5 years. This syndrome has a variable clinical course. Common symptoms include nonproductive cough, mild malaise, and fatigue. Eventually, all subjects develop dyspnea. Physical examination is usually normal, but inspiratory squeaks may be heard. Crackles are uncommon. Progressive air ow limitation, secondary to small airway obstruction, is the hallmark of the bronchiolitis obliterans syndrome. A reduction in the diffusing capacity of the lungs for carbon monoxide (DLCO) is common. Hypoxemia and hypocapnia are almost always present. Approximately 50% of all deaths after the frst year post-transplantation are due to bronchiolitis obliterans.

Hematopoietic Stem Cell Transplantation

Bronchiolitis obliterans syndrome may affect up to 6% of HSCT recipients and dramatically alters survival, with overall survival of only 13% at 5 years. Cases appear after the frst 100 days post-transplantation, usually in the setting of chronic graft-versus-host disease [50]. Graft-versus-host disease has been postulated to play a role in the development of this lung disease. Bronchiolitis obliterans is most prevalent in patients following allogeneic transplantation but is also seen with autologous bone marrow transplantation. The prognosis is variable—patients have had progressive or persistent disease; many have died secondary to respiratory failure (40–65% of subjects).

Drug-Induced Bronchiolitis

Bronchiolitis, usually with organizing pneumonia, has been reported in association with a number of drugs. Most reports are of single cases or small case series.

Difuse Panbronchiolitis

A familial occurrence has been described, with a signifcant increase in human leukocyte antigen (HLA)-Bw54 (63% frequency) [51]. Because HLA-Bw54 or its related haplotype is primarily confned to some mongoloid races (e.g., Japanese, Chinese, and Koreans), the genetic and ethnic background observed with this unique syndrome may be explained. Environmental factors also appear important because the disorder is highly uncommon in persons of Asian ancestry living abroad.

Diffuse panbronchiolitis is more prevalent in men, with a 2:1 men-to-women ratio. The peak incidence occurs between the fourth and seventh decades of life; the mean age at presentation is 50 years. Chronic sinusitis is present in 75–100% of cases. Sinus symptoms often precede chest symptoms by

years or decades. Chronic cough with expectoration of copious purulent sputum, exertional dyspnea, and wheezing are the most common clinical manifestations. Cigarette smoking or occupational exposures have not been shown to be predisposing factors. Physical examination reveals coarse crackles; clubbing is not a feature.

The most characteristic laboratory abnormality is persistent marked elevation of serum cold agglutinins. Mycoplasma antibody titers are negative. Rheumatoid factor may be elevated. Immunoglobulin levels are usually normal. BAL uid studies reveal marked neutrophilia.

A chest radiograph often reveals diffuse small nodular opacities up to 2 mm in diameter. A reticular “airway” pattern may be evident with more advanced disease. Hyperin ation may also be present. HRCT better re ects the clinical stages and pathology. On HRCT scans, the nodular shadows are distributed in a centrilobular manner, often extending to small branching linear areas of attenuation. The nodular and linear densities correspond to thickened and dilated bronchiolar walls with intraluminal mucus plugs. Peripheral air trapping may be present. Bronchiectasis may be prominent in advanced disease. Pulmonary function tests reveal marked obstruction and hypoxemia.

Treatment

Constrictive Bronchiolitis

Constrictive bronchiolitis tends to be progressive and less responsive to therapy. Macrolide antibiotics are commonly used in the long-term management of bronchiolitis, largely based on their success in improving symptoms, lung function, and mortality in patients with diffuse panbronchiolitis (see below) [52]. Inhaled bronchodilators and cough suppressants are used to control the cough.

In the setting of rheumatoid arthritis, any potential culprit medications (e.g., penicillamine, gold) should be discontinued. High-dose systemic glucocorticoids have been used with variable success. The tumor necrosis factor-alpha (TNF-alpha) inhibitors etanercept and in iximab have been suggested as possible treatment for constrictive bronchiolitis associated with rheumatoid arthritis [53]. It is not known whether they would be benefcial in other forms of constrictive bronchiolitis.

A variety of therapies have been tried for BO/BOS, but no well-established protocol has been developed [47]. Bronchiolitis obliterans following organ transplantation is often managed by intensifcation of immunosuppression. Gastroesophageal re ux disease (GERD) is prevalent in lung transplantation recipients, and non-acid re ux has been associated with the development of bronchiolitis obliterans syndrome [47, 54]. Aggressive therapy for GERD, possibly including surgery, has been proposed to prevent progression