Lesson 17, Volume 15—Pulmonary Complications Related to Bone Marrow Transplantation

By Anthony A. Floreani, MD, FCCP; Craig A. Piquette, MD, FCCP; and Austin B. Thompson, MD, FCCP

Objectives

1. To recognize that there are infectious and noninfectious complications that occur both early and later after bone marrow transplantation.
2. To understand the need for aggressive identification of pulmonary fungal infections in the posttransplant period, specifically for localized invasive pulmonary aspergillosis, which may be treated with surgical resection.
3. To recognize late complications such as bronchiolitis obliterans, their diagnosis, and possible management.

Key words

aspergillosis; bone marrow; bronchoalveolar lavage; cytomegalovirus; transplantation

Abbreviations

BMT = bone marrow transplantation; BOOP = bronchiolitis obliterans with organizing pneumonia; CMV = cytomegalovirus; DAH = diffuse alveolar hemorrhage; ELISA = enzyme-linked immunosorbent assay; HHV-6 = human herpesvirus 6; IPA = invasive pulmonary aspergillosis; OLB = open lung biopsy; PCR = polymerase chain reaction; RSV = respiratory syncytial virus; SIRS = systemic inflammatory response syndrome; VATS = video-assisted thoracic surgery

Early Complications

Invasive Pulmonary Aspergillosis

Invasive fungal infections remain one of the most dreaded complications that can develop early after bone marrow transplantation. Aspergillus and Candida spp are responsible for the majority of these infections, with a reported incidence of 18 to 55% in various series. Invasive pulmonary aspergillosis (IPA) occurs in 4.5 to 38% of patients after BMT, with a mortality rate that approaches 90%.² The incidence of IPA increases with the duration of neutropenia, usually presenting early on as a focal process (focal or localized IPA), and later as diffuse pulmonary infection (diffuse IPA). Localized IPA can initially be seen on plain chest radiographs as small nodules or nodular infiltrates. These nodules histologically correspond to target lesions of vascular invasion by aspergillosis causing thrombosis of small vessels and hemorrhagic infarction of surrounding lung parenchyma. Kuhlman and colleagues³ have described the appearance on thoracic CT of a nodular density with a surrounding halo of low attenuation, the so-called "halo sign." It has been reported that the halo sign is indicative of focal IPA present during the first 2 to 3 weeks of infection. Later, these lesions progress to larger consolidations or cavitary masses, which in turn may form a peripheral crescent-shaped lucency termed an "air crescent sign" when viewed on plain chest radiograph or CT of the thorax. This radiographic appearance is due to the peripheral resorption of necrotic tissue from the center of the lesion, forming a sequestrum of necrotic lung tissue that is separated by air from the adjacent lung. The presence of one lesion seen on thoracic CT suggestive of Aspergillus had a 90% predictive value for the eventual diagnosis of IPA in one recent series involving 87 patients.⁴

Direct detection of Aspergillus spp, either by cytologic identification or by culture of respiratory secretions, can be difficult, leading to a delay in diagnosis. In general, the sensitivity of BAL fluid cultures for pulmonary aspergillosis is < 50%, while its specificity ranges from 80 to 90% and its negative predictive value approximates 90% in various studies. Recently, Maertens et al⁵ described the efficacy of a screening method in hematologic patients at risk for IPA using circulating galactomannan in an enzyme-linked immunosorbent assay (ELISA). Utilizing autopsy specimens and cultures as positive confirmation for Aspergillus spp, this assay had a reported sensitivity of 92.6%, specificity of 95%, positive predictive value of 93%, and negative predictive value of 95%. Another method that has shown great promise for the rapid and potentially earlier detection of Aspergillus in patients at risk for IPA is by polymerase chain reaction (PCR). The use of transthoracic and transbronchial biopsies does not appear to significantly enhance the identification of Aspergillus in lung tissue and biopsies usually are not performed because of concurrent thrombocytopenia.

In addition to the use of amphotericin B, several studies have advocated surgical resection of localized IPA in high-risk patients. In the study by Robinson et al,⁶ 11 of 16 immunocompromised patients with localized IPA had successful resection and survived hospitalization. Overall mortality was 31.3%, with four of the five deaths occurring in allogeneic bone marrow recipients.⁶ Recently, Salerno and colleagues⁷ performed 18 operations in 13 allogeneic bone marrow recipients and other immunocompromised patients. Of the five patients who died, four were allogeneic bone marrow recipients who survived their hospitalization but died an average of 79 days after resection. Surgical resection of IPA was believed to clear the infection in 69% of the patients in this series.⁷ Extrapulmonic extension of the Aspergillus infection, allogeneic BMT, and neutropenia were risk factors that predicted a poor outcome. In addition, Yeghen et al⁴ reported a 2-year actuarial survival of 36% in 37 patients with IPA treated by surgical resection. Individuals who develop multiple, bilateral densities or diffuse IPA are not candidates for surgical resection. Among patients with localized disease, survivors previously treated only with medical therapy for IPA are at risk for relapse of Aspergillus infection if they receive subsequent chemotherapy or other immunosuppressive medication. Prospective randomized studies are lacking that compare the efficacy of medical therapy alone with medical therapy and early surgical resection for localized IPA. However, the collective data from the above studies suggest that surgical therapy early after the diagnosis of focal IPA is effective in selected high-risk patients.

