Utility of Fiberoptic Bronchoscopy in Bone Marrow Transplant Patients

Utility of ﬁberoptic bronchoscopy in bone marrow transplant patients

P White1,2,3, JT Bonacum1,2 and CB Miller2

Departments of 1Medicine and 2Oncology, 3Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Summary: idiopathic noninfectious pneumonia; (3) pulmonary edema (hydrostatic or noncardiogenic); (4) respiratory failure Fiberoptic bronchoscopy (FOB) has been reported to (pulmonary and extrapulmonary etiologies); (5) inflamma- have a high diagnostic yield and to be safe in BMT tory conditions (diffuse alveolar damage (DAD), bronchio- patients with pulmonary infiltrates. At our institution, litis obliterans organizing pneumonia (BOOP), bronchiolitis BMT patients with respiratory symptoms and/or pul- obliterans (BO), and pulmonary graft-versus-host disease); monary infiltrates had a thoracic CT and bronchoalveo- (6) pulmonary hemorrhage; and (7) pulmonary veno- lar lavage (BAL). Transbronchial biopsy (TBBx) was occlusive disease (VOD). Clinical signs, symptoms, and considered if the platelet count could be raised to radiographic infiltrates consistent with pneumonia occur in Ͼ30 × 109/l. From March 1993 to August 1995, 52 30–60% of patients following BMT and the mortality rate patients had 68 FOBs (42 BAL + TBBx, 26 BAL only) is 60–80%.1,2 Fiberoptic bronchoscopy (FOB), a safe well for 60 episodes of clinical pneumonia. Patients’ charac- tolerated procedure capable of obtaining samples from dis- teristics were: 38 males, mean age 42 years, and 39 allo- tal airways and alveoli, is commonly used to evaluate BMT geneic BMTs. Of the 68 FOBs, 47 were performed to patients with undiagnosed pulmonary infiltrates.2–4 In BMT evaluate diffuse infiltrates, 10 were done on mechan- patients with pulmonary infiltrates 50–80% of FOBs pro- ically ventilated patients, and 50 of the FOBs were pre- vide a definitive diagnosis.5–12 Prior reports of FOB in BMT ceded by a platelet transfusion. Thirty-one percent of patients have emphasized diagnosis,5–10,12 and have not FOBs (21 FOBs, 19 patients) were diagnostic. Twenty- indicated the impact of FOB on directing pharmacologic four percent of FOBs (11 diagnostic FOBs, six nondiag- therapy5,6,7,9,11,13 or stressed patient survival.5,8,11 nostic FOBs) changed therapy. Ten complications The use of FOB to evaluate pulmonary infiltrates in BMT (15%) occurred in 10 FOBs (five acute respiratory fail- patients was not previously standardized at our institution. ure, three pneumothoraces, one nose bleed, one death). Although the medical literature indicates that FOB in BMT Hospital and 6-month survival based on episodes of patients with pulmonary infiltrates is a safe and valuable clinical pneumonia were 47 and 32%, respectively. diagnostic procedure, its impact on providing a diagnosis, Patients who had a diagnostic FOB or a FOB that guiding treatment, and patient outcome at our institution changed treatment did not have better hospital or 6- was unclear. A data base was established to collect existing month survival compared to patients who had FOBs clinical information to assess the yield, impact on treat- that were nondiagnostic or did not change treatment. ment, safety and survival in BMT patients who had FOB to FOB in our BMT patient population, had a low diagnos- evaluate respiratory symptoms and/or pulmonary infiltrates. tic yield (31%), infrequently changed treatment (24%), a significant complication rate (15%) and was not associated with improved patient survival. The role of rou- Materials and methods tine diagnostic FOB in BMT patients with pulmonary infiltrates and/or respiratory symptoms should be re- Patient population evaluated. Keywords: BMT; bronchoscopy; FOB; pulmonary The Johns Hopkins Oncology Center (JHOC) BMT unit has infection 18 inpatient beds and performs approximately 150 marrow transplantations per year (ෂ50 allogeneic, ෂ100 autologous) for hematologic malignancies and aplastic anemia. (Patients who have autologous BMT following high-dose chemo- Bone marrow transplantation (BMT), is a well accepted therapy for breast cancer or ovarian cancer are not cared form of treatment for certain hematologic and nonhemato- for on this unit and are not included in this data base.) logic malignancies, and various hematologic or immuno- Since March 1993, pulmonary physicians evaluating BMT logic disorders. Pulmonary complications following BMT patients for respiratory symptoms (cough, dyspnea, and/or include: (1) infection (bacterial, viral, fungal, parasitic); (2) chest pain), fevers and/or pulmonary infiltrates were encouraged but not required to perform FOB for: (1) patients with diffuse infiltrates provided pulmonary edema Correspondence: Dr P White, The Johns Hopkins University, Division of Pulmonary and Critical Medicine, 720 Rutland Avenue, Ross Research is excluded on clinical grounds; (2) patients with focal Building, Room 858, Baltimore, MD 21205-2196, USA infiltrates or pulmonary nodules greater than 2 cm in dia- Received 12 March 1997; accepted 19 June 1997 meter who did not respond promptly to empiric antibiotics FOB in BMT patients P White et al 682 and/or antifungal therapy. This approach was approved by Chest CT criteria the JHOC BMT Clinical Studies Committee and the JHOC Pulmonary and Critical Care Medicine Committee. Data Diffuse pulmonary infiltrates were defined as bilateral were collected on all BMT patients who had FOB between infiltrates that involved у1 lobe. Presumed basilar atelecta- 17 March 1993 and 31 August 1995 for respiratory symp- sis with bilateral pleural effusion were coded as