Case 1: From Classroom to Care: A Teacher’s Swift Referral Unveils a Rare Disease at a School-Based Health Center

Presented here are three patients who have a common chief complaint. All three cases have discussions on presentation, the differential diagnosis, and management that collectively serve as a Review article. Following the three cases, an expert weighs in a short commentary with 5 questions for CME credit.Upon the first day of school, a prekindergarten teacher observed abnormal breathing in a 4-year-old boy and promptly referred him for a same-day evaluation at an embedded school-based health center (SBHC). His mother was called by the school to pick him up and bring him to the clinic. She reported that the patient has a history of 8 to 9 months of noisy breathing initially noticed during his migration journey from Nicaragua to the United States. At that time, he also had cough and nasal congestion, which resolved within a few days. Upon moving to the United States 5 months before presentation, the patient visited an emergency department, where he was diagnosed with croup and was reportedly treated with steroids. However, his noisy breathing persisted, occurring in the absence of illness and increasing with sickness, when he was supine, and with physical activity. Gradually, he has developed episodes of aphonia and increased work of breathing at rest. Neck radiographs ordered 3 months prior by his primary care physician revealed symmetric subglottic tracheal narrowing consistent with croup. A referral was made to a pediatric otolaryngologist; however, he was unable to be seen before his presentation to the SBHC. Three days before starting school, he developed a cough and nasal congestion and complained of throat pain, pointing to his neck as the source of discomfort. He has no significant medical history or hospitalizations and was born full-term without complications. He has no fevers, chills, night sweats, or weight loss. Over-the-counter children’s cough medicine has provided no relief. The patient’s eating habits and activity levels are unchanged.On physical examination, he is alert and oriented, without acute distress. He is responsive but noted to have aphonia. His vital signs are within normal limits, and notably, he has a heart rate of 106 bpm, respiratory rate of 24/min, and oxygen saturation of 97% on room air. He has rhinorrhea and erythema of the posterior oropharynx. He has no lymphadenopathy, and tonsils were 2+ bilaterally. His lung examination demonstrates inspiratory and expiratory stridor, decreased lung sounds throughout, occasional wheezes, and slight suprasternal retractions.Due to retractions and severity of stridor, the patient is referred urgently to a children’s hospital emergency department for further evaluation and treatment. On arrival, his vital signs remain stable. Laboratory examination results are notable for a white blood cell count of 15.75 × 103/μL with 70.6% neutrophils, 0.4% immature granulocytes, 24.6% lymphocytes, 3.5% monocytes, 0.6% eosinophils, 0.3% basophils, hemoglobin 14.0 g/dL, hematocrit 40.4%, potassium 5.4 mmol/L, and bicarbonate 16 mmol/L, and respiratory viral panel results are notably positive for rhinovirus/enterovirus and negative for SARS-CoV-2. Chest and neck radiograph (Figure 1) show symmetric subglottic tracheal narrowing (similar to radiograph from 3 months prior) with mild enlargement of the tonsils and adenoids. He receives 0.6 mg/kg dexamethasone and nebulized racemic epinephrine with moderate improvement. He is admitted to the hospital medicine team with plans to treat with dexamethasone every 8 hours and nebulized racemic epinephrine as needed.Inspiratory, expiratory, and biphasic stridor have distinct causes that are important to consider in developing a differential diagnosis. Namely, inspiratory stridor occurs after obstruction or narrowing of supraglottic and glottic areas.1 Expiratory stridor arises when subglottic areas, including intrathoracic areas, are affected.1 Biphasic stridor is often caused by a fixed central airway obstruction that can occur at any level.1 Differential diagnosis of biphasic stridor includes external compression, intraluminal airway masses such as hemangiomas and foreign bodies, subglottic stenosis, and vocal cord obstruction.2 Moreover, congenital and acquired causes of stridor can be differentiated by chronicity. Congenital causes, including laryngomalacia, tracheomalacia, vascular ring, bronchogenic cyst, laryngeal malformations (including cysts, stenosis, clefts, and webs), and infantile hemangiomas, are most likely to present soon after birth.1 Acquired causes, including vocal cord paralysis, acquired subglottic stenosis, tumor, recurrent respiratory papillomatosis (RRP), and hypocalcemic laryngeal spasm, can present later in life. Given the age of presentation, acquired causes of biphasic stridor are most relevant to consider for this patient.1 Of the acquired causes of chronic stridor in children, vocal cord paralysis, tumors, and RRP all present with biphasic stridor.Vocal cord paralysis can be congenital or