospitalization for COVID-19 where she was intubated for 16 days. Following extubation she experienced progressive dyspnea. Posterior glottic stenosis was identified with an interarytenoid adhesion and a fixed right cricoarytenoid joint.

To accomplish this, Dr. Pitman and his colleagues will address three knowledge gaps: the magnitude of vocal communication dysfunction resulting from prolonged intubation; the risk factors for intubation-related laryngeal injury in COVID-19 patients; and interventions that minimize the risk and morbidity of laryngeal injury. The investigators will leverage the established NoAAC digital infrastructure, which includes prospective collection of clinical data, mobile voice monitoring on a smartphone app, and validated patient-reported outcome measures (PROMs).

The study will enroll 500 patients from centers throughout the country. Subjects will complete a baseline assessment within three months of their hospital discharge that includes hospital admission data, laryngoscopy, voice recording, and PROMs to quantify voice, communication, and general quality-of-life impairment. “We hypothesize that more than 50 percent of survivors will have acute impairments in voice and communication, the degree to which will correlate with the intubation duration and endotracheal tube size,” says Dr. Pitman.

“The major goals of our study are to quantify the impact of COVID-19 infection and its treatment on laryngeal function, voice, communication and quality of life and to identify interventions to prevent and treat these injuries. Through these efforts, we hope to minimize laryngeal function impairment and maximize quality of life for survivors.”

— Dr. Michael J. Pitman

The second aim of the study is to quantify the long-term burden of COVID-19 infection and treatment on laryngeal function, voice, communication, and quality of life within the survivor cohort by collecting patient-related health data since enrollment, including treatment data related to the laryngeal injury. They will re-administer PROMs six months after baseline assessment to measure long-term effects, hypothesizing that clinically significant long-term impairments in voice and communication in COVID-19 survivors will persist among those identified with injury at baseline and also will correlate with intubation duration and endotracheal tube size. The third aim is to identify potential intervention targets to prevent and treat post-intubation related laryngeal injuries.

“In another project we are evaluating cadaver tissue from people who were intubated and then passed away from COVID-19,” says Dr. Pitman. “We’ll be investigating the mucosa in the infraglottic cavity for different inflammatory factors to see if the inflammation is similar to other patients who’ve had prolonged intubation or if it’s actually different in COVID-19. If someone doesn’t have COVID-19 and is intubated for 21 days, would it be exactly the same as a patient with COVID-19? Maybe there’s a difference in the inflammatory process. We don’t know, but we’re going to look into it, and we’ve already started banking that tissue.”

Investigating Molecular Mechanisms in Laryngeal Reinnervation

“The voice is a unique and integral part of each person’s identity, impacting virtually every aspect of our daily lives, from speaking to loved ones, to engaging in business, or simply completing daily tasks,” says Dr. Pitman. “Recurrent laryngeal nerve injury and the resulting vocal fold paralysis cause voice dysfunction that leads to frustration, isolation, fear, and altered self-identity, as well as impaired quality of life and lost worker productivity. It is also associated with disability claims at rates similar to those of chronic diseases such as congestive heart failure, COPD, and severe depression.”

Following severe injury, despite the ability for the recurrent laryngeal nerve to regenerate, the vocal fold remains permanently paralyzed due to misguided, non-selective, synkinetic reinnervation of the laryngeal adductor and abductor muscles. “The abductor muscles open the vocal folds during respiration while the adductor muscles close the vocal folds during phonation,” says Dr. Pitman. “In normal innervation, adductor muscles are solely innervated by adductor axons, and abductor muscles by abductor axons. However, in synkinesis each muscle is non-selectively innervated by a mix of adductor and abductor axons, resulting in contraction of antagonistic muscle groups and a net absence of motion.”

“The treatments that we have now are suboptimal,” continues Dr. Pitman. “They do make the voice better, but they don’t actually restore the natural dynamic voice. The restoration of normal vocal fold function requires restoration of normal non-synknetic laryngeal innervation, which can only be achieved only through therapeutic manipulation of reinnervating axons, guiding them back to the appropriate laryngeal muscles.”

In 2019, Dr. Pitman received NIH funding for a five-year grant to study the molecular mechanisms underlying axonal guidance during nerve regeneration. The study will build on previous work of Dr. Pitman and his colleagues that revealed laryngeal muscles are innervated in similar sequences in both embryologic development and post-recurrent laryngeal nerve injury. However, reinnervation following injury is disordered, resulting in synkinesis with vocal fold dysfunction.

Dr. Pitman’s lab identified Netrin-1 and GDNF as the factors that play a significant role in axon guidance in the larynx. “We have shown that the expression of Netrin-1 and GDNF in laryngeal muscles and the expression of their receptors in the nucleus ambiguus are chronologically coordinated with axonal reinnervation,” explains Dr. Pitman. “Manipulation of these guidance cues can alter the pattern of reinnervation. These findings suggest the presence of a controlled but dysfunctional expression of guidance cues resulting in synkinetic reinnervation and vocal fold paralysis after recurrent laryngeal nerve injury. In comparison, developmental innervation, which is also tightly controlled chronologically, results in normal vocal fold function. Essentially, we’re investigating the gene expression of these factors in the muscles, nerves, and brainstem in rat models and their mechanisms of action and evaluating the differences between embryos and adult animals post injury.”

images of axons

(A) Brainstem explant containing labeled motoneurons of the facial nucleus. (B) Axon (*) from the explant in A. (C) Nodose ganglion explant. (D) Magnification of axons (*) of C. (E) Neuron extending axon into microfluidic chamber channel along Netrin-1 positive gradient. (F) Magnification of the axon showing branching into two channels (*). Courtesy of Dr. Michael Pitman.

The new study seeks to determine the mechanisms of the pathways of Netrin-1 and GDNF signaling in embryologic development that lead to normal laryngeal innervation, followed by an evaluation of the effects on axon pathfinding of manipulating these same pathways in an adult rat model of recurrent laryngeal nerve injury and reinnervation so they mimic those in embryology. “By recapitulating in the adult rat what occurs during embryogenesis, our goal is to compare the two and identify any differences that have potential as a therapeutic target,” says Dr. Pitman. “After we identify the differences between the adult rat and the embryologic rat, we will then have an in vitro model of the brainstem and laryngeal muscles, which will enable us to actually manipulate the growth of those axons. Capitalizing on these differences for the treatment of recurrent laryngeal nerve injury is a novel strategy. What is significant about our approach is that it is a focused investigation of two guidance cues across one integrated system of innervation, including the brainstem, axon and muscle.”

Dr. Pitman and his colleagues will be the first to investigate pathways that influence developmental innervation in the larynx and, moreover, compare the pathway to that of reinnervation. The research will broadly impact the field of nerve regeneration, advancing understanding of the mechanisms of axonal pathfinding with the potential to ultimately transform the treatment of vocal fold paralysis.

 

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Dr. Michael J. Pitman

NewYork-Presbyterian

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