Bronchiolitis Obliterans Syndrome 2001: an Update of the Diagnostic Criteria.

Bronchiolitis obliterans (BO) is a major cause of allograft dysfunction in lung and heart lung transplant recipients.1Burke C.M Theodore J Dawkins K.D et al.Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation.Chest. 1984; 86: 824-829Crossref PubMed Google Scholar, 2Glanville A.R Baldwin J.C Burke C.M et al.Obliterative bronchiolitis after heart-lung transplantation apparent arrest by augmented immunosuppression.Ann Intern Med. 1987; 107: 300-304Crossref PubMed Google Scholar Clinically, progressive airflow limitation develops because of small airway obstruction. The disease has a variable course. Some patients experience rapid loss of lung function and respiratory failure. Others experience either slow progression or intermittent loss of function with long plateaus during which pulmonary function is stable. Histologic confirmation is difficult because transbronchial biopsy specimens often are not sufficiently sensitive for diagnosis. Because BO is difficult to document histologically, in 1993 a committee sponsored by the International Society for Heart and Lung Transplantation (ISHLT) proposed a clinical description of BO, termed bronchiolitis obliterans syndrome (BOS) and defined by pulmonary function changes rather than histology. Although this system does not require histologic diagnosis, it does recognize it.3Cooper J.D Billingham M Egan T et al.A working formulation for the standardization of nomenclature for clinical staging of chronic dysfunction in lung allografts International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar Transplant centers worldwide have adopted the BOS system as a descriptor of lung allograft dysfunction. This allows centers to use a common language to compare program results. In the years since publication of the BOS system, transplant scientists have studied basic and clinical aspects of lung transplant BO. In this document, we update and summarize new information obtained from this research and incorporate, where appropriate, the results into the BOS criteria. The document will include the following topics: (1) criteria for BOS, (2) BOS considerations in pediatric patients, (3) risk factors for BOS, (4) pathology of BO, (5) surrogate markers for BOS, (6) confounding factors in making a BOS diagnosis, and (7) assessment of response to treatment of BOS. When the original definition of BOS was formulated in 1993, the working group had several goals. The group aimed to provide a classification system for airway disease after lung transplantation that did not rely on histopathologic findings, was sensitive and specific, relied on diagnostic techniques available to all lung transplant physicians, and was relatively simple to understand and apply. The resulting classification system defined post-transplant pulmonary function using the forced expiratory volume in 1 second (FEV1) as the primary parameter. For each lung transplant recipient, a stable post-transplant baseline FEV1 is defined as BOS Stage 0. In patients who experience a decrease in FEV1, progressive stages of BOS, from 1 to 3, are defined according to the magnitude of the decrease. An additional notation can reflect histologic findings: “a” designates that no BO has been identified, or that no biopsy has been done; and “b” designates that BO has been identified.3Cooper J.D Billingham M Egan T et al.A working formulation for the standardization of nomenclature for clinical staging of chronic dysfunction in lung allografts International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 1993; 12: 713-716PubMed Google Scholar Although the ISHLT classification system for BOS has gained universal acceptance, several limitations have been identified. First, the current grading system—which defines BOS 1 as a >20% decrease in FEV1 from baseline—was not sensitive enough to pick up early, small, but potentially important changes in pulmonary function.4Patterson G.M Wilson S Whang J.L et al.Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second.J Heart Lung Transplant. 1996; 15: 175-181PubMed Google Scholar, 5Estenne M Van Muylem A Knoop C Antoine M Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution.Am J Respir Crit Care Med. 2000; 162: 1047-1051Crossref PubMed Google Scholar, 6Reynaud-Gaubert M Thomas P Badier M Cau P Giudicelli R Fuentes P Early detection of airway involvement in obliterative bronchiolitis after lung transplantation Functional and bronchoalveolar cell findings.Am J Respir Crit Care Med. 2000; 161: 1924-1929Crossref PubMed Google Scholar In addition, the mid-expiratory flow rate (FEF25–75) was not used for defining airflow obstruction because the wider intrasubject variability of this index, in particular in recipients of unilateral transplants,7Martinez J.A Paradis I.L Dauber J.H et al.Spirometry values in stable lung transplant recipients.Am J Respir Crit Care Med. 1997; 155: 285-290Crossref PubMed Google Scholar and the very high values observed in some patients early after surgery were considered as potential limitations. Yet several reports in recipients of bilateral and heart–lung grafts have shown that FEF25–75 is more sensitive than FEV1 for early detection of airflow obstruction in BOS4Patterson G.M Wilson S Whang J.L et al.Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second.J Heart Lung Transplant. 1996; 15: 175-181PubMed Google Scholar, 5Estenne M Van Muylem A Knoop C Antoine M Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution.Am J Respir Crit Care Med. 2000; 162: 1047-1051Crossref PubMed Google Scholar, 6Reynaud-Gaubert M Thomas P Badier M Cau P Giudicelli R Fuentes P Early detection of airway involvement in obliterative bronchiolitis after lung transplantation Functional and bronchoalveolar cell findings.Am J Respir Crit Care Med. 2000; 161: 1924-1929Crossref PubMed Google Scholar (one study also included recipients of single lung transplants but results in these patients were not reported specifically8Chacon R.A Corris P.A Dark J.H Gibson G.J Tests of airway function in detecting and monitoring treatment of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 2000; 19: 263-269Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). These observations have led to a critical re-examination of the BOS criteria, and formulation of the revised classification system as detailed in this document. 1.Definition of BOS: We use the term bronchiolitis obliterans syndrome to connote graft deterioration secondary to persistent airflow obstruction (however, note that not all patients in whom airflow obstruction develops have BOS—see confounding conditions discussed below). It is widely presumed, but unproved, that chronic rejection often contributes to functional deterioration. BOS does not necessarily require histologic confirmation; in contrast, the term bronchiolitis obliterans is used for a histologically proven diagnosis.2.Definition of equipment: Spirometric measurements must be made with equipment that conforms to the American Thoracic Society standards for spirometric testing.9American Thoracic SocietyStandardization of spirometry 1994 update.Am Rev Respir Dis. 1995; 152: 1107-1136Crossref Google Scholar3.Definition of baseline: The baseline value, to which subsequent measures are referred, is defined as the average of the 2 highest (not necessarily consecutive) measurements obtained at least 3 weeks apart, such measurements being made without the use of an inhaled bronchodilator preceding the study. The baseline date is defined as the date of the first measurement used to compute the baseline. The values used to compute the baselines for FEV1 and for FEF25–75 may be obtained on different days. Because spirometric values may increase with post-operative time, the baseline should be recalculated using the highest values achieved. The definition of baseline, and hence of BOS stages, is expected to be more accurate as more functional tests are performed.4.Definition of confounding conditions: Patients are evaluated under this system only after evaluation of other conditions that may alter graft function and after treatment of these conditions if found. Interpretation of changes in lung function should take into account confounding conditions, which are discussed below.5.Definition of variables: In the original staging system, a ≥20% decrease in FEV1 from previous baseline was used to diagnosis BOS. Studies of intrasubject variability of spirometry in lung transplant recipients indicate that using a 10% to 15% decrease in FEV1 may be more appropriate for early detection of BOS.5Estenne M Van Muylem A Knoop C Antoine M Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution.Am J Respir Crit Care Med. 2000; 162: 1047-1051Crossref PubMed Google Scholar, 6Reynaud-Gaubert M Thomas P Badier M Cau P Giudicelli R Fuentes P Early detection of airway involvement in obliterative bronchiolitis after lung transplantation Functional and bronchoalveolar cell findings.Am J Respir Crit Care Med. 2000; 161: 1924-1929Crossref PubMed Google Scholar, 7Martinez J.A Paradis I.L Dauber J.H et al.Spirometry values in stable lung transplant recipients.Am J Respir Crit Care Med. 1997; 155: 285-290Crossref PubMed Google Scholar In addition, evidence suggests that FEF25–75 deteriorates before FEV1 in most bilateral and heart–lung transplant recipients with BOS.4Patterson G.M Wilson S Whang J.L et al.Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second.J Heart Lung Transplant. 1996; 15: 175-181PubMed Google Scholar, 5Estenne M Van Muylem A Knoop C Antoine M Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution.Am J Respir Crit Care Med. 2000; 162: 1047-1051Crossref PubMed Google Scholar, 6Reynaud-Gaubert M Thomas P Badier M Cau P Giudicelli R Fuentes P Early detection of airway involvement in obliterative bronchiolitis after lung transplantation Functional and bronchoalveolar cell findings.Am J Respir Crit Care Med. 2000; 161: 1924-1929Crossref PubMed Google Scholar Therefore, a potential-BOS stage (BOS 0-p), defined by a 10% to 19% decrease in FEV1 and/or by a ≥25% decrease in FEF25–75 from baseline is added to the original staging system. This potential-BOS stage alerts the physician to the need for close functional monitoring and in-depth assessment, which might include surrogate markers for BOS (see below).6.Definition of BOS stages: For the purpose of staging, a significant decrease in FEV1 or FEF25–75 will be determined by the average of 2 measurements made at least 3 weeks apart, without patient use of an inhaled bronchodilator. Patients having a single measurement of decreased FEV1 or FEF25–75 are not evaluated until a second measurement is obtained at least 3 weeks after the initial data point. Because BOS is meant to represent a persistent alteration in lung function, additional values of FEV1 or FEF25–75, which may be obtained during this 3-week period, should also show a significant decrease from baseline value. The date at which a patient enters the new BOS stage is the date of the first of the 2 measurements used to confirm the stage. In case of a concomitant decrease in vital capacity (VC) and FEV1, a restrictive ventilatory defect should be excluded before categorizing the patient in a new BOS stage (see confounding conditions discussed below).7.Definition of functional decline: Because a universal table for converting the absolute value of FEV1 and FEF25–75 to “percent predicted” does not exist, a fractional decrease in FEV1 and FEF25–75 should be determined from absolute values. The fractional decrease in FEV1 and FEF25–75 shall be expressed as the percent of decrease from the previously established baseline, i.e., the highest previous baseline value is used for all subsequent calculations.8.Definition of staging system: A proposed staging system is outlined in Table I. Within each of the staging categories is an “a” and a “b” sub-category. These relate to histologic findings of biopsy specimens. This staging system is intended to describe the recipient’s current status. Although BOS is considered irreversible, a minority of patients may show improvement in lung function over time. When a patient experiences such improvement in BOS stage, the worst stage that the patient has ever achieved may be noted in parentheses, if desired for study purposes. Therefore, BOS 1(2) will indicate a patient currently in BOS 1 who has been in BOS 2 at some point in the past.TABLE IOriginal and proposed classifications of BOSOriginal classificationCurrent propositionBOS 0FEV1 80% or more of baselineBOS 0FEV1 > 90% of baseline and FEF25–75 > 75% of baselineBOS 0-pFEV1 81% to 90% of baseline and/or FEF25–75 ≤ 75% of baselineBOS 1FEV1 66% to 80% of baselineBOS 1FEV1 66% to 80% of baselineBOS 2FEV1 51% to 65% of baselineBOS 2FEV1 51% to 65% of baselineBOS 3FEV1 50% or less of baselineBOS 3FEV1 50% or less of baselineBOS, bronchiolitis obliterans syndrome; FEF25–75, mid-expiratory flow rate; FEV1, forced expiratory volume in 1 second. Open table in a new tab BOS, bronchiolitis obliterans syndrome; FEF25–75, mid-expiratory flow rate; FEV1, forced expiratory volume in 1 second. Approximately 2.5% of lung transplant candidates are ≤17 years of age. In terms of the number of transplants, number of patients on the waiting list, and number of active centers, pediatric lung transplantation lags behind adult lung transplantation and other pediatric solid-organ transplantation. Published reports indicate an incidence of BO similar to that of adults,10Sweet S.C Spray T.L Huddleston C.B et al.Pediatric lung transplantation at St. Louis Children’s Hospital, 1990–1995.Am J Respir Crit Care Med. 1997; 155: 1027-1035Crossref PubMed Google Scholar, 11Balfour Lynn I.M Martin I Whitehead B.F et al.Heart-lung transplantation for patients under 10 with cystic fibrosis.Arch Dis Child. 1997; 76: 38-40Crossref PubMed Google Scholar, 12Madden B.P Hodson M.E Tsang V et al.Intermediate-term results of heart-lung transplantation for cystic fibrosis.Lancet. 