Volume 13, Issue 7 , Pages 831-837, July 2007
Diagnostic Yield of Bronchoalveolar Lavage Is Low in Allogeneic Hematopoietic Stem Cell Recipients Receiving Immunosuppressive Therapy or with Acute Graft-versus-Host Disease: The St. Jude Experience, 1990-2002
Article Outline
Abstract
Management of pulmonary complications after hematopoietic stem cell transplantation (HSCT) often includes bronchoalveolar lavage (BAL), but the diagnostic yield of BAL remains unclear in pediatric HSCT patients. We reviewed the records of 78 allogeneic and 11 autologous transplant recipients who underwent BAL after HSCT at St. Jude Children’s Research Hospital (1990-2002). We analyzed donor and recipient information, clinical variables, adverse events during bronchoscopy, outcome, and medical management at the time of the procedure to determine the diagnostic yield of BAL and factors that affect its success. Seventy-eight allogeneic and 11 autologous transplant recipients underwent BAL at a median of 68 days (range, 6-528 days) and 23 days (range, 6-705 days) after HSCT, respectively. The median age at the time of BAL was 12.2 years (0.8-23.5 years) in allogeneic patients and 16.9 years (4.8-26.2 years) in autologous patients. The most common indications for BAL in both populations were fever, hypoxia, and abnormality on chest auscultation. BAL identified an etiology in 53 allogeneic (67.9%) and 7 autologous (63.6%) patients (BAL positive); only 1 etiology was identified in 30 of the 53 allogeneic patients (56.6%). The most common finding was bacterial infection in both allogeneic (59.0%) and autologous (71.4%) patients. Of 39 allogeneic patients who had concurrent extrapulmonary infection, 30 (76.9%) had a positive BAL. Seven (9.0%) allogeneic patients experienced hypoxia (generally transient) during bronchoscopy. Approximately 68% of those with a positive BAL were receiving immunosuppressive therapy, whereas 96% of patients with a negative BAL were receiving immunosuppressive therapy (P = .008). Further, 26.4% of the BAL-positive cohort had grade II-IV acute graft-versus-host disease (aGVHD), whereas 60% of the BAL-negative group had grade II-IV aGVHD (P = .004). In our experience, the safety and diagnostic yield of BAL in this set of patients is relatively high, but the likelihood of informative findings is reduced among allogeneic recipients with grade II-IV aGVHD and those receiving immunosuppressive therapy.
Key Words: Bronchoalveolar lavage, Bronchoscopy, Pediatric, HSCT, Acute GVHD, Immunosuppressive therapy
Introduction
Respiratory complications are common (occurring in 40%-60% of patients) after hematopoietic stem cell transplantation (HSCT) [1]. As the differential diagnosis is broad and specific therapies may incur risk, optimal treatment depends on an accurate diagnosis. Immunocompromised patients are vulnerable to multiple causes of respiratory deterioration, including the primary disease, previous therapy, infection, and graft-versus-host disease (GVHD) [2].
Bronchoalveolar lavage (BAL) is a diagnostic tool used to obtain specimens in children with respiratory decompensation who have undergone HSCT, but its yield in these patients has been variable and the procedure carries certain risks. Furthermore, we are unaware whether certain groups of patients may have a greater benefit from undergoing a BAL. Therefore, we conducted a retrospective study to determine the rate of complications with BAL in children who have undergone HSCT, the diagnostic value of BAL, and patient characteristics that predict the likelihood that the procedure will be of benefit.
Materials and Methods
Patients
After obtaining approval from the St. Jude Children’s Research Hospital Institutional review board (IRB), we retrospectively reviewed the charts of 89 patients who had undergone HSCT at St. Jude between 1990 and 2002, and a BAL as identified by the Transplant and Gene Therapy database. Information gathered from the medical records and the transplant database included type of HSCT (allogeneic or autologous), primary diagnosis, disease status at the time of HSCT, age at the time of BAL, and previous allogeneic or autologous HSCT. Recipients received myeloablative conditioning before allogeneic HSCT and high-dose chemotherapy before autologous HSCT. All transplant protocols were IRB-approved, and signed informed consent for protocol or best clinical management plan was obtained from parents or the patients prior to the initiation of therapy. Patients received preparative regimens that have been previously published [3, 4, 5, 6]. Survivors were followed at St. Jude until either 10 years posttransplantation or 18 years of age, which ever occurred last.
