Pulmonary Alveolar Proteinosis as a Reaction to Fentanyl Patch SmokeFentanyl Smoke and Alveolar Proteinosis FREE TO VIEW

A 50-year-old woman presented with shortness of breath on exertion, cough productive of a small amount of sputum, dull chest pain, fevers, night sweats, weight loss, and general malaise present for 3 months. Physical examination revealed bilateral coarse crackles concentrated at the lung bases. There was no clubbing or cyanosis. Past medical history included burns (no inhalational injury) treated with skin grafting, chronic pain treated with fentanyl patches, and minor surgeries. She smoked one-half pack of cigarettes per day for 35 years. Three to four months previously she had switched to smoking her fentanyl patches rather than applying them to the skin.¹ She had no travel history, no occupational or avocational exposures, and no sick contacts.

Laboratory investigations showed a mild anemia and mild leukocytosis. C-reactive protein level was 101 mg/L. Serology for collagen vascular disease showed only a positive rheumatoid factor. HIV serology was negative. Viral nasopharyngeal swab and sputum culture for bacteria, fungi, and mycobacteria were all negative.

Chest radiograph revealed diffuse bilateral nodular opacities with linear opacities. The subsequent CT scan showed subcarinal, mediastinal, and hilar lymphadenopathy; a small left pleural effusion; and extensive diffuse centrilobular ground glass nodules in all lobes with focal septal thickening (Fig 1).

The initial impression was pneumonia, and the patient was treated with an antiinfluenzals and antibiotics; however, she failed to improve. A video-assisted thoracoscopic surgery lung biopsy was performed and showed alveolar filling by granular eosinophilic (Fig 2A) and digested periodic acid-Schiff-positive (Fig 2B) material typical of pulmonary alveolar proteinosis (PAP). In addition, there was mild chronic interstitial inflammation (including a few eosinophils) and, focally, interstitial fibrosis that colocalized with the proteinosis (Fig 2A). Special stains for organisms were negative. The patient was diagnosed with PAP as a reaction to fentanyl patch smoke.

After the diagnosis, the patient stopped smoking the patches and her shortness of breath rapidly resolved. Four months after the biopsy a plain chest film was interpreted as showing minimal residual interstitial infiltrates in the mid and lower zones, but was otherwise unremarkable.

PAP is a rare disease characterized by the accumulation of lipoproteinaceous surfactant components in the alveoli.² In recent years, the adult form of the disease has been divided into primary and secondary forms.² The bulk (90%) of cases are primary and are characterized by autoantibodies to granulocyte-macrophage colony stimulating factor. Secondary PAP occurs with a variety of underlying conditions, including dust inhalation exposures, in association with malignancies, especially hematolymphoid malignancies, and, uncommonly, as a drug reaction.^2,3 Antibodies to granulocyte-macrophage colony stimulating factor were not measured in this patient, but with the inhalational history this case is best categorized as secondary.

The presentation of PAP can be nonspecific but most often includes a several-months-long history of progressive exertional dyspnea and minimally productive cough. Less frequent symptoms include fatigue, weight loss, chest pain, and low-grade fever.⁴ The mean age of presentation is around 40 years, two-thirds of patients are male, and three-quarters are smokers.² Physical examination is generally noncontributory but may show crackles, clubbing, and cyanosis.⁴ Laboratory investigations show a nonspecific increase in lactate dehydrogenase level.² Spirometry demonstrates normal volumes or a restrictive defect with a disproportionate reduction in diffusing capacity of lung for carbon monoxide.⁵

Although many of the clinical aspects of this case are typical of PAP, the imaging and some of the pathologic findings are unusual. On CT scan, PAP usually shows a “crazy paving” pattern (ie, diffuse ground glass opacities with superimposed interlobular septal thickening).⁶ In this case, the predominant pattern was that of centrilobular ground glass nodular opacities. This pattern is typical of inhalation injuries, particularly hypersensitivity pneumonitis, but not of PAP, even PAP caused by inhalation of dusts such as silica. We have not been able to find a report of PAP with this pattern of inhalational injury on CT scan.^6,7 A recent article describes five cases of pathologically and radiologically overlapping PAP and hypersensitivity pneumonitis, but none of those cases had the centrilobular nodules seen in the patient.⁸ Pathologically, mild interstitial fibrosis and mild chronic interstitial inflammation are occasionally seen on biopsy in PAP but are not common. The extent of the fibrosis and the occasional interstitial eosinophils in this case are not typical of most cases of PAP.^2,4

This case is also unusual in that PAP is a rare drug reaction that has been described with leflunomide, mitomycin C and sirolimus, but has not been reported in reaction to fentanyl or to other inhaled drugs.³ Fentanyl patches are not intended to be smoked, but there appears to be a significant subset of patients who do smoke them (see, for example, http://www.drugs-forum.com/forum/showthread.php?t=60701, one of several online sites that discuss how to smoke the patches). Whether this patient’s disease is a reaction to fentanyl itself or to some component of the patch is not clear, but the development of symptoms after she commenced smoking her patches, the inhalational pattern of injury on CT scan, and the disappearance of disease when smoking was stopped all strongly support the idea that this woman’s disease is an unusual type of inhalation drug reaction.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Leipsic has received a grant of $60,000 from GE Healthcare and is a member of the Medical Advisory Board of GE Healthcare. Dr Churg has received research grants totaling $1,500,000 from AstraZeneca R&D. Drs Chapman and Satkunam have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Callisto Tarukandirwa, MD, and Natalia Leah, MD, from Red Deer Regional Hospital Centre of David Thompson Health Region, Alberta, for supplying clinical details. Our institution does not require Institutional Review Board approval for case reports.