The patient is a 62-year-old Caucasian woman who is seeking consultation for progressive dyspnea on exertion.  She can walk a few city blocks at a leisurely pace and a single flight of stairs but no longer participates in fitness activities.  She was previously diagnosed with COPD but had never smoked or lived with a smoker.  Her dyspnea gradually began 5 years ago.  She has no history of asthma. She has noticed very rare wheezing, a minimal nonproductive cough, but no chest tightness.  Previous treatments have included oral and inhaled corticosteroids, and immediate- and long-acting beta₂ agonists and anticholinergic inhalers.  She did not experience a change in her dyspnea or spirometry with any medication. Twenty-five years ago she was hit in the neck with a batted baseball.  A few years later she developed pain in her hands and wrists and episodic dysphonia. Her dysphonia worsened and culminated in severe stridor and acute respiratory distress, necessitating an emergent tracheostomy and surgical fixation of the left vocal cord.  She attributes these problems to the baseball accident. Her joint pain has persisted and is associated with swelling and stiffness.

Past Medical and Surgical History: left vocal cord paralysis, dysphonia, COPD, tracheostomy, hypothyroidism, gastroesophageal reflux, and three uncomplicated vaginal deliveries. There is no history of asthma, allergic rhinitis, ocular disease, hepatorenal diseases, circulatory diseases, gastrointestinal problems or diabetes mellitus.

Allergies: none  

Medications: daily use of inhaled tiotropium and oral levothyroxine, esomeprazole, and naproxen.

Family History: mother died of ovarian cancer and father died of complications associated with Alzheimer’s dementia.  She has three adult children who are in good health. There is no family history of lung disease.

Social History: negative for tobacco, alcohol or illicit drug use. She works as a secretary and lives with her husband who is a schoolteacher in the suburbs of a large city.

Review of Systems: a careful review revealed a history of more than 20 years of joint pain accompanied by morning stiffness and both dry eyes and mouth.  The joint pain is generally symmetric, and involves her wrists, shoulders, knees, and most of the small joints of the hands. 

While the vast majority of the world’s COPD burden is caused by chronic inhalation of tobacco smoke (>90%) and biomass fuel exhaust, especially when used for domestic cooking and heating, our patient had neither exposure. Alpha-1 antitrypsin deficiency should be considered if airflow obstruction and emphysema are present with minimal or no exposure history.  However, her alpha-1 antitrypsin level was normal and emphysema was not present on her chest CT scan. She has no history of asthma and historically there wasn’t a response to the bronchodilator challenge during spirometry. Additionally, she did not show a symptomatic improvement with inhaled or oral corticosteroid therapies.  Our patient’s history of vocal cord paralysis or perhaps dysfunction raises concern for a partial fixed extrathoracic upper airway obstruction.  However, the inspiratory and expiratory limbs of the flow volume loop do not "flatten" or "plateau," which would be indicative of either a fixed or variable upper airway flow limitation.  Though there is no spirometric evidence of significant upper airway obstruction, she likely has underlying cricoarytenoid arthritis as a complication of chronic rheumatoid disease.  Cricoaretynoid arthritis can complicate endotracheal intubation and has been reported as a cause of sudden vocal cord paralysis and respiratory failure (9,10), and was the likely cause of her episode of respiratory failure.   This patient has seronegative rheumatoid arthritis, which raises the clinical suspicion of obliterative bronchiolitis (OB) and cricoaretenoid arthritis.  OB is an uncommon but important cause of chronic airflow obstruction. The major ventilatory defect in OB is obstructive airflow disease, with or without lung hyperinflation.  A bronchodilator response is typically absent.  Chest radiographs can be normal or show gas trapping. High-resolution CT scan is typically normal or has evidence of gas trapping demonstrated best with mosaicism on inspiratory and expiratory maneuvers.  Histopathologically, OB is characterized by luminal narrowing of the small airways.  This histopathologic pattern is referred to as "constrictive bronchiolitis" because the walls of the membranous and respiratory bronchioles are concentrically narrowed or obliterated by nonspecific inflammation, cellular hyperplasia and fibrosis that are extrinsic to the airway. Alveolar walls and ducts are spared, which helps distinguish OB from bronchiolitis obliterans with organizing pneumonia (BOOP), which is now known as cryptogenic organizing pneumonia (COP). It is important to distinguish OB from BOOP/COP.  While both entities are nonspecific tissue findings and share associated conditions and a similar differential diagnosis, they are clinically and histopathologically distinct. BOOP/COP is defined histopathologically by a "proliferative bronchiolitis," which is characterized by regional intraluminal fibrotic buds and inflammatory changes with prominent foamy macrophages that extend into alveolar spaces.  Clinically, the diffuse bronchiolar involvement in BO commonly presents as airflow obstruction with or without hyperinflation as mentioned above.  Though BOOP/COP is similarly associated with narrowing and obstruction of the terminal bronchiole and alveolar space, the regional involvement with sparing of adjacent airways leads to a predominantly restrictive process.    Rheumatoid arthritis (RA) has long been associated with OB.  Originally thought to be related to the use of penicillamine and/or gold therapy, OB has been found in RA patients without exposure to either medication.  Though RA is the most common connective tissue disease associated with OB, associations have been found with systemic lupus erythematosus, ulcerative colitis, and polymyositis.  OB is the structural complication of chronic rejection in heart-lung and lung allografts and is seen in native lungs of bone marrow transplant recipients, a possible result of graft versus host disease.  OB is also associated with inhalation injury from toxic fume exposures (ammonia, chlorine, mineral dust, and sulfur dioxide).  Several respiratory infections have been implicated including adenovirus, mycoplasma pneumoniae, and respiratory syncytial virus.  Recently, diacetyl (the butter flavoring in microwave popcorn) has been implicated as a volatile toxin responsible for OB in "popcorn workers lung."  Finally, some cases are truly idiopathic.

Question 2

How is the diagnosis of Obliterative Bronchiolitis made?

	A.	Exhaled nitric oxide Incorrect!
	B.	Open lung biopsy Incorrect!
	C.	Transbronchial biopsy Incorrect!
	D.	Clinically after carefully excluding other causes of airflow obstruction Correct!
	E.	Trial of prednisone Incorrect!