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* From the Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Marc B. Feinstein, MD, Pulmonary Division, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: feinstem{at}mskcc.org
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Abstract |
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Design: The records of 174 adult patients undergoing BMT between January 1997 and December 1999 were reviewed to determine the diagnostic yield of FOB and the frequency by which FOB altered management.
Results: Sixty-one patients underwent 76 bronchoscopies. FOB was diagnostic in 32 patients (42.1% of cases) and directly changed management in 24 patients (31.6% of cases). Half of these changes included the withdrawal of an antimicrobial agent. The most common findings were infection (32 cases) and diffuse alveolar hemorrhage (6 cases). CMV was the most prevalent infection identified, but FOB resulted in the addition of antiviral therapy to only two patients. P carinii pneumonia was not diagnosed in any patient studied.
Conclusions: These data suggest a changing spectrum of pulmonary disease in BMT patients. FOB has limited impact on the diagnoses of CMV disease or P carinii pneumonia with current prophylaxis and screening strategies. It may be useful in identifying other infectious etiologies and in eliminating unnecessary antimicrobials.
Key Words: BAL • bone marrow transplantation • bronchoscopy • cytomegalovirus • pneumonia, bacterial • transplantation, homologous
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5 years after
allogeneic transplantation.1
Conditioning regimens,
high-dose chemotherapy, and total body irradiation induce prolonged
immunosuppression, which allows engraftment but renders the patient
vulnerable to infectious and inflammatory complications. Approximately
50% of the complications of allogeneic transplants affect the lung,
and pulmonary complications cause about 30% of all
deaths.2
3
These include pneumonia from bacteria, fungi,
viruses, and Pneumocystis carinii, as well as noninfectious
complications, including bronchiolitis obliterans (BO) with and without
organizing pneumonia, diffuse alveolar hemorrhage (DAH), and toxic lung
injury due to drugs or radiation. Fiberoptic bronchoscopy (FOB), usually performed with BAL, is a safe and minimally invasive procedure that has surpassed open-lung biopsy in the evaluation of allogeneic bone marrow transplantation (BMT) patients.4 FOB has also been used to screen for such infections as cytomegalovirus (CMV) in patients considered at high risk.5 Prior reports in mixed allogeneic/autologous transplant populations suggest that the diagnostic yield of FOB varies between 40% and 60%, and that FOB alters clinical management 30 to 60% of the time.6 7 8 9 However, reports concerning allogeneic transplant patients alone are limited.
In recent years, various changes have been implemented that may have affected the role of FOB in allogeneic transplant patients. Prophylaxis against P carinii, as well as against fungal10 and CMV infections,11 is now routinely administered to decrease the role of these organisms as pulmonary pathogens. The advent of testing for serum CMV antigen has also allowed the diagnosis and treatment of CMV viremia and disease—including pneumonia—without requiring an invasive procedure.
In this current era of antibiotic prophylaxis and serum CMV antigen screening, we reviewed the 3-year experience (from 1997 to 1999) of FOB in the allogeneic transplant population at a major cancer hospital, and sought answers to the following questions: has the frequency of FOB use changed since the advent of P carinii pneumonia prophylaxis and serum CMV antigen screening, what is the diagnostic yield of FOB, and how often is therapy altered by FOB results?
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Materials and Methods |
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Data were obtained from medical charts and bronchoscopy reports. The
following were collected: (1) age, gender, race, underlying diagnosis,
date of allogeneic BMT, and date of death; (2) reason for bronchoscopy;
and (3) results of chest radiographs (CT scan or conventional chest
radiograph; if an infiltrate was present, it was described as diffuse
[involving more than one lobe], focal [involving one lobe or less],
or nodular); (4) FOB procedure performed (eg, BAL and/or
transbronchial biopsy); (5) presence or absence of neutropenia and
systemic glucocorticoid use; (6) complications of bronchoscopy,
including respiratory failure, bronchospasm, bleeding > 30 mL, oxygen
desaturation < 88% for 2 min, cardiac arrhythmias, hypotension,
and pneumothorax; (7) microbiologic and cytologic results within 10
days of FOB; (8) referrals for other diagnostic procedures, such
as open-lung biopsy; and (9) any changes in pharmacologic treatment.
FOB
There is no standardized protocol at the Memorial
Sloan-Kettering Cancer Center regarding FOB. All patients were managed
by a specialist in BMT, and were seen in consultation by an attending
physician in pulmonary medicine. The most common indications for
bronchoscopy were pulmonary infiltrates, nodules or masses, or
hemoptysis. Contraindications to FOB and BAL were at the discretion of
the pulmonary attending physician, but typically included inadequate
oxygenation or hemodynamic instability. Abnormal results of coagulation
studies were an absolute contraindication to transbronchial biopsy, but
usually not for BAL unless there was ongoing bleeding or hemoptysis.