BAL Procedure
Bronchoalveolar lavage was performed by a pulmonologist, using a fiberoptic bronchoscope of the appropriate size. Transbronchial biopsy was performed at the time of BAL at the discretion of the pulmonologist. Specimens were sent for pathology review and microbiological evaluation that included Gram stain, silver stain, and bacterial, viral, and fungal culture. A diagnosis of inflammation was made by the pathologist if inflammatory cells were present, regardless of whether an infectious etiology was identified.
Variables Analyzed
For recipients of allogeneic HSCT, we analyzed donor type (matched sibling, unrelated, or partially mismatched family member), recipient and donor cytomegalovirus (CMV) serologic status, graft manipulation (T cell depletion), the stem cell source (bone marrow or mobilized peripheral blood stem cells), the presence and extent of aGVHD and chronic graft-versus-host disease (cGVHD), and the use of immunosuppressive therapy (such as cyclosporine, methylprednisolone) at the time of BAL. Adverse events during BAL and final diagnosis were documented. We also reviewed the number of transbronchial biopsies performed at the time of BAL as well as the number of open-lung biopsies performed.
For all patients studied, we also noted the history of pre-HSCT pulmonary complications; age at the time of HSCT and BAL; day post-HSCT when BAL was performed; the frequency of respiratory symptoms that prompted the procedure; neutrophil engraftment status (ANC ≥500/μL); concurrent infectious illness (bacterial, viral, or fungal infection or colonization); antimicrobial, antifungal, and antiviral therapy at the time of BAL, including prophylactic and treatment agents; survival status; and cause of death. Chest radiographs and computed tomography (CT) imaging reports prior to BAL were reviewed. We also noted whether patients were intubated before BAL and whether intubation was elective or urgent.
Statistical Analysis
If patients underwent multiple BAL procedures, only the first was included in this analysis. BAL was considered nondiagnostic (negative) if it provided no etiologic information. If any etiology for the respiratory dysfunction was identified, the BAL was considered diagnostic (positive). The differences in the distribution of categorical clinical and biological features between patients with positive and negative BAL were examined by using 2-tailed Fisher’s or chi-square exact tests. The differences between continuous variables were examined by using the Student’s t test. The criterion for statistical significance in all analyses was a P value <.05. All statistical analyses were performed with SAS Release 9.1 software (Cary, NC).
Results
Patient Characteristics
Bronchoalveolar lavage was performed on 89 of the 917 patients who had received HSCT during the study period (401 autologous and 516 allogeneic). Seventy-eight (87.6%) were the recipients of allogeneic transplants and 11 (12.4%) received autologous transplants; 8 had undergone previous HSCTs. The median age at the time of HSCT was 12.8 years (range: 0.7-26.2 years). Seventy-nine of 87 patients (90.8%) who had diagnostic imaging studies had abnormal findings; evidence that imaging was performed prior to the procedure could not be found for 2 patients. The clinical characteristics of the patients and transplants are summarized in Table 1.
