A 20-year-old woman presented to an internal medicine physician at our community-based free clinic due to increasing difficulty breathing. Her symptoms began 9 years earlier with the feeling of “something stuck in her throat.” At that time she was living in South America and did not seek medical attention. Over the years, her shortness of breath progressively worsened without relief.
After immigrating to the United States at age 18, she was seen by a variety of clinicians and was given diagnoses of bronchitis, asthma, and COVID-19. She was treated with antibiotics, including tetracycline, erythromycin, and amoxicillin, as well as inhaled bronchodilators and steroids, without improvement.
Before presenting to our clinic, she was seen by a nurse practitioner, who documented decreased breath sounds and wheezing on physical examination and prescribed amoxicillin and guaifenesin. The patient knew that these medications did not improve her symptoms in the past and did not fill these prescriptions. She presented to our community-based clinic the following day and was not taking any medications.
On presentation, the patient complained of chest tightness and shortness of breath that worsened on exertion. She was having considerable difficulty performing normal activities of daily living, was unable to walk up a flight of stairs, had frequent nighttime waking due to shortness of breath, and had an intermittent nonproductive cough. She reported no fever, chills, night sweats, weight loss, or hemoptysis and did not have a history of tuberculosis or prior hospitalizations, surgeries, or intubations.
Her family history was significant for an older brother who experienced similar symptoms that resolved after surgery. She did not use tobacco, alcohol, or recreational drugs, and had no known history of occupational or toxic environmental exposures.
INITIAL EVALUATION
In the clinic, her temperature was 98.1°F (36.7°C), heart rate 96 beats per minute, blood pressure 105/60 mm Hg, respiratory rate 16 breaths per minute, oxygen saturation 97% on room air, and body mass index 25.7 kg/m2.
On physical examination, she was neatly groomed but withdrawn. High-pitched inspiratory and expiratory sounds were audible without a stethoscope, and breathing was labored, engaging accessory muscles. The nares were patent. The oral cavity and oropharynx showed no erythema, exudate, masses, or lesions. The tonsils were not enlarged. Her voice was clear without hoarseness. There was no cervical adenopathy. Cervical musculature was bulky and prominent. Her trachea was midline, and thyroid was nontender without nodules and was not enlarged. Inspiratory and expiratory high-pitched sounds were most prominent with auscultation over the neck. Chest expansion was symmetrical. Lungs were clear to percussion and auscultation without wheezing or crackles.
Palpation of the chest revealed no abnormal pulsations, lifts, thrills, or heaves. Heart rate and rhythm were regular, with no extra heart sounds or murmurs. Abdomen was soft, without hepatomegaly, masses, or tenderness. There was no peripheral edema or nail clubbing.
DIAGNOSTIC CLUES IN INITIAL FINDINGS
1. Which aspects of this patient’s presentation made the diagnosis of asthma less likely?
Presence of biphasic stridor
Shortness of breath and wheezing
Duration of symptoms
Lack of response to medications
A critical diagnostic clue in this patient’s evaluation was the identification of stridor, distinct from wheezing. It is imperative to distinguish stridor from wheezing. Stridor is a physical finding described as a high-pitched respiratory sound produced by turbulent airflow through a partially obstructed airway.1 It is loudest with auscultation over the neck, although at times it can be transmitted to the chest. Wheezing is also a high-pitched sound but originates from narrowing of the small airways of the lungs. Wheezes are loudest with auscultation over the lung fields, and minimally audible or absent over the neck.
Stridor is a much less common finding than wheezing but has multiple potential and serious etiologies (Table 1).1–5 The categorization of this patient’s stridor as chronic and biphasic narrows the diagnostic possibilities. The presence of stridor, particularly biphasic stridor, makes the more common diagnoses of asthma or bronchitis unlikely. Although severe asthma may present with biphasic wheezing, the sound is high pitched and loudest over the lung fields (rather than over the neck, as observed in our patient).
Categorization of stridor
Asthma is a condition whose duration can be similar to the duration of symptoms seen in this patient, beginning in childhood and continuing into adulthood. An infectious process could exacerbate an underlying chronic respiratory issue like asthma6; however, upper respiratory infections are typically acute in nature,7 while our patient’s symptoms continued to progress over many years. Further, recurrent treatment of an acute problem without addressing the underlying chronic issue is ineffective. The patient was repeatedly treated with antibiotics, beta-agonist inhalers, and corticosteroids. Her lack of response to these treatments certainly put the diagnoses of bronchitis or asthma in question.