diffuse toms and/or undiagnosed pulmonary infiltrates. infiltrates. Focal infiltrates were defined as unilateral infiltrates involving one lung (uninvolved ipsilateral lobes and contralateral lung appear normal). Pulmonary nodule(s) (Ͻ3 cm in diameter), pulmonary mass (Ͼ3 cm in diameter), Data collection were coded as focal infiltrates. Existing clinical data were obtained from the Oncology Center Information Systems computer, the Johns Hopkins Patient management Medical Institutions computer, the patient’s hospital chart and FOB reports. The following data were collected for A change in patient management was defined as the with- each patient within 48 h of FOB: age, gender, underlying drawal or addition of a pharmacologic treatment within 72 diagnosis, type and date of BMT, type of infiltrate on chest h of the procedure for nondiagnostic FOB and within 48 h CT (diffuse vs focal), FOB procedure(s) performed of the result for a diagnostic FOB. (bronchoalveolar lavage (BAL), and transbronchial biopsy (TBBx) vs BAL alone), FOB results (microbiology, cyto- Bronchoscopy technique pathology, histology), FOB complications (pneumothorax, acute respiratory failure requiring mechanical ventilation FOB was performed by a Pulmonary and Critical Care within 24 h of FOB, estimated blood loss Ͼ30 ml, death Medicine fellow and attending physician. The patient or within 24 h of FOB), platelet number and white blood cell surrogate signed informed consent prior to the procedure count, and whether the patient had a platelet transfusion which was performed in either a dedicated Endoscopy Unit prior to FOB. We also recorded change in pharmacologic (spontaneously breathing patient) or in the patient’s room treatment, date of discharge or death, vital status 6 months (mechanically ventilated patient). Patients were monitored after FOB, and results of autopsy or post mortem lung with continuous electrocardiograms and pulse oximetry. biopsy performed within 10 days of FOB. Blood pressure was monitored every 5–10 min. The standard practice for sedation was i.v. midazolam (typical dose 5 mg) and i.v. fentanyl (typical dose 100 ␮g). The nasal Diagnostic criteria passage, vocal cords and airways were anesthetized with lidocaine. If the patient’s heart rate was Ͻ100 b.p.m., i.v. Identification of Pneumocystis carinii or Legionella species atropine (0.5–1 mg) was administered. FOB in mechan- from FOB specimens was assumed to be diagnostic of par- ically ventilated patients was performed via a swivel-Y enchymal lung infection. Bacterial pneumonia was diag- adaptor while the patient was ventilated with 100% oxygen. nosed in patients on antibiotics when thoracic CT showed Mechanically ventilated patients were sedated as outlined an alveolar infiltrate and: (a) blood or pleural fluid cultures above and commonly received short-acting neuromuscular grew pathogenic bacteria; or (b) histologic evidence of blocking agents. The bronchoscopist determined which acute bacteria pneumonia was demonstrated by surgical lung segment(s) were lavaged and/or biopsied. In general, lung biopsy or autopsy; or (c) quantitative bacterial cultures the middle lobe or lingula was lavaged and/or biopsied for from BAL fluid grew Ͼ105 colony-forming units. In diffuse infiltrates, and the subsegment most affected on CT patients not on antibiotics, in addition to the above, a com- was lavaged and/or biopsied for focal infiltrates. BAL was patible Gram stain (organisms and neutrophils) and heavy done using 20 ml or 50 ml aliquots of room temperature growth was adequate for diagnosing bacterial pneumonia. normal saline. A total of 80 to 150 ml of saline (typical Cytomegalovirus (CMV) pneumonia was diagnosed by a amount 100 ml) was instilled. Contraindications to FOB positive CMV culture (standard viral culture, or early anti- or BAL were: uncooperative patient, active bronchospasm, gen culture) and/or characteristic ‘owl-eyed’ intranuclear hemodynamic instability, unstable arrhythmia, and refrac- and/or intracytoplasmic inclusions on BAL cytopathology tory hypoxemia (PaO2 Ͻ100 mmHg on high flow oxygen or TBBx histology. Invasive pulmonary aspergillosis (IPA) via non-rebreather face mask). TBBx were performed with was diagnosed in neutropenic patients with compatible fluoroscopy using 2 ml elipcoid cupped forceps. The num- infiltrates/nodules on CT by microscopic identification of ber of TBBx attempted was determined by the operator septate hyphal forms consistent with Aspergillus (BAL (generally 3–6). In addition to the general contraindications cytopathology or potassium hydroxide (KOH), and/or lung to FOB, contraindications to TBBx were: (1) 1 h post-plate- histology) or positive BAL cultures. In non-neutropenic let transfusion platelet number Ͻ30 × 109/l; (2) PT Ͼ15 patients IPA was diagnosed by demonstration of tissue s; (3) PTT Ͼ1.3 times control; (4) BUN Ͼ50 mg/dl; (5) invasion by fungal forms consistent with Aspergillus. Can- spontaneous mucocutaneous bleeding; and (6) mechanical dida pneumonia was diagnosed by a positive BAL culture ventilation with positive end expiratory pressure. An ante- and histologic evidence of tissue invasion. DAD, BOOP, roposterior chest X-ray was obtained 15–45 min after BO were diagnosed by standard surgical pathology criteria. TBBx to examine for pneumothorax. BAL fluid was sub- TBBx specimens which were ‘consistent with’ DAD, mitted to cytopathology and microbiology (gram stain and BOOP, or BO were recorded as diagnostic. aerobic bacterial culture; Legionella culture and direct flu- FOB in BMT patients P White et al 683 Table 1 Patient demographics