1992; 339: 1583-1587Abstract PubMed Scopus (46) Google Scholar except in children <3 years old, in whom it may be lower.10Sweet S.C Spray T.L Huddleston C.B et al.Pediatric lung transplantation at St. Louis Children’s Hospital, 1990–1995.Am J Respir Crit Care Med. 1997; 155: 1027-1035Crossref PubMed Google Scholar Airway inspection is particularly important in children to assess for stenosis and/or malacia at the anastomotic site. In general, the BOS criteria can be used in children who can perform pulmonary function tests reproducibly (usually at least 5 years of age). However, in defining functional decline, a decrease in percent predicted rather than a change in absolute value (see 7 above) should be used. The use of percent predicted values for FEV1 and FEF25–75 should be a more accurate indicator in children because absolute values of lung function should increase with the child’s growth. In older children who can perform reproducible respiratory maneuvers, the adult criteria with the use of predicted values should be easily applied. Because of the difficulty in performing pulmonary function studies in some pediatric patients, surrogate markers for BOS may assume more importance. Infants and young children require lung function testing by other techniques, most commonly through the rapid compression technique. The combined use of forced expiratory flow at functional residual capacity, normalized by the measured functional residual capacity, is a useful technique to separate anastomotic complications from peripheral airflow obstruction. Techniques for lung function testing in infants and young toddlers provide tools for performing serial lung function testing in lung transplant recipients of this age.13Jones M Castile R Davis S et al.Forced expiratory flows and volumes in infants Normative data and lung growth.Am J Respir Crit Care Med. 2000; 161: 353-359Crossref PubMed Google Scholar, 14Jones M.H Davis S.D Kisling J.A Howard J.M Castile Tepper R.S Flow limitation in infants assessed by negative expiratory pressure.Am J Respir Crit Care Med. 2000; 161: 713-717Crossref PubMed Google Scholar Experience with such techniques is limited to 1 pediatric lung transplant center,15Cohen A.H Mallory G.B Ross K et al.Growth of lungs after transplantation in infants and in children younger than 3 years old.Am J Resp Crit Care Med. 1999; 159: 1747-1751Crossref PubMed Google Scholar and further clinical research with newer techniques is clearly indicated. 1.Pediatric patients suspected of having BO should undergo bronchoscopic examination of the airways and transbronchial biopsy when possible. On occasion in young patients or in those with obscuring clinical or large airway pathology, an open lung biopsy to assess for histopathology may facilitate early therapeutic intervention.2.In general, the criteria for BOS can be applied in children who can complete pulmonary function tests satisfactorily. However, declines in function should be expressed in terms of percent predicted instead of absolute values because of lung and airway growth. Newer techniques facilitate measurements in infants and have been used to assess for BOS. Many factors have been reported as risk factors for BOS. However, quality of data is often a problem because almost all existing information derives from retrospective studies with no control groups and reflects the experience of single centers. Numbers are small and often difficult to interpret. In some cases, risk factors seem to have been more important in the earlier years of lung transplantation, e.g., cytomegalovirus (CMV) infection. This may reflect a change in the risk environment because of the use of prophylactic antimicrobial regimens, changing immunosuppressive approaches, or the increasing experience of transplant management teams. Alloimmunologic injury directed against endothelial and epithelial structures have been thought to mediate BOS, but non-alloimmunologic inflammatory conditions including viral infections or ischemic injury may also play a role. Risk factors reported in the literature will be designated as (1) probable risk factors, (2) potential risk factors in need of further analysis, and (3) hypothetic risk factors. Acute rejection and lymphocytic bronchitis/bronchiolitis belong to this category. Six separate publications document the increased incidence of BOS in patients with acute rejection episodes, especially when multiple and/or long-lasting and/or high-grade episodes occur.16Keller C.A Cagle P.T Brown R.W Noon G Frost A.E Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation.Chest. 