Stephen W. Crawford

Withdrawing Life Support from Mechanically Ventilated Recipients of Bone Marrow Transplants: A Case for Evidence-Based Guidelines

The use of bone marrow transplantation to treat malignant and nonmalignant disease is growing. In 1990, more than 10 000 bone marrow transplantations were done worldwide. The procedure has become standard therapy for aplastic anemia, acute and chronic myeloid leukemia, and lymphoma [1]. Autologous marrow transplantation is becoming more common for the treatment of neuroblastoma, breast cancer, and testicular cancer [1, 2]. Bone marrow transplantation can result in serious complications that lead to the need for mechanical ventilation. These complications include hepatic failure, pneumonia, adverse reactions to drugs, mucositis, massive intracranial hemorrhage, and septic shock. Patients who are older than 20 years of age, who receive a transplant while the malignant condition is in relapse, and who receive a graft that is not HLA-identical have a 50% chance of requiring mechanical ventilation after transplantation [3]. Decision making in these critically ill patients is complicated by their relatively young age, the potential for a cure of the underlying disease, and the uncertainty of the outcome [4, 5]. The emotional and physical burdens endured by the patients, their loved ones, and their caregivers are enormous. Scarce community financial resources and blood products are expended for a process that inevitably leads to the death of the patient. Early and accurate identification of patients destined to die is needed to relieve this burden without compromising the chances of potential survivors. Eleven studies [3, 6-15] have reported on 979 patients using mechanical ventilation who received bone marrow transplants (Table 1). In these studies, survival in bone marrow transplant recipients after they receive mechanical ventilation varied from 0% to 11%, although many studies enrolled fewer than 50 patients. Attempts to identify predictors of mortality have yielded conflicting results (Table 1). Older age, longer duration of mechanical ventilation, and more severe illness as measured by organ failure or Acute Physiology and Chronic Health Evaluation (APACHE) score have been associated with poor outcome, but not in every study. Even if older patients have a higher risk for death, this may be of little use in bedside decisions or discussions with family members. It would be more clinically useful to define a subgroup of patients whose survival is so low that reasonable physicians and patients would agree that intensive care can no longer effectively fulfill the goals of transplantation. Table 1. Survival of Bone Marrow Transplant Recipients after Mechanical Ventilation: Previous Studies* We hypothesized that combinations of hepatic failure, renal failure, hemodynamic instability, and lung injury would identify a group of patients whose survival rate approached zero. To address this question, we evaluated a cohort that was nearly equal in size to the number of bone marrow transplant recipients who had mechanical ventilation studied in published reports. Methods Design We used a nested casecontrol study design. Because marrow transplant recipients rarely survive after receiving mechanical ventilation, we defined cases as all survivors from the cohort and controls as a sample of the patients who died to conclude that no one with that combination of risk factors would survive. The control group of patients who did not survive allowed us to estimate the number of patients in the entire cohort who died with any given combination of risk factors [16]. From this, we estimated probability of survival with a specified combination of risk factors. Study Population The Fred Hutchinson Cancer Research Center (Seattle, Washington) does bone marrow transplantation in a high-risk, referral population. All patients are cared for by a multidisciplinary team led by an oncologist who is experienced with transplantation. Attending physicians and fellows specializing in pulmonary and critical care, infectious disease, gastroenterology, and nephrology are available 24 hours per day for in-house consultation. Patients are followed closely in Seattle for a minimum of 100 days after they receive their transplant. The Center maintains a computerized registry that includes demographic and long-term follow-up information for transplant recipients. All patients who required mechanical ventilation after receiving their first transplant between January 1980 and July 1992 were eligible for inclusion in the study. Patients who were ventilated for less than 24 hours after a procedure (open lung biopsy, bronchoscopy, or computed tomography) were excluded; the remaining patients form the study cohort. Patients who were intubated but only received continuous positive airway pressure and patients who were not intubated but who received noninvasive, mask ventilation were not defined as having mechanical ventilation. All patients who met the definition of a survivor were selected as cases. All other patients in the