What is really causing this woman's asthma exacerbation?

A 43-year-old woman presented to the emergency department with complaints of severe dyspnea, wheezing, and cough productive of white sputum. She had received a diagnosis of asthma 3 years earlier, based on symptoms of wheezing and cough. Since then, her drug regimen has included intermittent use of albuterol.

Her present complaints began about 2 weeks previously and had progressively worsened over the past 4 days. She denied chest pain, fever, and chills but noted extreme fatigue when attempting her daily activities. She had a 30-pack-year history of cigarette smoking.

Two primary care visits in the preceding 2 weeks resulted in empiric treatment of an infectious asthma flare with oral prednisone (30 mg once daily), a 7-day course of azithromycin, inhaled fluticasone, and as-needed use of an albuterol inhaler. Her albuterol use had escalated to a minimum of 6 times per day, with only modest symptom relief.

On initial examination, the patient was in extremis, sitting upright in bed, using accessory respiratory muscles, and unable to complete sentences because of severe dyspnea. Her temperature was 37°C (98.6°F), respiration rate was 28 breaths per minute, heart rate was 120 beats per minute, and oxygen saturation on room air was 85%. Chest auscultation revealed wheeze and bilateral diffuse, coarse crackles. A chest radiograph demonstrated prominence of the interstitial markings (Figure 1).

The patient was admitted with a tentative diagnosis of infectious exacerbation of asthma and pneumonia. She was treated with supplemental oxygen via nasal cannula (4 L/min); intravenous hydrocortisone, levofloxacin, and metronidazole; and nebulized albuterol every 4 hours. She also received smoking cessation counseling.

A pulmonary consultation was requested on day 5 because the patient did not have an appreciable clinical response to therapy. A CT scan of the chest revealed bilateral diffuse, ground-glass opacities without significant air trapping (Figure 2).

Bronchoscopy was subsequently performed. Findings included clear secretions and thick mucous plugs. Bronchoalveolar lavage (BAL) and transbronchial biopsy specimens were obtained from the right upper and lower lobes. BAL fluid was negative for fungi, Mycobacterium tuberculosis, and viruses; cytological examination of the specimens yielded negative results. Bacterial culture revealed Klebsiella pneumoniae that was sensitive to levofloxacin. The presumed diagnosis at this time remained an asthma flare with diffuse mucous plugging and pneumonia caused by K pneumoniae.

The patient's symptoms, exercise tolerance, and oxygen requirement improved gradually. She was discharged 5 days later with portable oxygen, a 10-day oral prednisone taper, inhaled fluticasone, and nebulized albuterol. Outpatient pulmonary and smoking cessation follow-up appointments 1 week later were missed. The patient returned 8 weeks later and reported that her respiratory symptoms had not changed. Pulmonary function test results are shown in the Table.

A repeated CT scan revealed persistent ground-glass infiltrates. The patient underwent thoracoscopic biopsy. The results are shown in Figure 3.

What is the likely diagnosis? How would you proceed?

Answers on page 352.

What is really causing this woman's asthma exacerbation? The low-power view of the biopsy specimen shows a terminal and a respiratory bronchiole surrounded by scar tissue and alveolar septal thickening. The presence of light brown-pigment-ed macrophages abundant in the airspace adjacent to the affected bronchioles led to a diagnosis of respiratory bronchiolitis interstitial lung disease (RB-ILD).

Discussion

RB-ILD was first described by Myers and colleagues¹ in 1987 in their report of 6 heavy smokers who had clinical, radiological, and physical evidence of interstitial lung disease. Open lung biopsy specimens showed respiratory bronchioles with inflammatory cellular infiltration, thickened alveolar septae, and a clustering of light brown-pigmented macrophages in the airspaces.

A rare interstitial lung disease, RB-ILD is almost always associated with a history of smoking, with rare exceptions related to inhalation of noxious substances.² RB-ILD may represent a progression of smoking-related respiratory bronchiolitis ("smokers' bronchiolitis"), which is a very common asymptomatic histopathological finding, first described in 1974 by Niewoehner and colleagues.³

The distinction between smokers' bronchiolitis and RB-ILD lies in the onset of symptoms and biopsy findings of interstitial inflammation and/or fibrosis. Both conditions share the characteristic findings of bronchiolar inflammation and a clustering of light brown-pigmented macrophages.

Until 1989, the largest series of RB-ILD were from 2 studies involving a total of 24 patients.^1,4 Since then, a handful of published case series have described 200 cases. Based on this collective experience, patients present in the fourth or fifth decade with dyspnea and cough that is sometimes productive, accompanied by mild restriction and reduction in carbon monoxide-diffusing capacity.

The chest radiographic findings are abnormal in 70% to 80% of cases.⁵ CT scans and chest radiographs most frequently demonstrate ground-glass opacities that are known to correlate with macrophage accumulation in the alveolar spaces and ducts.⁶

RB-ILD is similar to another interstitial lung disease, desquamative interstitial pneumonia (DIP), and many researchers believe both diseases should be addressed as one under the term "smoking-related interstitial lung disease." Both share a common presentation and radiological and pathological findings. Smoking is highly associated with both conditions, occurring in more than 90% of cases.⁶

The pathological distinction between RB-ILD and DIP pertains to the distribution and extent of involvement: the disease process in RB-ILD centers on the small airways with some extension into the airspace, in contrast to a more uniform and widespread pattern with DIP. This apparently simple differentiation is often difficult to make because of overlap.

Treatment of both RB-ILD and DIP includes smoking cessation, supportive care, and a consideration of corticosteroids. Case reports suggest disease remission with complete smoking cessation, including avoidance of secondary tobacco smoke exposure.^6,7 Many report remission with administration of corticosteroids over several months. The course of RB-ILD appears stable and benign, although radiological findings can persist for many years. Deaths have been reported in patients with DIP but not in those with RB-ILD.

Outcome in this case

The patient's symptoms, exercise tolerance, and pulmonary function gradually improved following a lengthy course of oral prednisone. Unfortunately, complete abstinence from tobacco was difficult for our patient to achieve, despite strong encouragement and education. This case emphasizes the need to consider alternative diagnoses in a patient unresponsive to conventional asthma medications.⁸

Case and photographs courtesy of Nirav P. Patel, MD, Chirag Shah, MD, and Scott Manaker, MD, PhD, of the pulmonary, allergy, and critical care division at the Hospital of the University of Pennsylvania in Philadelphia.

References:

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Myers JL, Veal CF Jr, Shin MS, Katzenstein AL. Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases.

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Moon J, du Bois RM, Colby TV, et al. Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking related interstitial lung disease.

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Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers.

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