After obtaining informed consent, all bronchoscopies were performed by
a fellow and attending physician in a dedicated endoscopy unit or, for
intubated and critically ill patients, in an ICU. Patients were
monitored with continuous cardiac telemetry and pulse oximetry. BP was
measured every 5 to 10 min. Monitored conscious sedation was
administered by the attending physician, most commonly including IV
midazolam (typical dose, 3 to 5 mg) and, in the absence of
thrombocytopenia, IM codeine (typical dose, 60 mg). If the heart rate
was < 100/min, 0.6 mg of IV atropine was also administered.
For each case, the bronchoscope was introduced through the nose or, in profoundly thrombocytopenic patients, through the oral cavity. In patients receiving mechanical ventilation, ventilation was performed with 100% oxygen and the bronchoscope was advanced through a swivel-Y adapter. Topical anesthesia of the nasal or oral passages, vocal cords, and major airways was obtained with lidocaine (2% for upper airways and 1% for lower airways). BAL was performed in the lung segment(s) most affected on CT scan and/or chest radiograph. If no such segment was identified, BAL was performed in the right middle lobe and/or lingula. Transbronchial biopsy was performed with cupped forceps under fluoroscopic guidance. Each transbronchial biopsy necessitated that an anterior-posterior chest radiograph be obtained within 15 to 30 min of the procedure. This was interpreted by a radiologist and pulmonary physician to eliminate the possibility of pneumothorax.
Radiographic Criteria
All radiographs were formally interpreted by an attending
radiologist. Focal infiltrates were defined as those that involved one
lobe or less. Diffuse pulmonary infiltrates involved more than one
lobe.
Diagnostic Criteria
All bronchial washing and BAL specimens were evaluated by the
microbiology and cytopathology laboratories of the Memorial
Sloan-Kettering Cancer Center. BAL specimens were routinely cultured
for bacteria, fungus, mycobacteria, and viruses, including CMV,
respiratory syncytial virus (RSV), adenovirus, and influenza A. CMV
antigen was detected in BAL and serum samples using monoclonal
antibodies to the pp65 lower matrix protein antigen. A fluorescent
label allows CMV-infected cells to be detected and
counted.12
BAL samples were considered to have a positive result if any of the following diagnostic criteria were met: (1) identification of P carinii by Gomori methenamine silver stain or direct fluorescent antibody; (2) positive culture results for any species of Mycobacterium, Nocardia, or Actinomycosis; (3) identification of RSV or influenza A by immunoflorescence; (4) positive CMV culture result (standard viral culture), CMV antigen, and/or characteristic "owl-eyed" intranuclear and/or intracytoplasmic inclusions on BAL cytopathology or transbronchial biopsy histology; (5) identification of septate hyphal forms consistent with Aspergillus or positive culture results for any Aspergillus species; invasive pulmonary aspergillosis was diagnosed by demonstration of tissue invasion on transbronchial biopsy specimen; (6) positive culture finding of any Candida or Torulopsis species if identical organisms are also cultured from a nonrespiratory tissue or fluid, such as the urine or blood; (7) positive culture finding of any Gram-positive or Gram-negative bacteria if identical organisms are also cultured from a nonrespiratory tissue or fluid; (8) confirmation of DAH by characteristic increasing bloody return of BAL fluid; and (9) confirmation of diffuse alveolar damage (DAD), BO, or bronchiolitis obliterans with organizing pneumonia (BOOP) by standard pathology criteria.
Patient Management
A change in patient management was defined as the addition or
subtraction of any antibiotic or systemic glucocorticoid within 72
h of completing the procedure. The transfusion of platelets to correct
DAH and/or ongoing hemoptysis was considered a change if it was
performed because of bronchoscopic findings. In every case,
documentation was required in the medical record that the change was
based on the bronchoscopy results, eg, the withdrawal of IV
trimethoprim/sulfamethoxazole because of a BAL not revealing P
carinii.
Statistical Analysis
For 28-day mortality calculations, a Student’s t
test was used to compare groups. A p value < 0.05 was considered to
indicate statistical significance. In cases in which patients underwent
more than one bronchoscopy, each bronchoscopy was counted individually.
