Bronchiolitis obliterans organizing pneumonia (BOOP) is a phenomenon that has been studied and documented in the literature since 1901 (Holland et al., 1988). As Ezri and colleagues (1994) stated, it is “a relatively rare disease whose precise prevalence is unknown.”

BOOP primarily damages the small conducting airways. The physiologic and radiographic findings are very similar to those of chronic obstructive pulmonary disease (COPD) (King, 1989). King (1989) notes that some of the processes may appear restrictive or both restrictive and obstructive; consequently, bronchiolitis obliterans may be confused with other diffuse infiltrative ventilatory lung disorders. For the purposes of this chapter, bronchiolitis obliterans is discussed as it applies to oncology patients, specifically individuals who have received an allogeneic bone marrow transplant (BMT).

Bronchiolitis obliterans occurs infrequently in patients who have received an allogeneic BMT. It affects approximately 10% of patients with chronic graft versus host disease (GVHD). It also has been identified in patients who received autologous transplants. The disease can present as a mixed restrictive and obstructive process, making diagnosis difficult.

Bronchiolitis obliterans is a pulmonary disease that primarily affects the conductive bronchioles. It is marked by partial or complete obliteration of the bronchiolar lumena either by plugs of granulation tissue or by fibrosis and scarring (Ezri et al., 1994; King, 1989). Bronchiolitis obliterans caused by the deposition of granulation tissue sometimes is referred to as proliferative bronchiolitis obliterans. Bronchiolitis obliterans caused by scarring is referred to as constrictive or obstructive bronchiolitis obliterans.

Proliferative bronchiolitis obliterans is most often characterized by an inflammatory process involving the respiratory bronchioles and alveoli. The resulting defect is restrictive. Understanding the exact defect is important for establishing the prognosis and evaluating the response to treatment. The restrictive, inflammatory defect of proliferative bronchiolitis obliterans is potentially reversible. Obstructive bronchiolitis obliterans, however, is irreversible, because the established fibrosis affects the proximal bronchioles (Ezri et al., 1994).

In the hematology and oncology literature, bronchiolitis obliterans has been described in patients with irradiation pneumonitis (Kaufman & Komorowoski, 1990), amphotericin B toxicity (Roncoroni et al., 1990), autologous BMT (Paz et al., 1992), and allogeneic BMT (King, 1989). Bronchiolitis obliterans occurs in patients who have received hematopoietic stem cell transplants, but it is uncommon. The term hematopoietic stem cell transplant (HSCT) has supplanted the previously used term bone marrow transplant to reflect the broader range of donor stem cell sources that are now available (e.g., bone marrow, fetal cord blood, and growth factor–stimulated peripheral blood) (Kotloff et al., 2004).

The exact pathogenesis of bronchiolitis obliterans in patients who have received an allogeneic BMT has not been determined. However, Ezri and colleagues (1994), King (1989) and Crawford and Clark (1993) all agree that the presence of chronic GVHD probably affects the development of this pulmonary complication.

Ezri and colleagues (1994) described “enhanced expression of major histocompatibility (MHC) class II antigens on bronchiolar epithelium…associated with cytotoxic T lymphocyte infiltration.” The assumption is that this is the initiating factor in a vicious cycle of inflammation and fibrosis. Similarly, King (1989) discusses a “lymphocytic bronchitis, characterized by lymphocyte-associated necrosis of the bronchial mucosa and submucosal glands.” In this case, lymphocytic bronchitis is thought to be a pulmonary manifestation of GVHD. King (1989) also discusses two additional theories to explain the pathogenesis of BOOP. Lung biopsies in many BMT patients suspected of having bronchiolitis obliterans have shown marked lymphocyte or plasma cell infiltration of the terminal respiratory bronchioles and obliteration of the bronchiolar lumina with interstitial fibrosis. Chronic GVHD is associated with a fibrosing mechanism in other organs, therefore bronchiolar fibrosis may be an additional manifestation of chronic GVHD. Also, chronic GVHD often contributes to esophageal and sinus disease, which may result in recurrent esophageal aspiration; this could contribute to and further complicate the lung injury.