cohort, including those who died while receiving mechanical ventilation, those who died after extubation with prolonged hospital survival, and those who were discharged and died less than 30 days after extubation, were considered nonsurvivors and thus potential controls. To control for changes in medical care during the 12 years of the study and to maximize statistical power, two nonsurvivors (controls) were matched by year of transplantation to each survivor (case) [16]. Data Abstraction Four experienced critical care chart abstractors (including the two authors and a nurse-clinician specializing in bone marrow transplantation) recorded laboratory, hemodynamic, and treatment variables for each day of mechanical ventilation. Survivor and nonsurvivor charts were evenly distributed among abstractors, who were blinded to mortality as much as possible. Fractional inspired oxygen concentration and positive airway pressure requirements were recorded every 8 hours during mechanical ventilation. Scores on APACHE III were calculated using the published weights for the physiologic variables [17]. All patients were assigned chronic health points for metastatic cancer, leukemia, or lymphoma according to diagnosis. Because most patients were heavily sedated and many received neuromuscular blocking agents, Glasgow Coma Scores could not reliably be ascertained and the APACHE III scores did not include a contribution from this variable. Scores on APACHE III calculated without a Glasgow Coma Score range from 0 to a theoretical maximum of 272. Patient demographics and long-term survival were taken from the computerized database of the Fred Hutchinson Cancer Research Center. Variable Definitions The definition of survival used to identify cases was chosen as a compromise between meaningful long-term survival, which may result from many factors (including the success of transplantation), and short-term survival, which is more directly related to the outcome of mechanical ventilation. Survival for 30 days after extubation with subsequent hospital discharge may not be as meaningful an end point as 6- or 12-month survival, but death after hospital discharge is difficult to relate to the efficacy of mechanical ventilation or intensive care. Definitions of risk factors were developed before data abstraction and were intentionally selected to reflect relatively minor physiologic impairment. Hepatic and renal failure was defined as a total bilirubin level greater than 68 mmol/L (4 mg/dL) and a serum creatinine level greater than 177 mmol/L (2 mg/dL) during the first 3 days of mechanical ventilation. Vasopressor use, which we used as a proxy for hemodynamic instability, was defined as dopamine, more than 5 g/kgmin1, or norepinephrine, epinephrine, or phenylephrine for more than 4 hours in any 24-hour period. Dopamine administered to increase splanchnic blood flow ( 5 g/kgmin1) and drugs used to increase cardiac output or heart rate (dobutamine, amrinone, or isoproterenol) were not included as vasopressors. Lung injury was defined as a fraction of inspired oxygen concentration greater than 0.6 or positive end-expiratory pressure greater than 5 cm H2O at any of the three daily recorded values after the first 24 hours of mechanical ventilation. We evaluated this variable after the initial 24 hours of mechanical ventilation because many patients who receive high inspired oxygen concentrations during the initial phase of critical illness are rapidly weaned from this level of support. Patients who met these criteria at any time during the period of data collection were counted as having the given risk factor. Thus, patients who received vasopressors for 12 hours on the first day of mechanical ventilation and who required an inspired oxygen concentration of 0.8 after another 3 days were counted as having vasopressor and lung injury risk factors. Such patients were considered to meet the combined criterion of lung injury and vasopressors on day 3 after mechanical ventilation. Statistical Analysis Continuous variables were compared by using the Student t-test or the Wilcoxon rank-sum test, depending on distribution. Categorical variables in matched cases and controls were compared using the Mantel-Haenszel chi-square test [18]. Trends over time in the continuous variables of timing of mechanical ventilation, age, and APACHE III score were evaluated using linear regression. Trends over time in the categorical variables of fractions of patients intubated, patient survival, and patients receiving an unmatched transplant were evaluated by using the chi-square test for trend. Statistically significant trends were indicated by a regression coefficient for year of transplant or a chi-square test for trend with a P value less than 0.05. Exact CIs for ratios were calculated from the binomial distribution. Analyses were done on a personal computer using STATA software (Stata Corp., College Station, Texas). The probability for survival of patients with one or more of the study risk factors

Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: the 21-year Seattle experience.