Viral Pneumonia: Cytomegalovirus

Cytomegalovirus (CMV) is a ubiquitous human herpes virus that is the most frequent cause of viral pneumonia early after transplantation. CMV pneumonia is significantly more frequent in recipients of allogeneic transplants (50 to 70%) as compared with their autologous counterparts with an incidence.⁸ CMV may present as a primary pneumonia or from latent reactivation of the virus in a previously infected individual who later develops drug- or disease-induced immunosuppression. Primary pneumonitis is associated with the clinical development of respiratory failure 1 to 2 months after BMT and is thought to result from the spread of CMV into the lungs in individuals who do not have preformed CMV-specific antibody. Latent infection usually occurs 3 to 4 months after BMT and is associated with underlying immunosuppression. CMV pneumonia clinically presents with dyspnea, a nonproductive cough leading to early hypoxemia, and acute respiratory failure. Radiographic patterns include a fine miliary pattern that is more commonly observed with primary pneumonitis, diffuse interstitial opacities, patchy or diffuse airspace consolidation, or mixed interstitial/alveolar opacities when viewed on chest radiographs or CT of the thorax.

BAL fluid recovered by bronchoscopy has traditionally been the source for the diagnosis of CMV pneumonitis. The presence of intranuclear or cytoplasmic inclusions in cells recovered by BAL can be found in 50 to 70% of patients with pneumonia caused by CMV. Several techniques have emerged to improve the sensitivity and specificity of bronchoscopy and BAL for detection of CMV in respiratory secretions. These include in situ hybridization, the detection of CMV DNA by PCR, and CMV detection by monoclonal antibodies against viral coat antigens.

A combination of ganciclovir and CMV-specific immune globulin to treat active CMV pneumonitis has decreased the mortality rate from this infection from approximately 85% to 35 to 48%. However, because pneumonitis from this virus still carries a high mortality rate even with therapy, preventive measures have been developed to decrease the incidence of CMV pneumonia. The use of bone marrow from CMV-seronegative donors and the infusion of CMV-negative blood products have reduced the frequency of CMV pneumonitis in recipients who are CMV-seronegative. Unfortunately, this preventive strategy does not avert the possibility of primary CMV infection and does not help recipients who are already CMV-seropositive prior to transplantation. Studies employing various prophylactic management regimens have shown that medical prophylaxis against CMV is effective in reducing subsequent CMV infection. Schmidt and colleagues⁹ demonstrated that when CMV was detected in BAL fluid 35 days after allogeneic BMT, preemptive treatment with ganciclovir prior to any clinical manifestation of CMV infection significantly reduced the incidence of CMV pneumonia from 70% in the control group to 10% in the treated group. Thus, the use of CMV-seronegative blood products/bone marrow in CMV-negative patients as well as prophylactic and preemptive therapy for CMV infection have dramatically decreased the frequency of clinical CMV pneumonitis in this patient population.

Other Herpes Viruses

Herpes simplex virus has been identified as a causative agent for pneumonia in the early posttransplant period, and human herpesvirus 6 (HHV-6) has been found to be an important pathogen in BMT recipients. In one study, HHV-6 was identified in lung biopsy specimens from 15 patients with pneumonia after BMT.¹⁰ There was a significant correlation with the presence of HHV-6 and the histopathologic findings of idiopathic pneumonitis, suggesting that HHV-6 may have a causative role in the development of the idiopathic pneumonitis syndrome after transplantation. Moreover, HHV-6 has been linked to bone marrow graft suppression and failure of hemopoietic reconstitution following transplantation.

Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is the most common community-acquired virus to cause lower respiratory tract infections in BMT recipients.¹¹ RSV infection can cause mild respiratory symptoms or can lead to pneumonia, acute respiratory failure requiring mechanical ventilation, and diffuse alveolar damage. Despite therapy, mortality rates up to 78% have been reported in BMT recipients with RSV lower respiratory tract infections. RSV antigen present in BAL fluid is detectable by an ELISA, which has a sensitivity of 82% and specificity of 96%. Use of this technique allows identification of the virus within 18 to 24 h instead of waiting up to 6 days for its isolation in culture. Adults with RSV pneumonia tend not to respond as predictably to antiviral therapy as do their pediatric counterparts. Therapy includes ribavirin given IV and/or by nebulization usually in combination with IV Ig. In one series, 19 of 42 hospitalized adult BMT recipients with acute respiratory illnesses were documented to have RSV-associated disease.¹² Two out of nine patients died when aerosolized ribavirin and IV Ig were initiated within 24 h of acute respiratory failure requiring mechanical ventilation. In contrast, all patients died when the identical treatment was administered 24 h after mechanical ventilation had been initiated for respiratory failure. Thus, this study suggests the importance of early diagnosis and therapy in those bone marrow patients with serious RSV respiratory infection.

Capillary Leak Syndrome

A noninfectious complication that occurs early after BMT may be linked to endothelial and epithelial cell injury. This syndrome has been termed capillary leak syndrome by some and the systemic inflammatory response syndrome (SIRS) by others. In a series by Cahill et al,¹³ 29 of 55 bone marrow recipients developed pulmonary edema with or without pleural effusions. In half of these cases, the pulmonary edema was suggested to be of a noncardiogenic nature as evidenced by low to normal central venous pressure measurements despite the radiographic appearance of pulmonary edema. The diagnosis of acute respiratory distress syndrome following BMT has been more often described in the setting of infection and sepsis.

Diffuse Alveolar Hemorrhage

Alveolar hemorrhage may be induced by pulmonary infection after BMT or may occur as an idiopathic syndrome early in the posttransplant period. This syndrome, referred to as diffuse alveolar hemorrhage (DAH), has been described in patients with both allogeneic and autologous bone marrow transplants. Huaringa et al¹⁴ recently reported that the DAH syndrome was the most common pulmonary complication diagnosed by BAL in their series of 89 BMT patients. The diagnosis of DAH, as described initially by Robbins et al,¹⁵ is established by demonstrating the return of sequentially bloodier lavage fluid during bronchoscopy in a patient with diffuse consolidations on chest radiography that are not explained by a known infection. They reported that the incidence of DAH tended to peak in the first 2 to 3 weeks after transplantation, paralleling the time of bone marrow recovery. In a recent postmortem review of DAH after allogeneic BMT, autopsy evidence of diffuse hemorrhage did not correlate with premorbid BAL findings of hemorrhage, although only 21 of the 47 BMT patients had a BAL performed before they died. The etiology of this syndrome remains unclear, but may be related to pretransplant radiation and chemotherapy regimens that induce pulmonary vascular damage. These effects may be compounded by the return of inflammatory cells to the pulmonary microvasculature coincident with recovery of bone marrow cells after transplantation. DAH was associated with a > 90% mortality rate in the study by Robbins and colleagues.¹⁵ This group also showed a 23% improvement in intrahospital survival for those treated with high-dose corticosteroids (> 30 mg of methylprednisolone or its equivalent) compared to patients given lower doses of steroids or not treated with steroids.¹⁵ In a prospective study of four patients diagnosed with DAH, Chao et al¹⁶ reported that all four individuals survived after treatment with high-dose corticosteroids.

Idiopathic Pneumonitis

In approximately 12% of allogeneic marrow recipients, a heterogenous syndrome consisting of nonproductive cough, dyspnea, hypoxemia, and usually diffuse interstitial opacities occurs, with a peak incidence at 14 days after transplantation.¹⁷ This form of acute lung injury has been termed the idiopathic pneumonia syndrome. The mortality of this syndrome approaches 70% and no specific treatment is available other than supportive care. By definition, this represents a noninfectious form of acute lung injury as infectious etiologies could not be identified in its original descriptions. However, latent viral infections have been recently suggested through PCR analysis of BAL fluid samples; BAL fluid obtained from patients with interstitial pneumonitis contained significantly higher levels of HHV-6 viral genomes than BAL samples from healthy individuals.¹⁷

Late Pulmonary Complications

Bronchiolitis Obliterans

Although respiratory infections may occur at any time after BMT, there are noninfectious pulmonary complications that tend to appear later (> 100 days) after marrow or stem cell engraftment. Bronchiolitis obliterans is a late-onset syndrome that occurs in 2 to 10% of BMT recipients, almost exclusively in allogeneic BMT or stem cell transplant recipients.¹⁸ The clinical presentation of bronchiolitis obliterans is marked by nonspecific symptoms such as dyspnea on exertion that progresses to dyspnea at rest, cough, wheezing, and occasionally fever. Chest radiographs are usually normal but may indicate hyperinflation. High-resolution CT of the thorax may show focal or diffuse areas of decreased parenchymal attenuation contrasted against normal lung (mosaic attenuation), focal air trapping, and bronchial and bronchiolar wall thickening. Other features may also include attenuation of pulmonary vessels (oligemia), bronchiectasis, and/or reticulonodular densities. Expiratory CT views tend to accentuate the air trapping observed in bronchiolar areas and possibly persistent hyperinflation. Pulmonary function abnormalities are usually indicative of airflow obstruction as reflected by a decreased FEV₁ and a decreased FEV₁/FVC ratio. Less often, such testing exhibits combined airflow obstruction and restriction to ventilation as well as a decreased diffusion capacity.