Diagnosis M/F Mean age Allogeneic Autologous Hospital 6-month (range) BMT BMT survivors survivors

CML (n = 15) 11/4 35.6 (18–53) 15 0 10 5 AML (n = 10) 6/4 46.9 (22–64) 10 0 4 2 ALL (n = 5) 5/0 42.4 (31–52) 4 1 0 0 NHL (n = 14) 11/3 49.8 (33–61) 6 8 8 7 Hodgkin’s disease (n = 2) 1/1 24 (23–25) 1 1 1 1 Other (n = 6)a 4/2 41.5 (24–58) 3 3 5 4 Total (n = 52) 38/14 42 (18–68) 39 13 28 19

CML = chronic myelogenous leukemia; AML = acute myelogenous leukemia; ALL = acute lymphocytic leukemia; NHL = non-Hodgkin’s lymphoma; M = male; F = female. Survival data are based on episodes of clinical pneumonia (n = 60). aOthers were: aplastic anemia (1), multiple myeloma (3), choriocarcinoma (1), germ cell (1). orescent antibody, mycology culture and KOH preparation, 2, IPA 3, Candida 2, bacterial pneumonia 2, Legionella mycobacteriology fluorochrome stain and culture, and viral pneumonia 1, DAD 2, BOOP 1, and BO 1). One of the cultures for CMV including early antigen culture, herpes diagnostic FOBs yielded two diagnoses (CMV and bac- simplex virus, respiratory syncytial virus, influenza virus, terial pneumonia) and one yielded three diagnoses (CMV, parainfluenza virus, and adenovirus). TBBx specimens Legionella, IPA). One patient had FOB twice for the same were placed in 10% formaldehyde and submitted for his- episode of CMV pneumonia. Nineteen pulmonary infec- tology, acid fast stains and methenamine silver stains. tions were identified in 17 FOBs in 13 patients. The diagnostic yield of FOB for focal vs diffuse infiltrates was 24 vs 34%, respectively (P = 0.40). Four noninfectious diag- Statistical analysis noses were established with four FOBs in four patients. All statistics (mean, ␹2, Kaplan–Meier survival analysis) Forty-seven FOBs in 33 patients were nondiagnostic. Sev- were calculated using the SPSS statistical package (version enteen (24%) FOBs (11 diagnostic FOBs and six nondiag- 6.1). ␹2 test was used to compare variables. P р 0.05 was nostic FOBs) in 14 patients (15 episodes of pneumonia) considered statistically significant. When a patient had Ͼ1 changed therapy. Therapy was not changed in either of the FOB, Kaplan–Meier analysis was done using data from the two FOBs that yielded Ͼ1 diagnosis. first FOB. Of the 68 FOBs, 65 (96%) were done when the patient was receiving antibiotics, 40 (59%) when the patient was on amphotericin, 19 (28%) when the patient was on gan- Results ciclovir or fosconnate, 32 (47%) when the patient was on antibiotics and amphotericin (18 without acyclovir, 14 with Between 17 March 1993 and 31 August 1995, 391 patients acyclovir), and six (9%) when the patient was on anti- had BMT (123 allogeneic, 268 autologous). During this biotics, amphotericin and ganciclovir or fosconnate. period, 52 patients (39 allogeneic and 13 autologous; 32% Four patients had surgical lung