Table 1. Disease- and Transplant-Related Factors of the 89 Patients Who Underwent a BAL after HSCT
| Primary Disease | N = Patients |
|---|---|
| Acute lymphoblastic leukemia | 22 |
| Acute myelogenous leukemia | 27 |
| Chronic myelogenous leukemia | 13 |
 Chronic phase 1 | 7 |
| Chronic phase 2 | 1 |
| Accelerated phase | 4 |
| Refractory phase | 1 |
| Myelodysplastic syndrome | 5 |
| Non-Hodgkin lymphoma | 8 |
| Hodgkin lymphoma | 1 |
| Juvenile myelomonocytic leukemia | 2 |
| Fanconi anemia | 1 |
| Severe aplastic anemia | 3 |
| Familiar erythrophagocytic lymphohistiocytosis | 1 |
| Wiskott-Aldrich syndrome | 2 |
| Medulloblastoma | 2 |
| Glioblastoma | 1 |
| Ewing sarcoma | 1 |
| Donor stem cell source | |
| Bone marrow | 82 |
| Mobilized peripheral blood | 7 |
| Allogeneic stem cell donor | |
| Matched sibling | 31 |
| Unrelated donor | 39 |
| Partially mismatched family member | 8 |
| T cell depletion of the graft | |
| Yes | 48 |
| No | 41 |
| Allogeneic graft | 30 |
| Autologous graft | 11 |
| Relapse risk classification (allogeneic HSCT) | |
| Standard risk (CR1, CR2, chronic phase) | 45 |
| High risk (>CR2, refractory disease, MDS < accelerated phase) | 25 |
| Nonmalignant disease (not classified) | 8 |
Autologous Recipients
Eleven patients received autologous HSCT. The median age at the time of BAL was 16.9 years (range: 4.8-26.2 years), and the median time between HSCT and BAL was 23 days (6-705 days). Only 1 patient had a BAL greater than 1 year from HSCT. Three patients had a history of previous pulmonary complications prior to HSCT. The most frequent symptoms prior to BAL, as reported by frequency of symptoms, were hypoxia (31.6%), fever (21.1%), cough, and abnormal auscultation (15.8% each). Radiographically, either by chest radiograph or chest CT, 8 patients had a diffuse pulmonary process and 2 had focal disease present prior to BAL. One patient had normal imaging. Five of 11 patients were electively intubated and 5 were urgently intubated prior to the procedure. Only 1 patient did not require intubation. Six of the 11 patients (54.5%) had achieved neutrophil engraftment. Nine patients (81.8%) were receiving antibiotics, 8 (72.7%) were receiving antifungal medications, and 5 (45.5%) were receiving antiviral medications. BAL was positive in 7 of 11 patients (63.6%). Of these 7 patients, 6 had 1 etiologic finding and 1 had 3 positive findings. The most common positive diagnoses were bacterial infection (38.5%), alveolar hemorrhage (23.1%), and inflammation as characterized by the pathologist (7.7%). Four autologous patients had concurrent infections, with 3 having a positive BAL and 1 a negative BAL. Results of BAL did not correspond to previous pulmonary complications prior to HSCT. Only 1 patient suffered a procedure complication, which was hypoxia. One patient had a transbronchial biopsy at the time of BAL that was negative, and 1 patient proceeded to have an open lung biopsy, which revealed pulmonary fibrosis.
Allogeneic Recipients
Time to BAL and Indications for BALThe median age of the 78 allogeneic recipients at the time of BAL was 12.2 years (range: 0.8-23.5 years) and a median of 68 days (range: 6-528 days) elapsed between HSCT and BAL. Only 1 allogeneic patient underwent BAL >1 year after HSCT. Twenty-six of the allogeneic patients (33.3%) had a history of previous pulmonary problems prior to HSCT. Sixty-six (84.6%) patients had experienced neutrophil engraftment at the time of the procedure. Most patients had 1 to 3 clinical signs and symptoms that prompted BAL, including the following, reported as a percentage of frequency occurrence: fever (25.3%), hypoxia (20.4%), abnormality on chest auscultation (19.9%), cough (12.9%), and tachypnea (12.9%). Seventy-four patients (94.9%) were receiving antimicrobial medications, 59 patients (75.6%) were receiving antifungal medications, and 52 (66.7%) were receiving antiviral medications. Prior to BAL, 62 patients had a diffuse pulmonary process and 6 patients had focal disease identified by either chest radiograph or CT. Ten patients had normal imaging prior to the procedure. Twenty-six patients were intubated prior to BAL (5 electively and 21 urgently). Seven patients (9%) had a transbronchial biopsy performed at the time of BAL, and 16 patients (20.8%) had an open lung biopsy performed, 5 performed prior to the BAL. The physician on service determined the need for proceeding to an open lung biopsy, taking into consideration the patient’s clinical status and any changes occurring since the BAL was performed. Upon analysis, none of these factors were statistically associated with the outcome of the BAL.