INITIAL EVALUATION OF STRIDOR
2. When stridor is suspected, which noninvasive diagnostic test is most useful in the initial evaluation?
Pulmonary function tests (PFTs) with flow-volume loops
Chest radiography
Chest computed tomography
Diffusing capacity of the lungs for carbon monoxide
Pulmonary function testing
Treating hypertension without obtaining a patient’s blood pressure or prescribing glasses without checking vision ignores the metrics that define the condition. In the same light, treating asthma without obtaining spirometry or full PFTs can result in both over- and underdiagnosis of asthma or a missed opportunity to diagnose other causes of respiratory symptoms.8
The diagnosis of asthma requires not only the presence of clinical symptoms of wheezing, shortness of breath, chest tightness, and cough, which fluctuate over time, but also documentation of variable expiratory airflow obstruction. A study of patients labeled as having persistent asthma, all of whom were treated in a single health system between 2016 and 2020, revealed that less than 15% had spirometry or PFTs ordered.9 Another study reported that 30% to 35% of adults diagnosed with asthma did not have current asthma.10 Furthermore, a recent case-finding trial showed that structured spirometry screening effectively identified previously undiagnosed asthma and chronic obstructive pulmonary disease.11 The lack of early spirometry measurements and PFTs are often key contributors to delayed diagnoses in patients with respiratory symptoms.
Updated technical standards for interpreting PFTs. Clinicians should understand the biological variability and limitations of lung function testing.12 When interpreting PFTs, clinicians must not only recognize patterns but also evaluate them in the clinical context to refine the differential diagnosis. In 2021, the European Respiratory Society/American Thoracic Society (ERS/ATS) joint task force updated its statement on PFT interpretation,12 emphasizing that PFTs should be used to classify physiology, not to make a diagnosis. The ERS/ATS task force also updated its recommendation for testing severity of lung function impairment, suggesting that clinicians use the z score, which quantifies how many standard deviations a given lung function value is from the mean of a healthy population, instead of percent predicted because the z score provides more consistent data across age and sex categories.12–14
The expiratory disproportion index ([forced expiratory volume in 1 second ÷ peak expiratory flow] × 100) can effectively distinguish upper airway stenosis from other respiratory pathology, including vocal cord dysfunction and asthma (sensitivity 95.9%, specificity 94.2%), when a threshold value of 50 is used.15–17 An expiratory disproportion index may be a valuable metric for assessing suspected airway obstruction and is widely accessible since it is derived from PFT results. However, it is not yet routinely included in the calculations in routine PFTs, and its accuracy may be limited in patients with obesity.
Imaging options
A chest radiograph may be indicated in certain cases of stridor, particularly expiratory stridor, to help exclude extrinsic causes of airway obstruction such as mediastinal masses, lymphadenopathy, or foreign bodies. However, chest radiography and chest computed tomography often appear normal when biphasic stridor is present because these modalities have limited sensitivity for detecting lesions within the larynx or trachea.
In contrast, computed tomography of the neck can more precisely characterize structural abnormalities in the extrathoracic airway, such as subglottic stenosis, laryngeal masses, or external compression from thyroid enlargement or cervical lymphadenopathy, and is useful once categorization of stridor (Table 1) points to the neck as the source of the finding.
Diffusing capacity of the lungs for carbon monoxide
This test measures gas exchange at the alveolar-capillary membrane. It is generally normal in isolated upper airway obstruction and offers little diagnostic value in this context.
CASE CONTINUED: PULMONARY FUNCTION TESTING
Chest radiography revealed no acute disease, and the patient was referred to a pulmonologist for further evaluation with PFTs. Complete blood cell count and comprehensive metabolic panel were obtained and were normal.
This patient’s PFT findings revealed good effort, with peripheral oxygen saturation of 99% on ambient air. Forced vital capacity was mildly reduced at 76% of predicted value (Table 2). Forced expiratory volume in 1 second and the forced expiratory volume in 1 second to forced vital capacity ratio were markedly reduced, at 30% of predicted and 35%, respectively, consistent with severe obstructive impairment. There was no improvement after a bronchodilator was administered. The patient’s z score was −4.16,18 indicating the highest severity level of lung function impairment per the ERS/ATS 4-tier z-score system.12
The patient’s spirometry results
The patient’s expiratory disproportion index was calculated as 93 ([0.81 ÷ 0.87] × 100), well above the threshold value of 50 for distinguishing upper airway stenosis from other respiratory pathology.