biopsies done following a of allogeneic BMTs, 5% of autologous BMTs, P Ͻ 0.0001) nondiagnostic FOB (two BAL and TBBx, two BAL alone). underwent 68 FOBs (42 BAL and TBBx, 26 BAL alone) Three of the surgical biopsies yielded a definitive diagnosis for 60 episodes of clinical pneumonia (fever, respiratory (two BOOP, one pulmonary VOD) and two changed treat- symptoms and/or pulmonary infiltrates). Ten patients had two FOBs, three patients had three FOBs, and eight patients had FOB for two separate episodes of clinical pneumonia. Table 2 Timing of FOB Patient demographics, pre-BMT diagnosis, type of trans- Days post-BMT at FOB Total P valuea plant and survival are listed in Table 1. Of the 68 FOBs, 47 (69%) were done to evaluate diffuse Ͻ30 30–90 Ͼ90 infiltrates, 21 (31%) were done to evaluate focal infiltrates, 10 (15%) were done on mechanically ventilated patients, No. FOB 25 24 19 68 NS 50 (74%) were done after a platelet transfusion and 14 Dx FOB 5 11 5 21 NS (21%) were done when the total white blood cell count Change in Rx 3 9 5 17 NS 9 was Ͻ5 × 10 /l. Hosp survivors 12 4 12 28 NS The number of days after BMT when a patient had FOB 6 mo survivors 7 4 8 19 NS (Ͻ30 days, 30–90 days, Ͼ90 days) was not significantly associated with the diagnostic yield, change in treatment, aCalculated by ␹2 analysis. or patient survival (Table 2). Dx = diagnostic; Rx = treatment; NS = not significant. The number of days status post-BMT when FOB was done was not sig- Table 3 reports the results (diagnosis, change in treat- nificantly associated with diagnostic yield or survival. Dx FOB and change ment, outcome) of FOB. Thirty-one percent of FOBs (21 in Rx are based on number of FOB (n = 68). Survival data are based on FOBs in 19 patients) yielded a diagnosis (CMV 10, PCP number of individual episodes of clinical pneumonia (n = 60). FOB in BMT patients P White et al 684 Table 3 Results of FOB in BMT patients

CT inﬁltrates Diagnostic proceduresa Change Survivors Rx Diffuse Focal BAL TBBx BAL/TBBx Hospital 6 month

Infection CMV (n = 10) 8 2 7 0 3 7 3 1 PCP (n = 2) 2 0 1 0 1 2 1 1 IPA (n = 3) 1 2 3 0 0 1 1 0 Candida (n = 2) 2 0 0 1 1 1 0 0 Bacterial (n = 2) 2 0 2 0 0 0 1 0 Legionella (n = 1) 1 0 1 0 0 0 0 0 Noninfectious DAD (n = 2) 2 0 0 2 0 0 0 0 BOOP (n = 1) 1 0 0 1 0 0 1 0 BO (n = 1) 1 0 0 1 0 0 0 0 Total 19 5 13 5 5 11 7 2 Nondiagnostic 31 16 0 0 0 6 21 17

BAL = bronchoalveolar lavage; TBBx = transbronchial biopsy; Change Rx = change in treatment. aBAL = diagnosis by BAL only; TBBx = diagnosis by TBBx only; BAL/TBBx diagnosis = present on both BAL and TBBx. For diagnostic FOBs CT inﬁltrates and diagnostic procedures are based on the number of identiﬁed diagnoses (n = 24 in FOBs). Change in Rx data is based on number of FOBs (n = 68). Survival data are based on number of episodes of clinical pneumonia (n = 60).