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Results |
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Discussion |
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One of the goals of this review was to determine the influence of FOB on clinical decision making. We hypothesized that changes in antibiotic prophylaxis and the implementation of serum CMV antigen screening would lessen the prevalence of unique pulmonary infections that occur among allogeneic transplant recipients, such as P carinii and CMV pneumonia, thereby diminishing the ability of FOB to identify "treatable" abnormalities within the lung. Our diagnostic yield of 42.1% was higher than expected, and is similar to recent reports of FOB in mixed allogeneic/autologous bone marrow transplant patients. White et al,6 for instance, reported a diagnostic yield of 31% in 52 patients undergoing at least one FOB, whereas Dunagan et al7 identified pathogens in 46% of 71 patients. In contrast to these studies, we elected to exclude the identification of Candida species from our calculations of positive results unless they were also cultured from another body tissue or fluid. This decision is supported by the infrequency of Candida pneumonia at our institution, as well as by multiple studies13 14 15 indicating that patients who have Candida species isolated from bronchoscopic samples, in the absence of Candida isolated from other tissues, are unlikely to have biopsy specimen-proven Candida pneumonia. Had all positive culture findings for Candida been included in this analysis, the overall diagnostic yield would have increased to approximately 55%.
Seven patients underwent transbronchial biopsy, and, after undergoing bronchoscopy, 13 patients went on to undergo open-lung biopsy. The major reason for withholding transbronchial biopsy was the high prevalence of profound thrombocytopenia in the population studied. BOOP was found in one patient by transbronchial biopsy, and in three more patients (all of whom had nondiagnostic bronchoscopies) by open-lung biopsy. All were successfully treated with systemic glucocorticoids. Open-lung biopsy also found two microbial infections that were not evident with bronchoscopy alone. On one occasion, biopsy of a cavitary lung lesion that had been enlarging despite empiric antifungal therapy revealed Legionella jordanis, resulting in a change of antibiotics. In another patient, open-lung biopsy was diagnostic of CMV infection, and antiviral therapy was begun. Unfortunately, neither transbronchial biopsy nor open-lung biopsy was performed with enough frequency in this population to make any generalized recommendations on its use.
Although two studies in the 1980s have examined the utility of bronchoscopy in allogeneic transplant patients, to our knowledge, ours is the first in the era of serum CMV antigen screening. Moreover, neither of these reports describes the impact of FOB on patient management. Cordonnier et al16 reviewed the results of 72 bronchoscopies in 69 allogeneic transplant patients who developed pneumonitis. The diagnostic yield of BAL was 66%, with 35% of patients receiving a diagnosis of CMV pneumonia. At approximately the same time, Milburn et al17 reported a diagnostic yield of 80%, with CMV pneumonia diagnosed in 40% of patients. Although CMV remained a common pathogen in our population, it was less prevalent than in these prior studies, suggesting that either the incidence of CMV pneumonia among allogeneic transplant patients is declining, or that potential CMV disease is now being diagnosed and prevented at the level of viremia before clinically evident pulmonary disease. Of the 11 patients in our series with CMV diagnosed by bronchoscopy, 9 patients also had CMV antigen present in serum samples and were already receiving antiviral medication at the time of their procedures. Anti-CMV therapy was initiated in only two patients because of BAL results, both of whom had unsatisfactory CMV serum antigen samples. In one of these patients, CMV serum antigen was not tested. In another patient, the serum sample was obtained in the setting of absolute neutropenia, when such testing is unreliable. Taken in sum, these findings suggest that when CMV serum antigen screening is adequately performed, FOB provides little new information regarding the diagnosis of CMV disease. This is consistent with other reports that CMV antigenemia is effective at predicting cases of CMV that are missed by surveillance bronchoscopy.5 The declining importance of FOB in diagnosing CMV may, at least in part, account for the decreasing numbers of procedures performed.
One potential criticism of these studies is that, over time, referral patterns for FOB may vary. Allogeneic transplantation is a rigorous medical process, of which FOB is an intermediate step. Multiple subspecialty physicians ultimately contribute to the patients’ care. Although changes in referral patterns among any of these could theoretically have influenced the frequency of bronchoscopies performed, we think that such an impact was relatively minor in this series. The interval between the time periods studied was small (4 years), during which time there were few adjustments to allogeneic transplant protocols, other than beginning serum CMV antigen screening. A second potential criticism is that bacterial cultures from BAL were not compared to any "gold standard" diagnostic test, such as surgical lung biopsy. This would have been beyond the scope of this retrospective study. However, for the purpose of this analysis, the presence of bacteria cultured from BAL fluid was not considered to be diagnostic unless identical bacteria were also cultured from a nonrespiratory tissue or body fluid. This technique may underestimate the prevalence of "true" bacterial infections within the lung. However, we believed it necessary to minimize the potentially confounding effects of oropharyngeal contamination.
