Robert Listernick, MD, is an Attending Physician, Ann and Robert H. Lurie Children’s Hospital of Chicago; and Professor of Pediatrics, Northwestern University, Feinberg School of Medicine, Division of Academic General Pediatrics, Chicago, IL.
A 15-year-old boy was evaluated for a 6-month history of increasing dyspnea with exertion. The symptoms typically occurred 5 to 10 minutes into activity. He says he feels like “it is hard to get a good breath of air in.” He has had no associated neck or chest pain. He does not appreciate any noisy breathing while dyspneic; however, at night he snores loudly and has breathing pauses, according to his brother. He was prescribed an inhaled corticosteroid and albuterol, but they provided no relief. Despite these symptoms, he continued to play as a defensive lineman on his high school football team.
His birth history was unremarkable. Medical history was remarkable for recurrent childhood viral infections. He had tonsillectomy and adenoidectomy at age 5 years. Family history was remarkable in that his father had airway surgery for obstructive sleep apnea.
On examination, he was a healthy-appearing boy. His weight was 105.8 kg. Blood pressure was 110/60 mm Hg. His head, ears, eyes, nose, and throat (HEENT) examination was unremarkable. Neck was supple without adenopathy or thyromegaly. He had a Mallampati class 2 airway. Cardiac examination was normal. Abdomen was soft without masses or organomegaly. Back was straight. Neurologic examination was normal. There were no rashes.
Spirometry was performed at the initial office visit. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were normal, but the patient had a decreased FEV1:FVC ratio suggestive of an obstructive defect. There was no improvement in airflow with bronchodilators.
Robert Listernick, MD, moderator: What the heck is a Mallampati airway?
Jennifer L. Trainor, MD, pediatric emergency department physician: The Mallampati scoring system was devised by anesthesiologists as a quick measure to predict ease of intubation by looking at one’s ability to see the uvula, tonsillar pillars, and soft palate. A score of 2 does not raise concerns about ease of intubation or significant pharyngeal airway obstruction.
Dr. Listernick: What do you think of his subjective complaint of his inability “to get a good breath of air in”?
Susanna A. McColley, MD, pediatric pulmonologist: This could signify a number of different problems. First, he’s clearly overweight, and dyspnea on exertion may be due to a lack of fitness. Dyspnea on inspiration may be due to a structural or functional upper airway problem. We see a lot of children who have vocal cord dysfunction causing inspiratory difficulty during sports. Finally, one of the symptoms of exercise-induced asthma is the feeling of being unable to take a deep breath, which is probably why he was started on the asthma medications. However, generally this is a symptom of exercise-induced asthma if it occurs when exercise ceases rather than when it begins.
Dr. Listernick: Can you interpret the pulmonary function testing?
Dr. McColley: He has a mild obstructive defect.
Dr. Listernick: Moving forward, the initial pulmonologist who saw him thought that his symptoms were attributable to upper airway obstruction and ordered a sleep study.According to the report, “There were frequent obstructive apneas and hypopneas noted in both non-REM and REM sleep. These occlusive and partially occlusive respiratory events were associated with arousals, sleep fragmentation, snoring, bruxism, limb movements and periodic oxygen desaturations with rapid and spontaneous returns to oxygen saturation baseline. Oxygen saturation periodically fell below 89% for a total of 37 minutes. Carbon dioxide remained greater than 50 mm Hg for 16% of the time. Transcutaneous PCO2 ranged from 38 to 53 mm Hg; this was interpreted as severe obstructive sleep disordered breathing.”
Nathan S. Alexander, MD, pediatric otolaryngologist: We had been told that the reason he had the tonsillectomy and adenoidectomy was for upper airway obstruction.
Dr. Listernick: Can they grow back?
Dr. Alexander: As long as it was a complete tonsillectomy, they don’t re-grow. However, there is often residual adenoidal tissue that may re-grow but usually by age 8 or 9 years; re-growth at age 15 years would be quite uncommon.