Findings and Complications of BAL
Fifty-three patients (67.9%) had positive BAL findings, and more than 50% of these patients were receiving antimicrobial, antifungal, or antiviral agents, either for treatment or prophylaxis. The most common finding was bacterial infection (46 patients). Of the 53 patients who had a positive BAL, 30 (56.6%) had only 1 identified etiology (Table 2). Six patients had fungal infections identified by BAL, 2 were yeast, 3 were molds, and 1 was not able to be grown in culture but was present on Gram stain. Only 1 patient had a pre-BAL diagnosis of fungal pneumonia; however, BAL results for this patient did not identify this type of infection. Thirty-nine allogeneic patients (50%) had 1 or more concurrent extrapulmonary infections (viral alone: 14; fungal alone: 10; bacterial alone: 7; fungal and viral: 5; fungal and bacterial: 2; viral and bacterial: 1), and 30 (76.9%) had a positive BAL. Ten patients had the same BAL finding as the concurrent infection; 4 had fungal diseases, 4 had viral diseases, 1 had bacterial infection, and 1 had both viral and fungal infections. Two patients had a pre-BAL diagnosis of aspergillosis; however, BAL was negative for fungal organisms in both cases. One of these patients did not have any concurrent infections, whereas the other had aspergillosis in the brain and fungal retinitis. Sixty-five allogeneic recipients (83.3%) did not experience complications from the procedure. Adverse events included hypoxia (7); respiratory distress, failure, or arrest (3); epistaxis (1); laryngospasm (1); and epistaxis and laryngospasm (1). BAL results did not correspond with past pulmonary complications.
Table 2. Summary of BAL Findings of the 78 Allogeneic Recipients and the Number of Etiologies Discovered between the Pathological Review and the Microbiological Evaluation
| BAL Results | Patients (n) | % |
|---|---|---|
| Negative | 25 | 32.1.% |
| Positive | 53 | 67.9% |
| Etiology (N = 88 positive etiologies) | ||
| Bacterial infection | 46 | 52.3% |
| Inflammation | 15 | 17.0% |
| Viral infection | 12 | 13.6% |
| Alveolar hemorrhage | 8 | 9.1% |
| Fungal infection | 6 | 6.8% |
| Unidentified organism | 1 | 1.1% |
| Number of etiologies | ||
| One | 30 | 56.6% |
| Two | 15 | 28.3% |
| Three | 5 | 9.4% |
| Four | 2 | 3.8% |
| Five | 1 | 1.9% |
Of the 7 patients who had a transbronchial biopsy performed at the time of BAL, all had positive BAL findings with 3 biopsy results correlating with the BAL results and 2 biopsy results proving the presence of inflammation. The other 2 biopsy results differed from the BAL results, with 1 transbronchial biopsy revealing the presence of viral inclusion bodies and another 1 revealing the presence of aspergillosis. Of the 11 allogeneic patients who proceeded to an open lung biopsy after BAL, 3 results correlated with the BAL results and 8 results did not correlate. Of the 8 open lung biopsies performed within 30 days of BAL, 3 biopsy results correlated with the BAL results. Open lung biopsy results were as follows: 8 inflammatory changes, 2 aspergillosis, 2 diffuse alveolar hemorrhage, 1 viral infection (CMV), and 1 bacterial infection. Although our numbers are small for those patients undergoing transbronchial biopsies and/or open lung biopsies, a transbronchial biopsy was only helpful in 2 cases and would have changed management. In our patient population, an open lung biopsy did not identify a new infectious organism but rather confirmed the presence of inflammation, such as in bronchiolitis obliterans organizing pneumonia and interstitial fibrosis.