1995; 107: 973-980Crossref PubMed Google Scholar, 17Bando K Paradis I.L Similo S et al.Obliterative bronchiolitis after lung and heart-lung transplantation An analysis of risk factors and management.J Thorac Cardiovasc Surg. 1995; 110: 4-13Abstract Full Text PDF PubMed Scopus (301) Google Scholar, 18Girgis R.E Tu I Berry G.J et al.Risk factors for the development of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 1996; 15: 1200-1208PubMed Google Scholar, 19Heng D Sharples L.D McNeil K Stewart S Wreghitt T Wallwork J Bronchiolitis obliterans syndrome incidence, natural history, prognosis, and risk factors.J Heart Lung Transplant. 1998; 17: 1255-1263PubMed Google Scholar, 20Husain A.N Siddiqui M.T Holmes E.W et al.Analysis of risk factors for the development of bronchiolitis obliterans syndrome.Am J Respir Crit Care Med. 1999; 159: 829-833Crossref PubMed Google Scholar, 21Sharples L.D Tamm M McNeil K Higenbottam T.W Stewart S Wallwork J Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation—early risk factors.Transplantation. 1996; 61: 560-566Crossref PubMed Google Scholar Two additional publications document the role of late acute rejection in the development of BOS.22Kroshus T.J Kshettry V.R Savik K John R Hertz M.I Bolman III, R.M Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation.J Thorac Cardiovasc Surg. 1997; 114: 195-202Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 23Kesten S Maidenberg A Winton T Maurer J Treatment of presumed and proven acute rejection following six months of lung transplant survival.Am J Respir Crit Care Med. 1995; 152: 1321-1324Crossref PubMed Google Scholar Five publications report that lymphocytic bronchitis/bronchiolitis is a risk factor for BOS, when infection has been excluded as a cause of an inflammatory airway process.18Girgis R.E Tu I Berry G.J et al.Risk factors for the development of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 1996; 15: 1200-1208PubMed Google Scholar, 20Husain A.N Siddiqui M.T Holmes E.W et al.Analysis of risk factors for the development of bronchiolitis obliterans syndrome.Am J Respir Crit Care Med. 1999; 159: 829-833Crossref PubMed Google Scholar, 24Ross D.J Marchevsky A Kramer M Kass R.M Refractoriness of airflow obstruction associated with isolated lymphocytic bronchiolitis/bronchitis in pulmonary allografts.J Heart Lung Transplant. 1997; 16: 832-838PubMed Google Scholar, 25Reichenspurner H Girgis R.E Robbins R.C et al.Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation.Ann Thorac Surg. 1996; 62: 1467-1472Abstract Full Text PDF PubMed Scopus (99) Google Scholar, 26El-Gamel A Sim E Hasleton P et al.Transforming growth factor-beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation.J Heart Lung Transplant. 1999; 18: 828-837Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Medication non-compliance is a known risk factor for rejection and graft loss after kidney, heart, and liver transplantation.27Schweizer R.T Rovelli M Palmeri D Vossler E Hull D Bartus S Noncompliance in organ transplant recipients.Transplantation. 1990; 49: 374-377Crossref PubMed Google Scholar, 28Chisholm M.A Vollenweider L.J Mulloy L.L et al.Renal transplant patient compliance with free immunosuppressive medications.Transplantation. 2000; 70: 1240-1244Crossref PubMed Google Scholar, 29DeGeest S Borgermans L Gemoets H et al.Incidence, determinants and consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant recipients.Transplantation. 1995; 59: 340-347Crossref PubMed Google Scholar, 30Raiz L.R Kilty K.M Henry M.L Ferguson R.M Medication compliance following renal transplantation.Transplantation. 1999; 68: 51-55Crossref PubMed Google Scholar Medication non-compliance also is perceived as a risk factor after lung transplantation, although results supporting this have not been published. Cytomegalovirus is difficult to interpret as a risk factor for 2 main reasons: the pattern of CMV has changed with the widespread use of prophylactic strategies directed against the virus and with varying definitions of infection, disease, and pneumonitis among institutions. Eight reports consider CMV a risk factor for BOS,16Keller C.A Cagle P.T Brown R.W Noon G Frost A.E Bronchiolitis obliterans in recipients of single, double, and heart-lung transplantation.Chest. 1995; 107: 973-980Crossref PubMed Google Scholar, 19Heng D Sharples L.D McNeil K Stewart S Wreghitt T Wallwork J Bronchiolitis obliterans syndrome incidence, natural history, prognosis, and risk factors.J Heart Lung Transplant. 1998; 17: 1255-1263PubMed Google Scholar, 22Kroshus T.J Kshettry V.R Savik K John R Hertz M.I Bolman III, R.M Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation.J Thorac Cardiovasc Surg. 1997; 114: 195-202Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 25Reichenspurner H Girgis R.E Robbins R.C et al.Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation.Ann Thorac Surg. 1996; 62: 1467-1472Abstract Full Text PDF PubMed Scopus (99) Google Scholar, 31Keenan R.J Lega M.E Dummer J.S et al.Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation.Transplantation. 1991; 51: 433-438Crossref PubMed Google Scholar, 32Maurer J.R Lung transplantation bronchiolitis obliterans.in: Epler G.R Diseases of the bronchioles. Raven Press, New York1994: 275-289Google Scholar, 33Kshettry V.R Kroshus T.J Savik K Hertz M.I Bolman R.M Primary pulmonary hypertension as a risk factor for the development of obliterative bronchiolitis in lung allograft recipients.Chest. 1996; 110: 704-709Crossref PubMed Google Scholar, 34Smith M.A Sundaresan S Mohanakumar T et al.Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome.J Thorac Cardiovasc Surg. 1998; 116: 812-820Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar whereas 4 other studies reported no impact of the virus.18Girgis R.E Tu I Berry G.J et al.Risk factors for the development of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 1996; 15: 1200-1208PubMed Google Scholar, 20Husain A.N Siddiqui M.T Holmes E.W et al.Analysis of risk factors for the development of bronchiolitis obliterans syndrome.Am J Respir Crit Care Med. 1999; 159: 829-833Crossref PubMed Google Scholar, 21Sharples L.D Tamm M McNeil K Higenbottam T.W Stewart S Wallwork J Development of bronchiolitis obliterans syndrome in recipients of heart-lung transplantation—early risk factors.Transplantation. 1996; 61: 560-566Crossref PubMed Google Scholar, 35Ettinger N.A Bailey T.C Trulock E.P et al.Cytomegalovirus infection and pneumonitis Impact after isolated lung transplantation. Washington University Lung Transplant Group.Am Rev Respir Dis. 1993; 147: 1017-1023Crossref PubMed Google Scholar Four other studies document a decreased risk of CMV in the development BOS—either decreased incidence or delay in onset—after the use of CMV prophylaxis.17Bando K Paradis I.L Similo S et al.Obliterative bronchiolitis after lung and heart-lung transplantation An analysis of risk factors and management.J Thorac Cardiovasc Surg. 1995; 110: 4-13Abstract Full Text PDF PubMed Scopus (301) Google Scholar, 36Duncan S.R Grgurich W.F Iacono A.T et al.A comparison of ganciclovir and acyclovir to prevent cytomegalovirus after lung transplantation.Am J Respir Crit Care Med. 1994; 150: 146-152Crossref PubMed Google Scholar, 37Soghikian M.V Valentine V.G Berry G.J Patel H.R Robbins R.C Theodore J Impact of ganciclovir prophylaxis on heart-lung and lung transplant recipients.J Heart Lung Transplant. 1996; 15: 881-887PubMed Google Scholar, 38Speich R Thurnheer R Gaspert A Weder W Boehler A Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus disease after lung transplantation.Transplantation. 1999; 67: 315-320Crossref PubMed Scopus (45) Google Scholar However, data from the pre-prophylaxis era in which CMV pneumonitis was more prevalent strongly correlates pneumonitis as a BOS risk factor. Potential risk factors are so designated because of conflicting data, suggestive but not definitive data, or differences in definitions of the specific risk factor between centers so that available data cannot be interpreted. These factors include (1) organizing pneumonia; (2) bacterial, fungal, and non-CMV viral infection; (3) older donor age; (4) longer graft ischemic time; and (5) donor antigen-specific reactivity. Two centers report that organizing pneumonia is a risk factor for BOS. One of these centers reported that it was a univariate risk factor for BOS. The data are from small numbers and not complete enough to designate it a probable risk.18Girgis R.E Tu I Berry G.J et al.Risk factors for the development of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 1996; 15: 1200-1208PubMed Google Scholar, 19Heng D Sharples L.D McNeil K Stewart S Wreghitt T Wallwork J Bronchiolitis obliterans syndrome incidence, natural history, prognosis, and risk factors.J Heart Lung Transplant. 1998; 17: 1255-1263PubMed Google Scholar A surprisingly small body of data has been published that report the impact of bacterial, fungal, and non-CMV viral infections. One center reported bacterial and P carinii pneumonia as risks during the period before broad-spectrum prophylaxis in lung transplantation.17Bando K Paradis I.L Similo S et al.Obliterative bronchiolitis after lung and heart-lung transplantation An analysis of risk factors and management.J Thorac Cardiovasc Surg. 1995; 110: 4-13Abstract Full Text PDF PubMed Scopus (301) Google Scholar In a more recent report, bacterial or fungal pneumonia was not associated as an univariate risk with an increased rate of BOS, but did increase the acute rejection score in a multivariate model.18Girgis R.E Tu I Berry G.J et al.Risk factors for the development of obliterative bronchiolitis after lung transplantation.J Heart Lung Transplant. 1996; 15: 1200-1208PubMed