ment (BOOP, and pulmonary VOD). Seven patients had 1.0 examination of post mortem lung tissue within 10 days of 0.9 FOB (ﬁve autopsies, two lung biopsies) of which one Change in therapy yielded a diagnosis not found on the prior FOB (CMV 0.8 pneumonia). Hospital and 6-month survival for the 60 episodes of 0.7 clinical pneumonia was 47 and 32%, respectively (Table No change in therapy 1). Survival by Kaplan–Meier analysis demonstrated that 0.6 patients who had a diagnostic FOB or a FOB that changed therapy did not have an increased probability of survival 0.5 compared to patients who had a FOB that did not yield a diagnosis or change therapy (Figures 1 and 2). 0.4 Cumulative survival 0.3

0.2 Log-rank; P = 0.68 1.0 0.1 0.9 Diagnostic FOB 0.0 0.8 030 60 90 120 150 180

Non-diagnostic FOB 0.7 Days post-bronchoscopy

0.6 Figure 2 There was no difference in survival between patients who had FOBs that did nor did not change therapy. 0.5

0.4 Complications

Cumulative survival 0.3 Ten complications (15%) occurred in 10 FOBs involving nine patients. Five patients (7%) required mechanical venti- 0.2 lation for acute respiratory failure within 24 h of FOB. 0.1 Log-rank; P = 0.34 Three pneumothoraces (4%) occurred (two after BAL in mechanically ventilated patients, one after TBBx and BAL 0.0 in a spontaneously breathing patient) but none required a 030 60 90 120 150 180 chest tube and all resolved with conservative management. Days post-bronchoscopy There was one bleeding complication (1.5%): a nose bleed Figure 1 There was no difference in survival between patients who had requiring packing. There were no episodes of significant diagnostic or nondiagnostic FOBs. parenchymal hemorrhage following TBBx or BAL. One FOB in BMT patients P White et al 685 patient (1.5%) died within 24 h of FOB. An autopsy indi- of pneumonia with non-lobar pulmonary infiltrates without cated the cause of death was sepsis and there was no indi- evidence of lower respiratory infection defined as a lack of cation that the patient’s death was related to the procedure. improvement on broad spectrum antibiotics and/or a nondi- Overall, two of the nine patients (22%) who had FOB- agnostic FOB.16 The historical incidence of idiopathic inter- related complications (pneumothorax, mechanical vent- stitial pneumonitis (defined as PO2 on room air Ͻ70 ilation) were discharged alive from the hospital. This was mmHg, nonlobar pulmonary infiltrates in the absence of not statistically different from hospital survival in patients heart failure and no evidence of infection based on culture without FOB-related complications (51%; P = 0.30). and histology of lung tissue) at our BMT center was 19% and 7% for allogeneic and autologous BMT patients, respectively.17 The incidence of IPS at other BMT centers Discussion is similar (10–20%).16 The reduction in the number of cases of CMV pneumonia relative to idiopathic interstitial pneu- In our BMT patient population, FOB had a low diagnostic monitis responsible for diffuse infiltrates at our BMT center yield (31%), infrequently changed therapy (24%), and a could partly account for the low FOB diagnostic yield seen significant complication rate (15%). Hospital and 6-month in this series, given that IPS cannot be definitively diag- survival in patients who had a diagnostic FOB or a FOB nosed by FOB. that changed treatment was not different compared to In our series, FOB diagnosed nine of 10 patients with patients who had a nondiagnostic FOB or a FOB which did clinically recognized CMV pneumonia. This is similar to not change therapy. other reports in BMT patients.7,8 The single case of CMV This observation raises an important issue. What is the pneumonia not identified by FOB in this report was diag- role of FOB in evaluating BMT patients with pulmonary nosed at autopsy 10 days after FOB in a patient with infiltrates and respiratory symptoms? A diagnostic pro- chronic graft-versus-host disease, CMV colitis, CMV cedure may benefit a patient by: (1) providing a diagnosis; viremia, acute respiratory distress syndrome and multi- (2) guiding treatment; (3) predicting prognosis. In this organ system failure. Post-mortem lung pathology showed report, FOB was found wanting on all three accounts. This ‘extensive acute organizing diffuse alveolar damage’ and raises the question whether the risk of FOB justifies the ‘rare CMV positive cells’. Our experience with CMV pneu- benefit and should FOB be done routinely to evaluate pul- monia strongly suggests that the low overall diagnostic monary infiltrates in BMT patients. A definitive statement yield of FOB was not an artifact of a