Factors Related to BAL Diagnostic YieldSixty of the 78 allogeneic recipients (76.9%) were receiving immunosuppressive therapy at the time of BAL. Forty-nine of these 78 patients (62.8%) had experienced acute GVHD (20 grade 1, 13 grade 2, 7 grade 3), and 19 patients (24.3%) had cGVHD (limited in 15 patients). Grade II-IV aGVHD and the current use of immunosuppressive therapy had an impact on BAL results. Sixty percent of those with a negative BAL had grade II-IV aGVHD whereas 26.4% of patients with a positive BAL had grade II-IV aGVHD; this was statistically significant (P = .004). Furthermore, 96% of those with negative BAL were receiving immunosuppressive therapy whereas 67.9% of those with positive BAL were receiving immunosuppressive therapy, and this was also statistically significant (P = .008) (Table 3). Those without GVHD or with grade I aGVHD and/or not receiving immunosuppressive therapy were more likely to have a positive BAL (Table 2). We performed an extensive analysis, including disease classification risk; prebronchoscopy intubation and whether urgent or elective; concurrent use of antibiotics, antifungals, antivirals, or immunosuppressive medications; and history of pre-HSCT pulmonary complications; however, we did not find any other factors associated with BAL results or within the subset of patients with grade II-IV aGVHD (data not shown).
Table 3. Demographic and Clinical Data for 78 Allogeneic Patients According to the Diagnostic Yield of BAL
| By BAL | ||||
|---|---|---|---|---|
| Factors | Overall | BAL Positive (n = 53) | BAL Negative (n = 25) | P-values |
| Age at BAL (in years) | .68 | |||
| Mean (standard deviation) | 12.4(6.1) | 12.2(5.9) | 12.8(6.6) | |
| Median (range) | 12.2(0.8,23.5) | 11.9(0.8,23.5) | 13.0(2.6,22.7) | |
| Time between HSCT and BAL (in days) | .48 | |||
| Mean (standard deviation) | 93.4(93.7) | 98.5(96.7) | 82.5(87.9) | |
| Median (range) | 68(6,528) | 74(7,528) | 58(6,361) | |
| Pre-BAL engraftment | 1.00 | |||
| No | 12(15.4) | 8(15.1) | 4(16.0) | |
| Yes | 66(84.6) | 45(84.9) | 21(84.0) | |
| Acute GVHD | ||||
| 0 | 29(37.2) | 24(45.3) | 5(20.0) | |
| 1 | 20(25.6) | 15(28.3) | 5(20.0) | |
| 2 | 13(16.7) | 8(15.1) | 5(20.0) | |
| 3 | 7(9.0) | 4(7.5) | 3(12.0) | |
| 4 | 9(11.5) | 2(3.8) | 7(28.0) | |
| Acute GVHD group | .004 | |||
| Grade 2-4 | 29(37.2) | 14(26.4) | 15(60.0) | |
| Grade 0-1 | 49(62.8) | 39(73.6) | 10(40.0) | |
| Chronic GVHD | .16 | |||
| Extensive | 4(5.1) | 1(1.9) | 3(12.0) | |
| N/A | 59(75.6) | 42(79.2) | 17(68.0) | |
| Limited | 15(19.2) | 10(18.9) | 5(20.0) | |
| Immunosuppressive therapy | .008 | |||
| No | 18(23.1) | 17(32.1) | 1(4.0) | |
| Yes | 60(76.9) | 36(67.9) | 24(96.0) | |
Of the 89 patients, 61 (68.5%) have died at the time of this report and 28 (31.4%) remain alive. Primary causes of death included respiratory (29 patients), relapse disease or second malignancy (8 patients), HSCT-related (8 patients), infectious (3 patients), and other etiologies (13 patients).
Discussion
Our study demonstrates that BAL can be safely performed in pediatric HSCT patients, and overall, the potential benefits of BAL outweigh its risks. The procedure is relatively rapid and may require minimal sedation, which is an important consideration in a patient with respiratory distress. In contrast, an open lung biopsy, another modality for determining the etiology of respiratory complications, requires general anesthesia and a postoperative chest tube. In a retrospective study of 19 patients at our institution who underwent open lung biopsy, the rate of postoperative morbidity, which was likely attributable to the procedure, was 47% at 30 days, and the 30-day survival rate was 63.2% ± 10.6% [7] Sixteen patients in our study underwent open lung biopsy after BAL. Upon retrospective review of the BAL pathology report, 14 of these 16 patients had a positive BAL, suggesting that an open lung biopsy is not necessarily required for diagnostic purposes.