Flow-volume loop diagrams showed significant truncation of both the inspiratory and expiratory limbs, suggesting a fixed airway obstruction of the glottis or upper trachea (Figure 1A). This finding can differentiate fixed airway obstruction from vocal cord dysfunction, which presents with either a normal flow loop (Figure 1B) or a flattened inspiratory limb.
(A) The patient’s spirometry flow-volume loop diagram showed truncation of both inspiratory and expiratory phases. (B) Typical flow-volume loop configuration.
Part B of this figure is adapted from Stanojevic S, Kaminsky DA, Miller MR, et al. ERS/ATS technical standard on interpretive strategies for routine lung function tests. Eur Respir J 2022; 60(1):2101499. doi:10.1183/13993003.01499-2021
DIFFERENTIAL DIAGNOSIS
3. Which of the following diagnoses best explains this patient’s clinical presentation and diagnostic findings?
Asthma
Cystic fibrosis
Vocal cord dysfunction
Subglottic stenosis
Asthma can have progressive symptoms and last many years, but the presence of stridor, rather than wheezing, as well as a lack of response to bronchodilators clinically and on spirometry, makes this diagnosis unlikely. Additionally, the patient was treated with agents for bronchospasm in the past without relief.
Cystic fibrosis is an inherited disease, with onset at a young age and ongoing progression. Cystic fibrosis is often characterized by chronic productive sputum, recurrent pneumonia, and gastrointestinal symptoms, none of which were part of her presentation. Findings of bronchiectasis on chest radiograph would also be expected with cystic fibrosis of this duration.
Vocal cord dysfunction presents with similar symptoms of shortness of breath, chest tightness, and stridor but does not have the PFT abnormalities seen in this patient. Also, the symptoms of vocal cord dysfunction are episodic, with intermittent periods of normal respiration, while the patient’s symptoms were unremitting.
Subglottic stenosis. Her history of chronic progressive symptoms, findings of biphasic stridor on physical examination, normal chest radiograph, and abnormal spirometry with plateauing of both limbs of the flow-volume loop are consistent with the diagnosis of subglottic stenosis. Biphasic stridor is the classic primary presenting symptom of subglottic stenosis, both acquired and idiopathic.4
Subglottic stenosis is a rare entity, and the phenomenon of patients with subglottic stenosis being misdiagnosed due to its similarities with other respiratory conditions is well documented.5,15,19,20 One study suggests that 33% to 37% of all patients with subglottic stenosis are initially diagnosed with asthma and have a mean diagnostic delay of 2 years.15
In the outpatient setting, PFT findings can strongly suggest the diagnosis of subglottic stenosis. It is important to remember that a simple spirogram will not make this diagnosis. It is essential to order PFTs with flow-volume loop when evaluating stridor. The gold standard for diagnosing subglottic stenosis is laryngoscopy or bronchoscopy.15
CASE CONTINUED: PULMONARY EVALUATION AND SURGICAL INTERVENTION
The pulmonologist suspected subglottic stenosis and ordered chest and neck computed tomography, which showed narrowing of the trachea (Figure 2), and subsequently referred the patient to an ear, nose, and throat (ENT) surgeon.
Neck computed tomography showed a narrowed trachea measuring 3.04 mm.
When the patient visited the ENT surgeon, her symptoms had worsened, and she was sent to a nearby emergency room, where she was admitted for airway observation. Initial inpatient bedside laryngoscopy showed evidence of 50% subglottic stenosis circumferentially. Later, while she was eating, she became acutely short of breath, and despite treatment with ipratropium bromide and albuterol sulfate inhalation solution, intravenous dexamethasone, and racemic epinephrine, she did not improve. She was sent to the operating room for emergent balloon dilation.
The patient underwent bronchoscopy and suspension microlaryngoscopy. (In this procedure, a rigid laryngoscope is inserted through the mouth to provide a direct microscopic view of the throat and vocal cords; the device is maintained in place by a “suspension” system, often placed on the patient’s chest, to allow the surgeon use of both hands.) Laryngoscopy revealed the presence of 65% to 70% stenosis in a circumferential pattern that began at the cricoid level and extended about 1.7 cm (Figure 3). Balloon dilation together with blue laser–assisted removal of the stenosis substantially improved airway patency. Triamcinolone was injected throughout the subglottis. The patient was discharged home on acetaminophen and prednisone, with an outpatient ENT follow-up scheduled for 6 weeks after discharge.
(A) Preoperative laryngoscopy revealed grade 2 subglottic stenosis (about 66% obstruction of the luminal area), with an airway caliber of about 5 mm. (B) Laryngoscopy after completion of the procedure showed no stenosis.
Pathology reported respiratory mucosa with chronic inflammation and fibrosis, negative for granulomas.