technical problem in would require this observation be confirmed in a large con- obtaining, transporting, processing or culturing specimens. trolled clinical trial comparing survival in BMT patients The yield of FOB in our series was not spuriously with clinical pneumonia randomized to empiric antimicro- depressed by overly stringent diagnostic criteria. The diag- bial therapy with or without FOB and antimicrobial therapy nostic criteria were similar to those used by others.6,7,12 The dictated by FOB and/or other invasive diagnostic pro- diagnosis of BOOP, BO, and DAD by TBBx were included cedures. Enthusiasm for such a clinical trial is problematic. which, given the size of the biopsies, may not be represen- Multiple uncontrolled reports have failed to show improved tative of the actual lung pathology.18 The diagnostic yield survival in immunocompromised patients who had open for FOB would be 25% if these noninfectious TBBx diag- lung biopsies,14 and FOB has a high diagnostic yield for noses are excluded. If the diagnostic criteria were too rigor- CMV pneumonia, a common cause of diffuse pulmonary ous, but the information obtained from FOB was used to infiltrates in BMT patients.7,8 direct patient management, or improved patient outcome, The medical literature for FOB in BMT patients is sum- this would be reflected in the change in therapy (Tables 2 marized in Table 4. FOB has been reported to yield a spe- and 3) and survival data (Figures 1 and 2). This was not cific diagnosis in 42% (13) to 89% (8) of patients. The the case. yield in our series (31%) was less than expected based on The addition of TBBx was of limited benefit. TBBx with the medical literature. The explanation for this was not aggressive platelet support was safe (no cases of pneumo- obvious. Patient population, treatment protocols, and thorax requiring a chest tube or significant parenchymal patient selection criteria vary between institutions and may bleeding in 42 FOBs). But, TBBx provided only one influence the diagnostic yield of FOB and patient survival. additional infectious diagnoses (Candida pneumonia) and Our patient population was heterogenous, was identified never by itself changed therapy. These results support the prospectively, and all FOBs were clinically indicated. The contention that the routine use of TBBx in this setting can- spectrum and timing of diagnosis in our series were similar not be recommended.2,8 to previous reports,1–3 suggesting that the low diagnostic In this series, all patients had CT scans within 48 h of yield was not an artifact of the patient population or selec- FOB. CT scans are more sensitive than plain chest X-rays tion criteria. in detecting lung nodules and metastasis,19 and may be In allogeneic BMT patients, CMV pneumonia is the most more sensitive than chest X-rays in detecting early invasive common pulmonary infection between 30–180 days after pulmonary aspergillosis and other opportunistic pulmonary marrow transplant.1–3 Historically, the incidence of CMV infections in BMT patients.19,20 Fewer pathogenic organ- pneumonia at our institution has been low (allogeneic, 12%; isms may be present in the lung when CT demonstrates autologous, 2%).15 Other BMT centers have reported an pulmonary infiltrates not seen on chest X-ray. This may incidence as high as 25% for allogeneic BMT patients.2,3 translate into a lower recovery rate by FOB. Idiopathic pneumonia syndrome (IPS) in BMT patients is BMT patients with infiltrates are commonly on multiple a clinical syndrome characterized by signs and symptoms broad spectrum antibiotics with or without antifungal FOB in BMT patients P White et al 686 Table 4 Clinical characteristic and utility of FOB in BMT patients: previous studies

Ref. Number Episodes of Type of BMT % % Complications Hospital patients pneumonias Inﬁltrates Diagnostic mortality bronchoscopy (%)

Springmeyer et al5 22 23 NR Diffuse 58 (TBBx) 13% NR (Bleeding) Cordonnier et al6 36 46 Allogeneic Diffuse 48 52 (BAL) 0% 24 Focal 52 Cordonnier et al7 69 81 Allogeneic NR 66 (BAL) NR 32 Springmeyer et al8 15 15 NR Diffuse 89 40% NR (BAL/TBBx) (Bleeding) Milburn et al9 30 40 Allogeneic Diffuse 48 80 (BAL) 0% 50 Focal 45 Normal 7 Abu-Farsakh et al13 77 NR Autologous 56% NR 42 (BAL) NR 79 Allogeneic 44% Campbell et al10 27 27 NR NR 74 11% (PNX) 74 (BAL/TBBx) Weiss et al11 47 66 Pretransplant 11% Diffuse 62 47 (BAL) 12% NR Autologous 9% Focal 29 Allogeneic 80% No inﬁltrate 9 Dunagan et al12 71 NR NR Diffuse 54 46 27% 61 Focal 40 (BAL/TBBx) (major 8%) No inﬁltrate 6 Current study 52 60 Autologous 25% Diffuse 69 31 15% 53 Allogeneic 75% Focal 31 (BAL/TBBx)