The high mortality rate in our patient population is unlikely to be secondary to FOB itself. We encountered no significant bleeding, arrhythmia, hypotension, or pneumothorax. Three patients had severe respiratory distress within 24 h of their procedures, and required mechanical ventilation. That any decompensation could have been prevented by not performing FOB in these patients is unclear, since the three patients were already receiving high levels of supplemental oxygen and were clinically decompensating at the time of bronchoscopy. Our mortality rate more likely reflects the clinical substrate of the patients themselves. Allogeneic transplant recipients typically develop respiratory complications much more frequently than those receiving autologous transplants.18 They receive higher levels of immunosuppression, and are more susceptible to pulmonary infections, graft-vs-host disease, BOOP, and BO. Dunagan et al7 reported that FOB was performed 3.37 times more often in allogeneic transplant patients than the autologous recipients. Indeed, 26.3% of all patients in our series were already receiving mechanical ventilation at the time of their procedures. This is worth noting since several studies19 20 have reported that < 20% of BMT patients receiving mechanical ventilation survive to hospital discharge. In these patients, therefore, FOB probably did not affect overall survival regardless of whether management was changed as a result of the procedure.
The complication rate in our study of 3.9% is lower than that reported by other studies.6,7 In part, this finding may reflect an observation bias, since few transbronchial biopsies were performed, most of the procedures being limited to BAL. Nevertheless, this does suggest that BAL is a safe procedure in allogeneic transplant patients with pulmonary complications.
Taken in sum, this study demonstrates a change in the types of pulmonary complications that affect allogeneic BMT patients. Historically, pneumonitis due to either P carinii or CMV was one of the most common infectious complications of transplant. We found no cases of P carinii pneumonia in this patient population, all of whom were receiving appropriate prophylaxis. Although CMV pneumonitis remains a common complication, these data suggest that serum CMV antigen screening may be as effective, and less invasive, than FOB in establishing a diagnosis. Indeed, FOB may be more helpful in eliminating the possibility of Pneumocystis or CMV infections than in diagnosing them. In six patients in this series, a negative FOB result allowed the withdrawal of either anti-Pneumocystis (four patients) or anti-CMV therapy (two patients).
What then is the current role of FOB in the evaluation of allogeneic transplant patients? We believe that FOB continues to provide important information, albeit in a smaller number of patients. It is useful in identifying a large number of other potentially pathogenic organisms, including bacteria, viruses, and fungi. In this series, FOB was safe and yielded a diagnosis in almost half the patients studied. In over one fourth of patients, FOB led to a significant change in management. Changes often included adding agents not included in traditional broad-spectrum antibiotic regimens, such as coverage against viruses other than CMV (eg, ribavirin for RSV pneumonitis). Moreover, FOB frequently allowed the discontinuation of antibiotic regimens, potentially minimizing such potential adverse complications as fluid overload, antibiotic resistance, and allergic reactions. Even in the absence of any short-term survival advantage, FOB often increased the available knowledge from which physicians could make decisions. We believe this to be preferable to empiric strategies and educated guesswork, and worth the low risks of the procedure. As such, we submit that FOB with BAL remains a valuable diagnostic tool in the evaluation of pulmonary complications in allogeneic transplant patients.
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Footnotes |
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Received for publication December 13, 2000. Accepted for publication March 21, 2001.
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This article has been cited by other articles:
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  S. Sharma, H. F. Nadrous, S. G. Peters, A. Tefferi, M. R. Litzow, M.-C. Aubry, and B. Afessa Pulmonary Complications in Adult Blood and Marrow Transplant Recipients: Autopsy Findings Chest, September 1, 2005; 128(3): 1385 - 1392. [Abstract] [Full Text] [PDF]
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N. R. Patel, P.-S. Lee, J. H. Kim, G. L. Weinhouse, and H. Koziel The Influence of Diagnostic Bronchoscopy on Clinical Outcomes Comparing Adult Autologous and Allogeneic Bone Marrow Transplant Patients Chest, April 1, 2005; 127(4): 1388 - 1396. [Abstract] [Full Text] [PDF]
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 J.-Y. Wang, Y.-L. Chang, L.-N. Lee, J.-H. Chen, J.-L. Tang, P.-C. Yang, and Y.-C. Lee Diffuse pulmonary infiltrates after bone marrow transplantation: the role of open lung biopsy Ann. Thorac. Surg., July 1, 2004; 78(1): 267 - 272. [Abstract] [Full Text] [PDF]
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 B. Afessa, A. Tefferi, M. R. Litzow, M. J. Krowka, M. E. Wylam, and S. G. Peters Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant Recipients Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 641 - 645. [Full Text] [PDF]
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