Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

John A. Belperio, MD; Kathleen Lake, PharmD; Henry Tazelaar, MD; Michael P. Keane, MD; Robert M. Strieter, MD; Joseph P. Lynch, III, MD

Disclosures

Semin Respir Crit Care Med. 2003;24(5) 

In This Article

Diagnosis of Bronchiolitis Obliterans Syndrome

Surveillance fiberoptic bronchoscopy is performed at many transplant centers at designated intervals[30] to diagnose histological AR prior to development of symptoms. However, randomized, prospective studies have not been performed and the value of routine surveillance fiberoptic bronchoscopy is unproven. Retrospective studies have not shown reductions in the frequency of BOS or patient survival among LTRs who undergo routine fiberoptic bronchoscopy (as compared with fiberoptic bronchscopy for appropriate clinical indications).[18,31,32] Treating symptomatic, clinically evident AR is inituitively obvious. However, it is unknown whether treating asymptomatic patients with histological evidence for AR reduces or delays the development of BOS.[31,33,34,35] The role of surveillance bronchoscopy is controversial.[31,33,36,37] Because of the patchy nature of OB and the small sample size, the yield of transbronchial lung biopsies (TBBs) in detecting OB is low (< 15-48%).[33,38,39,40,41,42] However, when LBB is observed on TBBs, the likelihood of subsequent development of BOS is extremely high,[25,26,27] Surgical lung biopsy has a higher yield but is expensive and has potential morbidity. Thus, surrogate markers of OB have been defined based upon clinical, physiological, and radiographic criteria (discussed following here) ( Table 2 ).

Pulmonary Function Tests

Because BO is difficult to document histologically, the term bronchiolitis obliterans syndrome (BOS) was adopted by the ISHLT Working Group to describe chronic allograft rejection in the absence of histological confirmation of BO.[43] The group concluded that forced expiratory volume in 1 second (FEV1) was the most reliable and consistent clinical pulmonary functional parameter that provided an indication of graft function. The maximum midexpiratory flow rate (MMEF25-75) was not used for defining airflow obstruction because of the greater intrasubject variability of this parameter, particularly in unilateral LTRs. A staging algorithm based upon FEV1 was developed. Maximum FEV1 levels were determined as the average of the two previous highest consecutive measurements obtained at least 3 to 6 weeks apart. Declines in FEV1 from these baseline values defined the severity of BOS. A decrease ≥ 20% from baseline defined BOS (stage I). More severe derangements defined later BOS stages ( Table 3 ).[43]

Subsequent studies support the premise that simple spirometric parameters (e.g., spirometry, FEV1, maximal expiratory flow rate at 50% of the vital capacity (MEF50), and the FEV1/forced vital capacity (FVC) ratio are adequate to diagnose and follow the course of BO (Figs. 4A-E). More sophisticated studies, such as time domain analysis of the spirogram, offer little or no advantage.[44] Several studies have shown that FEF25-75 (forced expiratory flow) is more sensitive than FEV1 for early detection of airflow obstruction[17,38,45,46] (see Figs. 4A-D). Thus, some investigators suggested cutoff points to herald possible BOS defined by > 12% decline in FEV1 among heart-lung or bilateral LTRs or > 13% decline in FEV1 among single LTRs[47] or a 30% decline in FEF25-75.[45] However, FEF25-75 may be abnormally elevated in the early postoperative period following bilateral LT, and declines in these parameters may not reflect allograft pathology.[17] Recently, an ISHLT consensus panel proposed a new stage, designated "potential BOS" or BOS 0-p, defined by an FEV1 of 81 to 90% of baseline or a midexpiratory phase (FEF25-75) < 75% of baseline.[11] This new stage is meant to alert the clinician to the increased risk for subsequent BOS among patients with slight declines in lung function, and to indicate the need for close functional monitoring. A recent retrospective analysis of serial pulmonary function tests (PFTs) in 43 LTRs found that FEF25-75 ≤ 75% baseline was a useful criterion for predicting BOS development in single LTRs (sensitivity 80%, specificity 83%).[48] Sensitivity and specificity depended upon underlying diagnosis. Among patients with idiopathic pulmonary fibrosis, sensitivity was 62.5% with specificity of 100%. For patients with chronic obstructive lung disease, sensitivity was 92%; specificity, 69%. The value of FEV1 81 to 90% of baseline was uncertain.[44]