Dr. Listernick: As an aside, do you always need a sleep study prior to tonsillectomy and adenoidectomy if the indication for surgery is upper airway obstruction?
Dr. Alexander: If there are clear symptoms of obstruction or significant tonsil or adenoid hypertrophy on examination or radiographically, most clinicians would perform surgery without obtaining a sleep study.
Dr. McColley: An important reason to perform a preoperative sleep study is to identify those patients at risk for post-operative complications. Few children completely resolve obstructive sleep apnea syndrome after adenotonsillectomy; those with moderate or severe obstruction might continue to have symptoms for a long period of time following surgery. In some cases, a postoperative sleep study is indicated to ensure that the obstruction has resolved.
Dr. Listernick: To continue, office laryngoscopy revealed a clear nasopharynx and normal vocal cord mobility with “prominent supraglottic tissue.” Because this appearance looked quite unusual, he underwent bronchoscopy the following day. There was very significant obstruction at the level of the supraglottic airway. The obstruction was so severe that we were unable to extubate him, a complication we had anticipated. He underwent tracheotomy and biopsies of the airway were obtained. What disease process did you think you were dealing with?
Dr. Alexander: We primarily wondered about angioedema because grossly the tissue appeared edematous but not inflamed. Neoplasia also seemed unlikely based on the gross appearance.
Dr. Listernick: The following tests were normal: complete blood count, erythrocyte sedimentation rate, C-reactive protein, C1 esterase inhibitor level and functional assay, C3, C4, and total hemolytic complement. Myxedema due to hypothyroidism may cause airway edema; free T4 was normal but thyroid-stimulating hormone (TSH) was mildly elevated at 11 mcIU/mL. Thyroid ultrasound revealed nonspecific heterogeneous appearing echotexture within both lobes of the thyroid gland without discrete masses. He was started on thyroid supplementation.
Laura Torchen, MD, pediatric endocrinologist: Airway edema is part of generalized myxedema seen in severe hypothyroidism, which was not the case in this young man. He had no symptoms of hypothyroidism other than the family’s perception that his obesity was related. They were hopeful that we were going to cure both his airway obstruction and his obesity with thyroid supplementation. I would describe his thyroid testing as indicative of subclinical hypothyroidism. Thyroid autoantibodies were negative.
Dr. Listernick: What did you think of the thyroid ultrasound abnormalities?
Dr. Torchen: The heterogeneous-appearing echotexture could be suggestive of inflammation, which could be suggestive of autoimmune hypothyroidism. We decided to treat him and repeat the antibody testing in the future.
Donald Zimmerman, MD, pediatric endocrinologist: In malnourished individuals, we sometimes see “sick euthyroid syndrome” in which the free T4 is normal and the TSH is low. Obese individuals may have a normal free T4 and elevated TSH due to leptin, which stimulates the pituitary production of TSH.
Dr. Listernick: Can we see the epiglottic and laryngeal biopsies?
Nitin Wadhwani, MD, pediatric pathologist: There were multiple non-necrotizing granulomas in all the biopsies. Routine stains for bacteria and acid-fast organisms were negative. The silver stain identified several spirochete-like structures; however, these structures were in the surrounding tissues rather than in the granulomas themselves.
Dr. Listernick: What is the significance of these findings?
Dr. Wadhwani: First, non-necrotizing granulomas are unlikely to be caused by an infectious process unless it’s very early in the course of the disease. Second, the spirochete-like structures are more likely to be artifact if they’re not found within the granulomas themselves.
Dr. Listernick: From an infectious standpoint, what would you have been thinking once granulomas were identified?
Ellen G. Chadwick, MD, pediatric infectious disease physician: Just to be clear, infection is quite unlikely in this case because the granulomas are non-necrotizing. That being said, you certainly need to do a thorough workup for mycobacterial and fungal disease. Infections caused by Bartonella henselae (cat-scratch disease) will also cause necrotizing granulomas. Even though the silver stain suggested the presence of spirochetes, such an infection would be extraordinarily rare.