NR = not reported.

and/or antiviral therapy. The early and aggressive use of during FOB documented major arrhythmias in 11 and 18% these empiric therapies may decrease the FOB yield for of FOBs.26,27 infectious pneumonias. Prior antibiotic therapy in immuno- In our series, respiratory failure requiring mechanical competent patients with ventilator-associated pneumonia ventilation was the most common adverse event due to drastically reduces the sensitivity and specificity of bron- FOB (7%) and is similar to a report in 71 BMT patients choscopically obtained quantitative bacterial cultures.21,22 (4%; P = 0.46).12 The five patients who required mechan- In this series, 94% of FOBs were done when the patient was ical ventilation for respiratory failure after FOB had diffuse receiving empiric antimicrobial therapy. One other study of infiltrates, and high oxygen requirements (50–100% O2 via FOB in BMT patients has reported the prevalence of face mask) prior to FOB. Which patients would have empiric therapy (94%).12 Prophylactic or pre-emptive anti- required mechanical ventilation had they not had FOB is microbial therapy is common in BMT patients because pre- not known. The temporal relationship between FOB and venting infections or treating asymptomatic infections mechanical ventilation speaks for itself, and the grim prog- rather than treating established infections is associated with nosis (approximately 95% hospital mortality) of BMT better patient survival.23 patients who require mechanical ventilation is well docu- The complication rate for FOB in this series was 15% mented.2,3 Hospital survival for our BMT patients who emphasizing that FOB is not a benign undertaking in BMT were mechanically ventilated at FOB or within 24 h of FOB patients. Although six of the FOB complications (five was 15%. mechanical ventilation and one death) may not have been In BMT patients, two studies have reported the impact a direct consequence of the procedure, the adverse event of FOB on therapy.8 Campbell et al10 reported that 63% of rate directly attributable to FOB would be 6%. FOB com- FOBs were used to modify therapy and Dunagan et al12 plications in BMT patients has been reported to vary reported that 42% of FOBs altered antimicrobial treatment. between 0% and 40% (Refs 6, 8 and 9; Table 4). The expla- In this report only a quarter of FOBs changed therapy and, nation for the wide range of complication rates in the litera- as in the above referenced studies, this did not translate into ture is not certain. The study methods of prior reports improved survival. Patient survival, in addition to being (retrospective, based on FOB reports or bronchoscopist’s easier to define than diagnostic FOB or change in treatment, recall, lack of defined outcomes, no comment regarding is the most important outcome. data verification) suggest serious limitations and a likeli- Based on this series, the value of routine diagnostic FOB hood of under reporting and/or a tendency to report only in BMT patients with clinical pneumonia should be re- serious or obvious complications. For example, two large evaluated. The diagnostic yield was low, the results series of FOB complications in general medical patients infrequently change treatment and the knowledge gained by report no cases of arrhythmias in 69 000 FOBs,24,25 while FOB did not improve patient survival. This observation two studies specifically assessing the risk of arrhythmias may not be unique to our institution. We suggest that a FOB in BMT patients P White et al 687 randomized trial assessing the efficacy of empiric treatment gation and management of pulmonary infiltrates following without FOB, empiric treatment with FOB (current bone marrow transplantation: an 8 year review. Thorax 1993; practice), and protocol-directed treatment based on FOB 48: 1248–1251. (including discontinuing antimicrobial therapy based on a 11 Weiss SM, Hert RC, Gianola FJ et al. Complications of fiber- nondiagnostic FOB) should be considered to better define optic bronchoscopy in thrombocytopenic patients. Chest 1993; 104: 1025–1028. the use of FOB in this patient population. 