The patient was seen by ENT in follow-up at the free clinic at 2 months. At that visit, fiber-optic laryngoscopy showed no stenosis. She was breathing comfortably without stridor, and she denied shortness of breath or dysphagia. Because all her symptoms had resolved, she canceled her primary care follow-up. The patient has moved out of the area and has not been seen at the community-based free clinic since.
The patient’s family history of a brother with similar symptoms that resolved after surgery raised the possibility of a genetic factor. Idiopathic subglottic stenosis is a rare condition with limited data, but there are reports of familial clustering in 2.5% of patients.21 Congenital subglottic stenosis in siblings at birth and familial clustering in young women have also been reported. Neither pattern fit this patient’s history.
FACTORS THAT CAN LEAD TO DELAYED DIAGNOSIS
4. Which of the following factors contributed to the delay in diagnosing subglottic stenosis in this patient?
Breakdown in the patient-practitioner clinical encounter
Lack of continuity of care
Availability bias
Limited economic resources
While it is difficult to evaluate the quality of a diagnosis, data suggest that 1 in 20 patients experience an error in outpatient diagnosis, and about half of those errors had the potential for patient harm.22 This patient had symptoms for more than 9 years before the correct diagnosis was made and treatment provided. All of the listed factors contributed to this delay in diagnosis.
Breakdowns in the patient-practitioner clinical encounter, which includes the skills of history taking, physical examination, and ordering of diagnostic tests, account for most errors in the outpatient setting.23 All these factors played a part in the delay of this patient’s diagnosis, specifically failure to identify the long history of progressive symptoms, acknowledge previous ineffective treatment, recognize the physical finding of stridor and its clinical significance, and order complete PFTs.
Continuity of care is a necessary component of optimal care but is often overlooked. Improved continuity of care lowers mortality rates, decreases hospital admissions, and reduces healthcare costs.24,25 Unfortunately, continuity is frequently lacking, especially with the emergence of acute care and urgent care facilities, or as in this case, when the patient is transient and receives care through multiple free or low-cost clinics. A patient may see multiple clinicians without a central record or an ongoing therapeutic relationship. For our patient, lack of continuity meant that no single clinician had the chance to reevaluate the working diagnosis when her presumed wheezing failed to respond to the given treatment.
Biases and social factors. Multiple biases, both cognitive and implicit, have been identified that can derail the diagnostic process. Availability bias is the tendency to overestimate the likelihood of a certain event occurring when it readily comes to mind.26 Clinicians influenced by a recent experience with a specific type of disease such as asthma or bronchitis may be more prone to misdiagnose diseases with similar signs and symptoms.27 Problems may arise when the first impression is wrong, as clinicians are vulnerable to anchoring bias when they look for evidence to confirm their initial diagnosis and premature closure when they fail to consider alternative diagnoses.
A 2016 study with a dataset of more than 200 million patient records revealed that in the United States women consistently experience longer time to diagnosis than men.28 The cause of this significant and consistent difference has not been elucidated, but the possibility that there is a systemic bias of discounting symptoms reported by women requires consideration and further investigation.
Studies have suggested that only 20% of an individual’s health is due to the medical care they receive and that up to 50% is determined by social determinants of health.29 The social determinants of health that affected this patient included limited economic resources, low health literacy, unstable safe housing, barriers to access to care, marginal financial resources, and limited transportation. Fortunately, free clinics exist to serve as the primary source of healthcare for uninsured patients; however, bureaucratic hurdles, discriminatory practices, stigma, and lack of social or financial capital remain.30,31
This patient’s case highlights how insufficient diagnostic assessment, premature closure and other biases, interrupted continuity, and social determinants can combine to obscure an uncommon but critical diagnosis—reminding clinicians always to broaden the differential when symptoms do not improve and to remember that “all that wheezes is not asthma.”
TAKE-HOME POINTS
It is critical to differentiate stridor from wheezing.
In many patients who have central airway stenosis but no risk factors, the presence of stridor is often overlooked, leading to erroneous diagnoses of other respiratory diseases.
Suspected airway obstruction should prompt early evaluation with PFTs. Spirometry with flow-volume loops and calculation of the expiratory disproportion index are useful to identify and characterize stridor and upper airway obstruction.
Normal chest radiography or chest computed tomography does not rule out pathologic airway obstruction.
Engage a broad differential diagnosis when the expected response to treatment does not occur.
Be aware of biases, diagnostic pitfalls, and social determinants of health that increase risk of missed or delayed diagnosis and treatment.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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