Dr. Listernick: Rapid plasma reagin (RPR) for syphilis, tuberculin testing, and Bartonella titers were all negative. What’s the correct approach for diagnosing histoplasmosis and blastomycosis?
Dr. Chadwick: Beyond fungal stain and culture, the best tests are looking for the fungal antigens in the urine, as long as the specimen is sent an experienced laboratory. The tests are very sensitive and specific for active infection. Serology is not very helpful in these diseases.
Stanford T. Shulman, MD, pediatric infectious disease physician: We shouldn’t talk about spirochetes without at least mentioning Lyme disease, which has been blamed for any number of strange illnesses. However, I’m not aware of it having been implicated in a case such as this.
Dr. Listernick: I don’t believe he was ever tested for Lyme disease. When he was in the hospital, granulomatous inflammatory diseases were considered.
Megan L. Curran, MD pediatric rheumatologist: Certainly one needs to think about granulomatosis with polyangiitis (GPA), what used to be called Wegener’s granulomatosis. Although rare, there are a number of cases in the literature of GPA airway involvement. However, his anti-neutrophil cytoplasmic antibody was negative; this test has high sensitivity for GPA.
Dr. Listernick: I also wondered about extraintestinal Crohn’s disease, but his complete blood count, serum albumin, inflammatory markers, and stool calprotectin were all normal. When I became involved, I felt that the leading diagnosis by far was sarcoidosis, but I was unwilling to commit him to treatment without as much confirmation as could be obtained. I asked our otolaryngology colleagues to perform another biopsy of the airway, as well as the thyroid gland. There were extensive noncaseating granulomas in both the airway and the thyroid. All the infectious stains were negative.
Dr. Alexander: The repeat bronchoscopy was 1 month after the first procedure; both the erythema and the edema looked even worse than they had appeared initially.
Dr. Listernick: Have we reached a definitive diagnosis of sarcoidosis?
Dr. Curran: I believe so. There are a number of cases of both laryngeal sarcoid as well as sarcoid involvement of the thyroid gland in the literature; some of these cases have normal inflammatory markers and angiotensin-converting enzyme (ACE) levels such as our patient. ACE levels are better for assessing disease activity in known cases of sarcoid than they are for diagnosis.
Dr. Listernick: How does sarcoidosis present in children?
Dr. Curran: There are two different classic presentations. We are more used to hearing about the adolescent with hilar adenopathy and interstitial lung disease who is dyspneic with a dry hacking cough. These individuals may also have constitutional symptoms such as fever, weight loss, and malaise and develop lymphadenopathy, uveitis, or a polymorphous rash. However, a less common presentation is Blau syndrome caused by mutation in the NOD2 gene, which is also associated with early-onset inflammatory bowel disease. These are young children, generally younger than age 4 years, who present with severe arthritis, uveitis, and skin disease.
Dr. Listernick: How do you make the diagnosis of sarcoidosis?
Dr. Curran: By demonstrating the presence of noncaseating granulomas in the appropriate clinical context and excluding all the other causes of granulomatous disease that have been mentioned, particularly infections.
Dr. Listernick: Treatment?
Dr. Curran: Corticosteroids. I read an article about a placebo-controlled trial of inhaled corticosteroids in laryngeal disease that failed to demonstrate efficacy so I will use systemic treatment. I will probably transition him to a steroid-sparing medication such as methotrexate or azathioprine.
Dr. Listernick: What about the thyroid disease?
Dr. Torchen: It certainly has been reported in the literature, but the case reports are quite old. It will be interesting to see if the hypothyroidism improves with the steroid treatment. For the moment, we’ll keep him on thyroid supplementation, which has kept him euthyroid.
Dr. Listernick: Thank you, everyone.