acquired, with many cases being idiopathic.3 Patients commonly present with dysphonia, hoarseness, stridor, recurrent respiratory infection, and respiratory distress.3 Diagnosis is made via flexible nasopharyngoscopy, which shows reduced or absent adduction or abduction of the paralyzed vocal cord or midline resting position. Further workup is performed to determine the underlying cause.3 An obstructive, fixed tumor, most commonly a mediastinal mass including thymoma or lymphoma, may also cause biphasic stridor, and computed tomography is commonly used for diagnosis.4 Finally, RRP also can present with biphasic stridor. Diagnosis requires laryngoscopy and positive human papillomavirus (HPV) testing results on biopsy.5Given the patient’s lack of improvement with racemic epinephrine and demonstration of chronic, persistent subglottic stenosis on neck radiograph, an otolaryngologist was consulted and a bedside flexible indirect laryngoscopy was performed, which revealed multiple verrucous lesions of the vocal folds, with extension inferiorly and airway obstruction, highly suspicious for juvenile recurrent respiratory papillomatosis (JoRRP) (Figure 2). The patient was taken urgently to the operating room for ablation of the lesions, and tissue was sent for pathology evaluation. Histological evaluation results were consistent with JoRRP, and lesions had positive test results for HPV type 6. The patient was diagnosed with JoRRP, a condition caused by HPV.RRP is a chronic condition of the upper airway caused by HPV infection that can present in youth (JoRRP) or in adulthood (adult-onset RRP).6 JoRRP is the most common cause of benign laryngeal tumors in children, with an incidence of 4.3 per 100 000 children per year.7 It is a chronic condition caused primarily by HPV-6 and HPV-11 strains that most often presents between 2 and 3 years of age with recurrent exophytic papillomas of the upper respiratory tract, including the true vocal folds, false vocal folds, subglottic region, and trachea.8 Infection is thought to occur during vaginal delivery by a mother positive for HPV-6 or HPV-11.9 The papillomas cause progressive dysphonia accompanied by stridor and occasional respiratory distress. Symptoms caused by papillomas include chronic cough, hoarseness, recurrent upper respiratory tract infections, and hemoptysis.10 Given the relative rarity of JoRRP, misdiagnoses of asthma, croup, laryngotracheobronchitis, and foreign body aspiration are common.10 Definitive diagnosis requires visualization of papilloma by laryngoscopy and positive HPV testing results on biopsy or surgical excision.5Although the incidence of JoRRP is higher in low- or middle-income countries in which HPV vaccination rates are low and children are less likely to receive accurate diagnoses and appropriate treatment,10 children living in underserved areas or those who face financial barriers to health care in high-income countries may also experience delayed diagnosis or inappropriate treatment. The case presented here highlights the important role health care safety nets, such as SBHCs, can play in appropriate and timely access to care for children who are underinsured.There is no cure for JoRRP; treatment involves repeated microlaryngoscopic procedures to remove papillomas upon recurrence.10 Most patients undergo an average of 4.4 procedures per year before entering remission, most commonly by puberty.11 Little is known regarding factors that influence remission, with some patients continuing to develop recurrent papillomas into adulthood, although recent studies suggest that later age of diagnoses correlates with remission.12 Although microlaryngoscopic removal procedures remain the mainstay of treatment, bevacizumab and cidofovir are also used as adjuvant therapies to reduce the frequency and severity of recurrence.3Prevention of JoRRP is achieved primarily through vaccination against HPV with the quadrivalent vaccine and nonavalent vaccine, both of which protect against HPV-6 and HPV-11.13 Countries that have introduced national vaccination programs against HPV have seen significant reductions in the incidence of JoRRP, attributed largely to the decrease in HPV-6 and HPV-11 in pregnant mothers.13–15The patient tolerated ablation well (Figure 3) and had immediate improvement in symptoms of airway obstruction, particularly while sleeping. He was discharged home 2 days later with recommendations to follow up with an otolaryngologist in the interdisciplinary voice clinic. The HPV vaccination series was started while he was an inpatient. A social worker was consulted, and the family was enrolled in a financial assistance program. He was seen for follow-up 2 months later and was noted to have improved stridor but continued aphonia. Repeat indirect laryngoscopy showed recurrent lesions on bilateral vocal folds but with less bulk on the left side (site of previous excision). He has repeat surgery scheduled for the excision of lesions on the right. He was also seen in the interdisciplinary voice clinic, which recommended alternative communication strategies due to continued aphonia.