PURPOSE To analyze results of 127 patients undergoing myeloablative therapy followed by marrow transplantation for relapsed or refractory Hodgkins disease. PATIENTS AND METHODS Twenty-three patients had primary refractory disease, 34 were in early first relapse or second complete remission (CR), and 70 had refractory first relapse or disease beyond second CR. Preparative regimens included total-body irradiation (TBI) and chemotherapy (n = 61) or chemotherapy only (n = 66). Sixty-eight patients received autologous marrow, six syngeneic marrow, and 53 allogeneic marrow. RESULTS The 5-year actuarial probabilities of survival, event-free survival (EFS), relapse, and nonrelapse mortality for the entire group were 21%, 18%, 65%, and 49%, respectively. HLA-identical allogeneic marrow recipients had a statistically lower relapse rate compared with recipients of autologous marrow, but survival, EFS, and nonrelapse mortality rates were not significantly different. In the multivariate analysis, higher performance status and absence of bulky disease predicted for improved EFS and lower relapse rates, while fewer prior treatment regimens predicted for improved EFS and lower nonrelapse mortality rates. Additionally, the univariate analysis showed that patients who underwent transplantation with disease refractory to chemotherapy or beyond second CR had a worse outcome compared with those who had less advanced disease. CONCLUSION Outcome with transplantation for patients with Hodgkins disease is improved if transplantation is performed early after relapse when disease burden is less, tumor chemosensitivity is greater, and the patient is likely to have a better performance status. The use of HLA-matched sibling marrow results in a lower relapse rate and, thus, for some individuals, may be preferable to the use of autologous marrow.

Obstructive Lung Disease after Allogeneic Marrow Transplantation: Clinical Presentation and Course

To describe the clinical presentation and progression of obstructive lung disease after marrow transplantation, we examined a sequential sample of 35 patients who had allogeneic marrow transplantation between January 1980 and January 1987, were 16 years or older, had normal pulmonary function tests before transplantation, and developed airflow obstruction defined as FEV1/FVC less than 70% and FEV1 less than 80% predicted 50 days or more after transplantation. Cases were selected from 1029 adult (older than 16 years) patients who underwent allogeneic marrow transplantation during the same period. Patients with airflow obstruction presented with symptoms of cough, dyspnea, or wheezing, or a combination. In 80% the chest radiograph was normal. Airflow obstruction was diagnosed within 1.5 years after transplantation in 33 of 35 patients. Clinical, extensive, chronic graft-versus-host disease was present in 24 patients. Only 4 patients had a complete response to primary therapy of chronic graft-versus-host disease. Serum IgG and IgA levels were decreased in 15 and 25 patients, respectively. The FEV1 declined rapidly (decrease in FEV1 greater than 30% between tests) in 21 patients, but 14 patients with slowly progressive or reversible disease were identified. Mortality was 65% at 3 years after transplant, a significantly higher value (P = 0.016) than the 3-year mortality rate of 44% in a comparison group of 412 concurrent patients with chronic graft-versus-host disease who were 16 years or older, survived more than 80 days after transplantation, and had normal pulmonary function. We concluded that obstructive lung disease after marrow transplantation may be variable with respect to time of onset and rate of progression. Obstructive lung disease was frequently associated with serum immunoglobulin deficiency and clinical, extensive, chronic graft-versus-host disease that was not readily responsive to treatment. Mortality was high but long-term survivors were identified.