Although post-HSCT pulmonary complications can have many causes, the diagnostic yield may be limited in patients receiving immunosuppressive therapy or with grade II-IV GVHD. In our study, 53 of 78 allogeneic (67.9%) and 7 of 11 autologous (63.6%) patients had a positive BAL, which may have altered medical management. This rate is much higher than those previously reported (26%-51%) [8, 9, 10, 11, 12]. The frequency of identification of bacterial and fungal causes was consistent with those previously reported [8, 9]. Eleven of 60 patients (12.4%) with positive BAL findings were diagnosed with diffuse alveolar hemorrhage, also consistent with previous reports [13, 14]. Identification of an infectious or noninfectious cause leads to different therapeutic interventions. Whereas infectious causes are predominantly treated with tailored therapy (i.e., antibiotics for a bacterial infection), inflammation and diffuse alveolar hemorrhage may be treated with a variety of therapies depending on the clinical status [15].
Although multiple patient characteristics, disease characteristics, and HSCT-related factors were analyzed, only 2 differed significantly between allogeneic patients with positive (n = 53) and negative (n = 25) BAL results. Patients with grade II-IV aGVHD and those receiving immunosuppressive therapy were less likely than others to have an informative BAL, and therefore, may be less likely to benefit from BAL. However, we acknowledge that this finding may reflect the greater likelihood that patients in an immunocompromised state were receiving antibiotic, antiviral, or antifungal agents at the time of BAL, potentially at either prophylactic or therapeutic dosage, and that the number of viable organisms and inflammatory cells in the specimens may have been reduced for that reason. These patients may have remained symptomatic leading to BAL for other reasons, such as immunologically mediated pulmonary disease, noninfectious etiologies such as diffuse alveolar hemorrhage, partially treated infections with residual inflammatory cells, or a low colony number of drug-resistant organisms, which were not found on BAL. Furthermore, patients with grade II-IV aGVHD were also more likely than others to be receiving immunosuppressive therapy. Moreover, BAL fluid can currently only be tested for viral reactivation by polymerase chain reaction (PCR) for certain viruses, such as CMV and HHV-6; unlike blood, where the possibility of testing for a larger number of viruses is greater. Hence, identifying a lower respiratory tract viral infection may be more difficult. As some patients may have noninfectious etiologies for the respiratory symptoms, other modalities for evaluation should be considered, such as echocardiography, high-resolution CT, and pulmonary function tests, when feasible to perform.
Bronchoalveolar lavage has limitations other than those identified in our study. Respiratory distress caused by chemotherapy and radiation is difficult to diagnose by BAL. TBI and many of the chemotherapeutic agents used in the preparative regimens, such as busulfan, are known to cause respiratory complications after HSCT [16, 17]. Further, in an emergent situation, a clinician is likely to begin empiric therapy and broaden prophylaxis coverage in the immunocompromised patient before BAL is performed. The procedure requires a pulmonologist or an intensivist and may have to be scheduled, whereas a patient’s condition may indicate prompt broad coverage for multiple infectious agents. However, the yield of BAL may be low in some patients because of the experience of the physician performing the BAL, the stability of the patient during the procedure, and laboratory ability to identify organisms.
In conclusion, the safety and diagnostic yield of BAL appear to be relatively high in pediatric patients with respiratory distress after HSCT. Allogeneic recipients with grade II-IV aGVHD and those receiving immunosuppressive therapy are less likely than others to benefit from BAL. Other modalities, such as diagnostic imaging, may be an alternative for this cohort of patients.
Acknowledgments
This work was supported in part by NIH Cancer Center Support grant P 30CA 21765 and by the American Lebanese Syrian Associated Charities (ALSAC). The authors thank Nancy Wright for data management assistance and Sharon Naron for editorial assistance.
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PII: S1083-8791(07)00220-0
doi:10.1016/j.bbmt.2007.03.008
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 7 , Pages 831-837, July 2007