Crawford and Clark (1993) described a review of 21 BMT patients with pulmonary symptoms. Sixteen of the 21 patients showed small airway involvement with bronchiolitis, only occasionally with fibrinous obliteration of the bronchiolar lumena. The remaining five patients showed evidence only of bronchitis or interstitial pneumonia. This study shows that bronchiolitis obliterans is not always the causative factor for respiratory symptoms in BMT patients.

Paz and colleagues (1992) described the first reported cases of bronchiolitis obliterans in patients who had undergone autologous BMT without demonstrating chronic GVHD. Preparative regimens, the possibility of underlying infection, underlying connective tissue disorder, and an autoimmune response were postulated as possible initiators; however, no clear causative factors were identified in these patients. The important point is that the possibility of bronchiolitis obliterans must be considered in patients who develop clinical signs and symptoms consistent with the disorder after autologous BMT. (See Chapter 14 for further information on GVHD.)

Patients with BOOP usually develop respiratory complaints such as a dry, nonproductive cough; dyspnea on exertion; bibasilar rales and scattered wheezes; and hypoxemia (King, 1989). The chest radiograph may be read as normal or hyperinflated. Most sources report that physical examination is not particularly helpful early in the diagnostic process. Pulmonary function tests and, most likely, lung biopsy are required to confirm the diagnosis.

The etiologies implicated in bronchiolitis obliterans include viruses, toxic fume exposure, connective tissue disease, drugs or organ transplantation (“immune” bronchiolitis obliterans), and idiopathic factors (Ezri et al.,1994). The incidence of bronchiolitis obliterans in patients who have undergone allogeneic BMT is approximately 2% to 10% (Paz et al., 1992). As previously mentioned, a few cases have been documented in patients who had received an autologous transplant (Ezri et al, 1994; King, 1989; Crawford & Clark, 1993.)

Conditions: Chronic GVHD; treatment of chronic GVHD with methotrexate; (possibly) low serum immunoglobulin level; irradiation pneumonitis; chronic allograft dysfunction after lung transplantation (Pakhale et al., 2005); older age (adults).

Drugs: Methotrexate (for immunosuppression of GVHD), amphotericin B (single case report), amiodarone (Sveinsson et al., 2006).

Patients undergoing BMT are a risk for multiple pulmonary side effects. An accurate differential diagnosis is necessary to establish the prognosis. Once the diagnosis of bronchiolitis obliterans has been established, the prognosis usually is poor. Epler (1988) reported that bronchiolitis obliterans in association with BMT has a poor prognosis and does not respond well to steroid treatment. Fort and Graham-Pole (1990) stated that bronchiolitis obliterans is both irreversible and unresponsive to treatment; bronchiolitis obliterans progresses to recurrent pneumothoraces and hypoxia, which result in death. In a study by Schwarer and colleagues (1992), no identifying infectious component was found in 29 patients who developed late onset pulmonary syndrome (LOPS), and six of the patients (21%) died. According to these researchers, LOPS is the most frequent cause of nonrelapse death in patients 6 months after BMT. In the Schwarer study, the designation LOPS included airflow obstruction associated with bronchiolitis obliterans or interstitial lung disease, or both. Paz and colleagues (1992) studied 104 patients who underwent allogeneic BMT; 3.9% developed bronchiolitis obliterans. Crawford and Clark (1993) stated, “The clinical course is variable, but the process usually is fatal in cases with rapidly progressive or severe obstruction.”

Early recognition and treatment of bronchiolitis obliterans is important, because treatment often is ineffective when the disease has reached the late, fibrotic stage (Moore, 2003)

Chemotherapy: Cyclophosphamide—not yet established (Crawford & Clark, 1993).

Medications: Corticosteroids continue to be the drugs of choice for the treatment of BOOP, sometimes in conjunction with cyclosporine.