Phase 1 Evaluation of the Respiratory Syncytial Virus–Specific Monoclonal Antibody Palivizumab in Recipients of Hematopoietic Stem Cell Transplants

Intravenous palivizumab (15 mg/kg) was investigated in 2 phase 1 studies among recipients of hematopoietic stem cell transplants (HSCTs). Study 1 included 6 HSCT patients without active respiratory syncytial virus (RSV) infection. Study 2 included 15 HSCT patients with RSV upper respiratory tract infection (URTI; n=3) or RSV interstitial pneumonia (IP; n=12), all of whom also received aerosolized ribavirin. Peak serum concentrations of palivizumab in the 2 studies were similar. The mean serum half-life was 22.4 days in study 1, which mainly included autologous HSCT recipients, and 10.7 days in study 2, which mainly included allogeneic HSCT recipients. No antibodies to palivizumab were detected in study 1. No adverse events were attributed to palivizumab in the 2 studies. In study 2, all 3 patients with RSV URTI recovered without progression to lower respiratory tract disease, and 10 (83%) of the 12 patients with RSV IP survived the 28-day study period. Thus, palivizumab appears to be safe and well tolerated in HSCT recipients.

Risk Factors for Airflow Obstruction in Recipients of Bone Marrow Transplants

Obstructive lung disease is a complication of bone marrow transplantation. To identify risk factors we analyzed pulmonary function tests of 281 adult patients 1 year after marrow transplantation. The forced expiratory volume at 1 second divided by the forced vital capacity (FEV1/FVC) was used to measure airflow rates. Factors associated with a lower year-1 FEV1/FVC (%) included increased age (p less than 0.0001), male gender (p = 0.02), cigarette smoking (p = 0.01), lower FEV1/FVC before transplantation (p less than 0.0001), HLA-nonidentical grafts (p = 0.001), chronic graft-versus-host disease (p = 0.0002), and immunosuppressive therapy with methotrexate (p = 0.01). There was no significant association between the year-1 FEV1/FVC and underlying disease, dose of conditioning irradiation, or development of acute graft-versus-host disease. Linear multivariate regression analysis, after controlling for the FEV1/FVC before transplantation, shows both chronic graft-versus-host disease and administration of methotrexate independently associated with decrements in the year-1 FEV1/FVC. The combined occurrence of chronic graft-versus-host disease and methotrexate also was strongly associated with decreases in the year-1 FEV1/FVC, indicating an interaction of these risk factors.

Rapid Detection of Cytomegalovirus Pulmonary Infection by Bronchoalveolar Lavage and Centrifugation Culture

Cytomegalovirus infection remains a major cause of morbidity and mortality in marrow transplant recipients. Results of a rapid centrifugation viral culture of bronchoalveolar lavage specimens from 33 marrow transplant recipients with pneumonia were compared with those for conventional viral culture of concurrently or subsequently obtained lung tissue. The centrifugation culture results were also compared to results of cytologic and immunochemical examination of these specimens. Centrifugation culture was positive within 16 hours of inoculation in 22 of 23 (96%) specimens from patients with positive conventional culture of lung tissue. Detection of cells positive for cytomegalovirus by immunofluorescent antibody staining or cytologic identification was less sensitive (59% and 29%, respectively). There was no evidence of cytomegalovirus in specimens from patients without evidence of cytomegalovirus pulmonary infection by any technique. The sensitivity (96%) and specificity (100%) of centrifugation culture of specimens from marrow transplant recipients approach that of viral culture of lung tissue.