(A) Bronchiolitis obliterans syndrome (BOS), onset 4 years following bilateral lung transplantation (LT). Spirometry demonstrated normal forced expiratory volume in 1 second (FEV1) and FEF25-75 for nearly 4 years post-LT. Abrupt decline in FEF25-75 (forced expiratory flow) was noted on July 8, 1996, followed by a gradual decline in FEV1 to ~60% of predicted values by April 30, 1998. Over the next 4 years, pulmonary function tests remained remarkably stable. (B) BOS, onset 8 years following single LT. Spirometry demonstrated FEV1 of ~60 to 70% of predicted values from December 1993 until May 16, 2001, at which time an abrupt decline in 25-75 was noted, followed by a gradual decline in FEV1 to ~30% of predicted values by August 13, 2001. Thereafter, pulmonary function tests remained stable. (C) BOS, onset > 7 years following bilateral LT. Following LT in 1993, spirometry demonstrated FEV1 of ~90 to 110% of predicted values from April 1993 until February 15, 2001, at which time the FEV1 dropped abruptly to ~55% of predicted values. Note that declines in FEF25-75 were noted beginning July 17, 2000. (D) BOS, onset > 2 years following single LT. Following LT in December 2000, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from March 2001 until April 22, 2002, at which time the FEV1 dropped to 76% of predicted values. Note that declines in FEF25-75 were noted beginning December 13, 2001. (E) BOS, onset > 2 years following single LT. Following LT in February 2001, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from June 18, 2001, until July 29, 2002, at which time the FEV1 dropped to 42% of predicted values. Progressive deterioration was noted, and the patient died of respiratory failure in January 2003.

(A) Bronchiolitis obliterans syndrome (BOS), onset 4 years following bilateral lung transplantation (LT). Spirometry demonstrated normal forced expiratory volume in 1 second (FEV1) and FEF25-75 for nearly 4 years post-LT. Abrupt decline in FEF25-75 (forced expiratory flow) was noted on July 8, 1996, followed by a gradual decline in FEV1 to ~60% of predicted values by April 30, 1998. Over the next 4 years, pulmonary function tests remained remarkably stable. (B) BOS, onset 8 years following single LT. Spirometry demonstrated FEV1 of ~60 to 70% of predicted values from December 1993 until May 16, 2001, at which time an abrupt decline in 25-75 was noted, followed by a gradual decline in FEV1 to ~30% of predicted values by August 13, 2001. Thereafter, pulmonary function tests remained stable. (C) BOS, onset > 7 years following bilateral LT. Following LT in 1993, spirometry demonstrated FEV1 of ~90 to 110% of predicted values from April 1993 until February 15, 2001, at which time the FEV1 dropped abruptly to ~55% of predicted values. Note that declines in FEF25-75 were noted beginning July 17, 2000. (D) BOS, onset > 2 years following single LT. Following LT in December 2000, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from March 2001 until April 22, 2002, at which time the FEV1 dropped to 76% of predicted values. Note that declines in FEF25-75 were noted beginning December 13, 2001. (E) BOS, onset > 2 years following single LT. Following LT in February 2001, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from June 18, 2001, until July 29, 2002, at which time the FEV1 dropped to 42% of predicted values. Progressive deterioration was noted, and the patient died of respiratory failure in January 2003.