12 Dunagan DP, Baker AM, Hurd DD, Haponik EF. Broncho- scopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 1997; 111: 135–141. Acknowledgements 13 Abu-Farsakh HA, Katz RL, Atkinson N, Champlin RE. Prog- nostic factors in bronchoalveolar lavage in 77 patients with bone marrow transplants. Acta Cytologica 1995; 39: 1081– We would like to thank David Shade for his statistical analysis 1088. of the data. We would also like to thank Heather Murphy for her 14 Robin ED, Burke CM. Lung biopsy in immunosuppressed manuscript preparation. patients. Chest 1986; 89: 276–278. 15 Wingard JR, Chen DY-H, Burns WH et al. Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow trans- References plantation. Blood 1988; 71: 1432–1437. 16 Clark JG, Hansen JA, Hertz MI et al. Idiopathic pneumonia 1 Krowka MJ, Rosenow ED, Hoagland HC. Pulmonary compli- syndrome after bone marrow transplantation. Am Rev Resp Dis cations of bone marrow transplantation. Chest 1985; 87: 1993; 147: 1601–1606. 237–246. 17 Wingard JR, Sostrin MB, Vriesendorp HM et al. Interstitial 2 Crawford SW, Meyers JD. Respiratory disease in bone mar- pneumonitis following autologous bone marrow transplan- row transplant patients. In: Shelhamer J, Pizzo` PA, Parrillo JE, tation. Transplantation 1990; 46: 61–65. Masur H (eds). Respiratory Disease in the Immunosuppressed 18 Myers JL, Colby TV. Pathologic manifestions of bronchiolitis, Host. JB Lippincott Company: Philadelphia, 1991, pp 595– constrictive bronchiolitis, cryptogenic organizing pneumonia, 623. and diffuse panbronchiolitis. Clin Chest Med 1993; 14: 611– 3 Quabeck K. The lung as a critical care organ in marrow trans- 622. plantation. Bone Marrow Transplant 1994; 14: S19–S28. 19 Kuhlman JE. The role of chest CT in evaluation of the febrile 4 Levine SJ, Stover DE. Bronchoscopy and related techniques. bone marrow transplant recipient. Chest 1991; 99: 794–795. In: Shelhamer J, Pizzo` PA, Parrillo JE, Masur H (eds). Respir- 20 Barloon TJ, Galvin JR, Mori M et al. High-resolution ultrafast atory Disease in the Immunosuppressed Host. JB Lippincott chest CT in the clinical management of febrile bone marrow Company: Philadelphia, 1991, pp 73–93. transplant patients with normal or nonspecific chest roent- 5 Springmeyer SC, Silvestri RC, Sale GE et al. The role of genograms. Chest 1991; 99: 928–933. transbronchial biopsy for the diagnosis of diffuse pneumonias 21 Rouby J-J, De Lassale EM, Poete P et al. Nosocomial bron- in immunocompromised marrow transplant recipients. Am Rev chopneumonia in the critically ill. Am Rev Resp Dis 1992; Resp Dis 1982; 126: 763–765. 146: 1059–1066. 6 Cordonnier C, Bernaudin J-F, Fleury J et al. Diagnostic yield 22 Torres A, El-Ebiary M, Padro L et al. Validation of different of bronchoalveolar lavage in pneumonitis occurring after allo- techniques for the diagnosis of ventilator-associated pneu- geneic bone marrow transplantation. Am Rev Resp Dis 1985; monia. Am J Crit Care Med 1994; 149: 324–334. 132: 1118–1123. 23 Momin F, Chandrasekar PH. Antimicrobial prophylaxis in 7 Cordonnier C, Bernaudin J-F, Bierling P et al. Pulmonary bone marrow transplantation. Ann Intern Med 1995; 123: complications occurring after allogeneic bone marrow trans- 205–215. plantation. Cancer 1986; 58: 1047–1054. 24 Credle WF, Smiddy JF, Elliott RC. Complications of fiber- 8 Springmeyer SC, Hackman RC, Holle R et al. Use of bron- optic bronchoscopy. Am Rev Resp Dis 1974; 109: 67–72. choalveolar lavage to diagnose acute diffuse pneumonia in the 25 Suratt PM, Smiddy JF, Fruber B. Deaths and complications immunocompromised host. J Infect Dis 1986; 154: 604–610. associated with fiberoptic bronchoscopy. Chest 1976; 69: 9 Milburn HJ, Prentice HG, Du Bois RM. Role of bronchoalveo- 747–751. lar lavage in the evaluation of interstitial pneumonitis in 26 Palojoki A, Kallio V, Tala E. Electrocardiographic changes recipients of bone marrow transplants. Thorax 1987; 42: during bronchoscopy. Scand J Resp Dis 1968; 49: 32–34. 766–778. 27 Shrader DL, Lakshminarayan S. The effect of fiberoptic bron- 10 Campbell JH, Blessing N, Burnett AK, Stevenson RD. Investi- choscopy on cardiac rhythm. Chest 1978; 73: 821–824.