High Rates of Pneumocystis carinii Pneumonia in Allogeneic Blood and Marrow Transplant Recipients Receiving Dapsone Prophylaxis

Chemoprophylaxis for Pneumocystis carinii pneumonia (PCP) is routinely given after allogeneic blood or marrow transplantation. We evaluated the effectiveness of dapsone prophylaxis (50 mg orally twice daily, 3 times per week) compared with twice-weekly trimethoprim-sulfamethoxazole (TMP-SMZ) in preventing PCP after allogeneic blood or marrow transplantation. Patients included all (n=646) who received allogeneic blood or marrow transplants between 1 September 1993 and 31 December 1996 who survived at least 100 days after transplantation. A cohort of 111 dapsone recipients was compared with the remaining 535 who received TMP-SMZ. Ten patients developed PCP; 8 were taking dapsone. PCP incidence in the TMP-SMZ cohort was 0.37% versus 7.2% for dapsone. The relative risk for PCP associated with dapsone use was 18.8 (P<.001) and was not accounted for by age, clinical extensive chronic graft-versus-host disease, donor source, or malignant relapse. Dapsone prophylaxis at this dosage is associated with significantly higher rates of PCP than is TMP-SMZ after allogeneic marrow transplantation. We advise caution in prescribing alternatives to TMP-SMZ prophylaxis in this setting.

Idiopathic pneumonia after bone marrow transplantation: cytokine activation and lipopolysaccharide amplification in the bronchoalveolar compartment.

OBJECTIVE To determine whether idiopathic pneumonia syndrome (IPS), a form of noninfectious lung injury that follows bone marrow transplantation, is associated with cytokine activation and increased susceptibility to lipopolysaccharide (LPS). DESIGN Case series. SETTING Tertiary referral center for marrow transplantation. PATIENTS Recipients with biopsy-confirmed IPS; normal volunteers and marrow transplant recipients without IPS were analyzed as controls. MEASUREMENTS AND MAIN RESULTS Levels of lymphocyte and macrophage-derived cytokines as well as components of the LPS, LPS-binding protein (LBP), and CD14 system in bronchoalveolar lavage (BAL) fluid were determined. We found evidence of increased vascular permeability (BAL protein) and inflammatory cytokine activation (interleukin-1, interleukin-2, interleukin-6, and tumor necrosis factor-alpha) in patients with IPS. Patients without IPS had BAL fluid cytokine and protein levels that were similar to levels in BAL fluid from normal volunteers. Moreover, components of the LPS amplification system (LBP and soluble CD14) were increased in patients with IPS but not in patients without IPS. CONCLUSIONS These results provide direct evidence for proinflammatory cytokine activation in IPS and suggest that these patients might be at increased risk for LPS-mediated injury through the LBP amplification pathway.