(A) Bronchiolitis obliterans syndrome (BOS), onset 4 years following bilateral lung transplantation (LT). Spirometry demonstrated normal forced expiratory volume in 1 second (FEV1) and FEF25-75 for nearly 4 years post-LT. Abrupt decline in FEF25-75 (forced expiratory flow) was noted on July 8, 1996, followed by a gradual decline in FEV1 to ~60% of predicted values by April 30, 1998. Over the next 4 years, pulmonary function tests remained remarkably stable. (B) BOS, onset 8 years following single LT. Spirometry demonstrated FEV1 of ~60 to 70% of predicted values from December 1993 until May 16, 2001, at which time an abrupt decline in 25-75 was noted, followed by a gradual decline in FEV1 to ~30% of predicted values by August 13, 2001. Thereafter, pulmonary function tests remained stable. (C) BOS, onset > 7 years following bilateral LT. Following LT in 1993, spirometry demonstrated FEV1 of ~90 to 110% of predicted values from April 1993 until February 15, 2001, at which time the FEV1 dropped abruptly to ~55% of predicted values. Note that declines in FEF25-75 were noted beginning July 17, 2000. (D) BOS, onset > 2 years following single LT. Following LT in December 2000, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from March 2001 until April 22, 2002, at which time the FEV1 dropped to 76% of predicted values. Note that declines in FEF25-75 were noted beginning December 13, 2001. (E) BOS, onset > 2 years following single LT. Following LT in February 2001, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from June 18, 2001, until July 29, 2002, at which time the FEV1 dropped to 42% of predicted values. Progressive deterioration was noted, and the patient died of respiratory failure in January 2003.

(A) Bronchiolitis obliterans syndrome (BOS), onset 4 years following bilateral lung transplantation (LT). Spirometry demonstrated normal forced expiratory volume in 1 second (FEV1) and FEF25-75 for nearly 4 years post-LT. Abrupt decline in FEF25-75 (forced expiratory flow) was noted on July 8, 1996, followed by a gradual decline in FEV1 to ~60% of predicted values by April 30, 1998. Over the next 4 years, pulmonary function tests remained remarkably stable. (B) BOS, onset 8 years following single LT. Spirometry demonstrated FEV1 of ~60 to 70% of predicted values from December 1993 until May 16, 2001, at which time an abrupt decline in 25-75 was noted, followed by a gradual decline in FEV1 to ~30% of predicted values by August 13, 2001. Thereafter, pulmonary function tests remained stable. (C) BOS, onset > 7 years following bilateral LT. Following LT in 1993, spirometry demonstrated FEV1 of ~90 to 110% of predicted values from April 1993 until February 15, 2001, at which time the FEV1 dropped abruptly to ~55% of predicted values. Note that declines in FEF25-75 were noted beginning July 17, 2000. (D) BOS, onset > 2 years following single LT. Following LT in December 2000, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from March 2001 until April 22, 2002, at which time the FEV1 dropped to 76% of predicted values. Note that declines in FEF25-75 were noted beginning December 13, 2001. (E) BOS, onset > 2 years following single LT. Following LT in February 2001, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from June 18, 2001, until July 29, 2002, at which time the FEV1 dropped to 42% of predicted values. Progressive deterioration was noted, and the patient died of respiratory failure in January 2003.

(A) Bronchiolitis obliterans syndrome (BOS), onset 4 years following bilateral lung transplantation (LT). Spirometry demonstrated normal forced expiratory volume in 1 second (FEV1) and FEF25-75 for nearly 4 years post-LT. Abrupt decline in FEF25-75 (forced expiratory flow) was noted on July 8, 1996, followed by a gradual decline in FEV1 to ~60% of predicted values by April 30, 1998. Over the next 4 years, pulmonary function tests remained remarkably stable. (B) BOS, onset 8 years following single LT. Spirometry demonstrated FEV1 of ~60 to 70% of predicted values from December 1993 until May 16, 2001, at which time an abrupt decline in 25-75 was noted, followed by a gradual decline in FEV1 to ~30% of predicted values by August 13, 2001. Thereafter, pulmonary function tests remained stable. (C) BOS, onset > 7 years following bilateral LT. Following LT in 1993, spirometry demonstrated FEV1 of ~90 to 110% of predicted values from April 1993 until February 15, 2001, at which time the FEV1 dropped abruptly to ~55% of predicted values. Note that declines in FEF25-75 were noted beginning July 17, 2000. (D) BOS, onset > 2 years following single LT. Following LT in December 2000, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from March 2001 until April 22, 2002, at which time the FEV1 dropped to 76% of predicted values. Note that declines in FEF25-75 were noted beginning December 13, 2001. (E) BOS, onset > 2 years following single LT. Following LT in February 2001, spirometry demonstrated marked improvement in FEV1 to > 80% of predicted values from June 18, 2001, until July 29, 2002, at which time the FEV1 dropped to 42% of predicted values. Progressive deterioration was noted, and the patient died of respiratory failure in January 2003.