The Laboratory Evaluation of Opportunistic Pulmonary Infections

Dr. James H. Shelhamer (Critical Care Medicine Department, Clinical Center, National Institutes of Health [NIH], Bethesda, Maryland): Because the spectrum of processes that cause pulmonary disease in immunosuppressed patients is so broad, eminently logical reasons exist for obtaining specific information about the causative processfor example, to make certain that the patient receives appropriate therapy and that inappropriate, potentially toxic, and expensive therapies are avoided. However, these arguments for specific diagnosis are countered by valid concerns that the most useful diagnostic tests will be invasive and may ultimately be nondefinitive, thus incurring expense and morbidity without altering the clinicians initial management plan. During the past several years, the ability to diagnose infectious causes of pulmonary disease has increased considerably. Sputum, tracheal secretion, bronchoalveolar lavage, blood, and even urine samples can be examined directly. The organism can be visualized by a tinctorial or fluorescent stain, or evidence of an organism may be detected by tests for specific antigens or nucleic acid. In some instances, with the use of newer methods, extremely sensitive assays can detect the presence of a pathogen within 24 or 48 hours of sample submission. Rapid-culture techniques can provide additional information within days about the presence of viruses, mycobacteria, or fungi as well as bacteria. Major issues for clinicians who manage immunosuppressed patients have emerged. These issues include 1) the availability of assays for specific pathogens; 2) the sensitivity and specificity of each assay; 3) whether determining the presence of organism by culture, antigen detection, or detection of its nucleic acid proves that the organism is the cause of pulmonary dysfunction; 4) whether a particular test result is accurate and reliable enough to use to determine therapy and to make decisions about epidemiologic issues, including isolation precautions; and 5) whether the morbidity that some procedures entail, the staff time that is required for the collection and processing of the samples, and the expense that the procedures incur are truly warranted. In this Combined Staff Conference, we review some of the major advances that have been made in rapid identification of microbial pathogens, and we assess the role of these assays in clinical practice. Laboratory Evaluation of Specimens Dr. Vee J. Gill (Clinical Pathology Department, Clinical Center, NIH): As the range of pathogens that a microbiology laboratory can detect increases, clinicians need to recognize the optimal type of specimen to submit (Table 1) and the types of tests that can be done (Table 2). Although Gram stain and culture remain the mainstay of traditional microbiologic tests, the implementation of new methods in the clinical laboratory has led to more sensitive and more rapid detection techniques. These, in turn, can benefit patient care. Table 1. Specimens for Optimal Diagnosis of Pulmonary Infections* Table 2. Direct Stains*, Direct Tests, and Culture Available for Common Pulmonary Pathogens For routine bacteria, Gram stains of lower respiratory tract secretion or tissue samples are still important for providing rapid initial guidance on the morphologic characteristics of the bacteria. Although Gram stain of sputum has fallen into disfavor with some clinicians, an abundance of organisms (10 per high-power field) in an adequate specimen with neutrophils (25 per high-power field) is still considered highly suggestive of significance. However, both Gram stains and cultures are admittedly difficult to interpret in neutropenic patients or in those who have already received extensive treatment with antimicrobial agents. Some clinicians are enthusiastic about specimens obtained by protected brushes or bronchoalveolar lavage, both of which reduce upper airway contamination of specimens. Such specimens can then be cultured quantitatively [1, 2]. Quantitative culturing can add sensitivity and specificity to the diagnosis of bacterial pneumonia, but it is time consuming. Many clinicians and laboratory directors question whether the additional information that is gained justifies the added expense. In subsequent sections, we present the current state of the art as well as new methods for the diagnosis of viruses, Legionella species, Mycoplasma pneumoniae, Chlamydia pneumoniae, Pneumocystis carinii, mycobacteria species, and fungi. For each of these major groups of pathogens, specific technical advances are ready to be incorporated into clinical laboratory procedures, and newer methods are being developed for use in the near future. Overview of New Laboratory Tests for the Diagnosis of Pulmonary Infections Viruses Rapid isolation and identification of respiratory viruses within 1 to 2 days can now be done using shell vial cultures that are stained with virus-specific fluorescent monoclonal antibodies. With the shell vial culture, the specimen is centrifuged onto a tissue culture monolayer contained within a screw-capped vial. The monolayer, which is grown on a coverslip within the vial, can be stained using various respiratory virus pools or virus-specific fluorescent monoclonal antibodies. By setting up multiple vials, one can stain a coverslip at 1-day or 2-day (or other) intervals as desired. This method is shown schematically in Figure 1. The technical simplicity of shell vial cultures has made it possible for them to be done in-house at many laboratories, providing useful information in a timely fashion. Figure 1. Schematic of the shell vial virus isolation technique. Legionella Species For the laboratory diagnosis of Legionella pneumonia, bronchoalveolar lavage fluid samples and lung biopsy specimens remain the most reliable specimens and are preferred to expectorated sputum samples. Currently available methods include direct fluorescent monoclonal antibody staining and cultures using supplemented media for Legionella species. A urinary antigen radioimmunoassay for L. pneumophila serotype 1 was introduced several years ago but has not been readily available because the radioimmunoassay format has not been practical for clinical microbiology laboratories to set up. A commercially available urinary antigen assay that uses an enzyme-linked immunoassay now enables more laboratories to use this test. However, because this test is highly specific for L. pneumophila serotype 1, infection with a different serotype or species would go undetected. Successful use of the polymerase chain reaction on respiratory specimens for the diagnosis of Legionella infection has recently been reported. Mycoplasma and Chlamydia Species Laboratory diagnosis of infection caused by M. pneumoniae and C. pneumoniae relies heavily on the detection of serologic conversion. Both agents can be cultivated, but with difficulty, so that this service is not routinely offered by clinical laboratories. In the future, polymerase chain reaction may be used to establish an early diagnosis for these pathogens. In addition to shell vial culturing, fluorescent antibody staining of smears made directly from specimens such as bronchoalveolar lavage fluid samples can yield quick results. Reagents that can be used for direct staining of specimens are available for respiratory syncytial virus, cytomegalovirus, herpes simplex virus, and varicella-zoster virus. Commercially available enzyme immunoassays have become more diverse and offer technically easy yet rapid testing; such tests are already available for respiratory syncytial virus and influenza A virus. Methods that provide results on the same day that the specimen is submitted, either by direct staining or by enzyme immunoassay, are attractive to clinical laboratories, but each assay must be assessed to ensure that its sensitivity and specificity are adequate. Pneumocystis carinii Advances in the detection of P. carinii are attributable to improvement in rapid direct staining of induced sputum, bronchoalveolar lavage fluid, and lung biopsy specimens. The ability of microbiology laboratories to provide same-day staining with stains such as monoclonal fluorescent antibody stains has resulted in more sensitive and timely detection of pneumocystis pneumonia. Polymerase chain reaction has also been shown to increase detection of P. carinii, particularly when done on induced sputum specimens. Mycobacteria Species Mycobacterial isolation and identification have been significantly improved by the use of more rapid-culture techniques such as the radiometric BACTEC (Becton-Dickinson, Sparks, Maryland) system. Used in conjunction with new commercially available DNA probes (Accuprobe, Gen-Probe, San Diego, California), the time required for the isolation and identification of the significant mycobacterial pathogens has been greatly reduced. Figure 2 describes this innovative probe technology, which detects specific ribosomal RNA targets, allowing identification of an isolate within 1 day by a simple chemiluminescent assay. Figure 2. Simplified schematic of the Accuprobe hybridization assay (Gen-Probe). Because direct detection of Mycobacterium tuberculosis in sputum specimens using molecular techniques such as polymerase chain reaction may yield even more sensitive and rapid diagnosis, continued progress in the use of these methods is especially warranted. Fungi Advances in fungal diagnostics have been limited. Direct detection by smears, culture, and specific antigen assays (for Cryptococcus and Histoplasma species) are the methods on which clinicians currently rely. One improvement that has increased the utility of direct smears for fungi is the use of the calcofluor white stain. This is a rapid, easy-to-read stain in which fungal elements brightly fluoresce, but it requires the use of a fluorescent microscope. Other recent developments include commercial DNA probes (Gen-Probe) [2-8] that are available for the identification of H.

Biopsy diagnosis and clinical outcome of persistent focal pulmonary lesions after marrow transplantation

We reviewed the results of all percutaneous fine needle aspirations (FNA) and open lung biopsies (OLB) after bone marrow transplantation at our center (1984-1987) for the evaluation of focal lung lesions that developed or persisted despite antibiotic administration. We sought to determine the prevalence and types of infections, the yield of diagnostic procedures, and the clinical outcome of these focal lesions. Infection was documented in 78% (18/23) of all lesions and was fungal in each case. FNA detected fungal lung infection with a sensitivity of 67% (10/15) but had a negative predictive value of only 50% (5/10). Complications occurred in 15% of FNA. OLB without prior FNA was performed in 6 cases and demonstrated fungal infections in 5. Overall, seven of the 18 patients with localized invasive fungal lung disease recovered after antifungal therapy. This study demonstrates that focal lung lesions that develop or persist despite antibiotics after BMT are most often fungal. FNA may safely identify these localized infections in selected patients and with appropriate treatment recovery may be achieved.