In summary, serial spirometric measurements at regular intervals are critically important to detect evidence for airflow obstruction, prior to development of clinical symptoms. During the first year posttransplant, biweekly or monthly spirometry is appropriate. At later time points, measurements every 2 or 3 months are often done. More frequent monitoring, via home spirometry, with interpretation via Internet-based algorithms, may be optimal but is expensive and not routinely available.[49] Daily home spirometry may detect a decline in pulmonary functional parameters earlier than regularly scheduled outpatient clinic visits,[50] and may be invaluable as a regular component of follow-up for LTRs.

Other Physiological Parameters to Predict Development of BOS

Nonspecific bronchial hyperreactivity was a risk factor for subsequent development of BOS in two studies of LTRs.[51,52] Two prospective studies have shown that indices of ventilation distribution (e.g., the slope of the single breath nitrogen[38,46] or helium washout curves)[38] were more sensitive than conventional PFTs (i.e., FEV1 or MMEF) in predicting the onset of BOS in bilateral LT or heart-lung transplant recipients. These data are intriguing but cannot be applied to single LT recipients.

High-Resolution Computed Tomographic Scans

High-resolution thin-section computed tomographic scans (HRCT) demonstrate dilatation of proximal bronchi, bronchial wall thickening, and a mosaic pattern of attenuation (defined as heterogeneous lung attenuation), in up to 62 to 80% of patients with OB.[53,54,55,56,57] Thin-section CT during suspended end expiration reveals air trapping, a surrogate marker of small airways disease, in 74 to 100% of LTRs with BOS, even when inspiratory CT scans are normal[53,54,55,56,58] ( Table 4 ). Quantitative expiratory CT scans (scoring the extent of air trapping) are more accurate than inspiratory CT in establishing the diagnosis of OB and correlate strongly with the extent of airflow obstruction.[55,56] One study of 38 heart-lung transplant recipients found that the extent of air trapping on expiratory CT correlated with BOS severity (p = 0.001).[56] Receiving operating characteristic (ROC) analysis suggested that a threshold of 32% of air trapping was optimal to distinguish between patients with and without BOS (sensitivity 83%, specificity 89%, accuracy 88%).[56] Further, patients without BOS who had > 32% air trapping were at increased risk to develop BOS in the future. In another study, serial CT scans were performed in 13 LTRs using a quantitative scoring system based upon multiple CT features consistent with BO.[59] The score of CT changes correlated inversely with FEV1 and FEF50 at 1 year posttransplantation (p < 0.05). However, FEF50 was more sensitive than CT. Thus, PFTs remain the best screening test for patients with suspected airflow obstruction. However, CT may have an adjunctive role in LTRs with declining PFTs as a means to exclude other causes of airflow obstruction from BOS (e.g., anastomotic complications or stenosis, opportunistic infections, hyperinflation of the contralateral native lung, etc.).

Other Parameters to Predict Development of BOS

Bronchoalveolar Lavage. Increased numbers of neutrophils in endobronchial biopsies or bronchoalveolar lavage (BAL) fluid may be observed in stable LTRs[60,61] and likely reflect subclinical allogeneic stimulation. More striking increases in BAL neutrophils are present in patients with BOS.[46,61,62,63] Certain cytokines are up-regulated in patients with BOS or at risk for BOS, even before symptoms or declines in PFTs are evident.[62,63,64,65,66,67,68] However, these measurements are complex and not available at most centers.

Exhaled Nitrous Oxide. Exhaled nitrous oxide (eNO) concentrations are increased in LTRs with BOS compared with stable patients, and correlate with expression of inducible NO synthase in the bronchial epithelium and with the percentage of neutrophils in BAL.[69] Measurement of eNO is a noninvasive means to assess the degree of airway inflammation,[70,71] but the sensitivity and specificity of this technique need to be better defined before this technique can be widely adopted in LTRs.

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