Philit and colleagues¹⁹ compared bronchiolitis obliterans occurring after BMT and after lung transplantation. The incidence of obliterative bronchiolitis was 5% after BMT vs 20% after lung transplantation. Clinical presentation was similar in both cases as was lung pathology; the chief abnormalities were a bronchiolar cellular inflammation with submucosal and peribronchiolar fibrosis (constrictive bronchiolitis) and more proximal airway evidence of bronchitis and bronchiectasis. The clinical courses for bronchiolitis obliterans associated with both BMT and lung transplantation were similar, with 5 of 9 BMT patients dying and 6 of 9 lung transplant patients dying of this disorder.

The best means of establishing a diagnosis of bronchiolitis obliterans remains controversial. Some individuals make this diagnosis based on clinical signs and symptoms, abnormal pulmonary function tests in the setting of allogeneic BMT, and a high-resolution CT scan that demonstrates the above findings. In immunosuppressed individuals, bronchoscopy with BAL is often performed to evaluate whether infection is the primary cause for the patient’s symptoms. Patients with obliterative bronchiolitis typically have a lymphocytic-predominant cell count in BAL fluid in the absence of infection. However, others have reported increased numbers of BAL fluid neutrophils or eosinophils for this condition when unrelated to BMT. The use of transbronchial biopsies to establish the diagnosis is also controversial, as sampling errors with this technique may provide insufficient tissue for evidence of typical histopathologic features. If the diagnosis is in doubt, video-assisted thoracic surgery (VATS) is recommended to obtain optimal tissue for recognition of histopathologic features compatible with bronchiolitis obliterans.

Treatment for obliterative bronchiolitis traditionally has been to increase the patient’s immunosuppression. This is usually accomplished with initially high doses of corticosteroids, eg, 1.0 to 1.5 mg/kg of prednisone (or its equivalent) alone or in combination with cyclosporine A or azathioprine for 4 to 6 weeks. Prednisone is then tapered, if possible, to 0.5 and then 0.25 mg/kg over the next several months. Bronchodilators tend to have little effect on lung function, but may help attenuate clinical symptoms such as dyspnea, cough, or wheezing. Unfortunately, the majority of patients have a poor response to immunosuppression, with the mortality rate of bronchiolitis obliterans approaching 65 to 70%.

Bronchiolitis Obliterans With Organizing Pneumonia

Patients who have bronchiolitis obliterans with organizing pneumonia (BOOP) usually present with a flu-like illness, dyspnea, and a nonproductive cough. Chest radiographs and CT commonly show bilateral, patchy ground-glass opacities, micronodular densities, or interstitial opacities.²⁰ In contrast to bronchiolitis obliterans, the pulmonary function abnormalities are generally of a restrictive ventilatory defect rather than airflow obstruction. Histologically, this lesion consists of organized exudates of mononuclear inflammatory cells and plugs of granulation and connective tissue that extend from bronchioles into alveolar spaces. In contrast to obliterative bronchiolitis, there is a favorable response to high-dose corticosteroids. Treatment for 8 to 12 weeks with tapering doses of corticosteroids results in improvement of symptoms and lung function in a majority of patients, although relapse of symptoms and radiographic abnormalities have been reported for other causes of BOOP.^19,20

Graft-Vs-Host Disease and Posttransplant Pulmonary Disease

Graft-vs-host disease (GVHD) is a frequent complication after allogeneic BMT. Typically the organ systems involved include the skin, liver, and large and small intestines. In 1978, Beschorner et al²¹ suggested that patients who developed a nonproductive cough and dyspnea after allogeneic transplantation may have developed airway GVHD. Airway biopsies obtained from these individuals showed the presence of increased numbers of lymphocytes in bronchial mucosa and submucosa associated with evidence of respiratory mucosal necrosis and hyperplasia. This lymphocytic bronchitis was thought to be an airway form of GVHD because (1) infiltration of airway lymphocytes significantly correlated with grade 2 or greater GVHD observed elsewhere in these patients; (2) the onset of cough and dyspnea in these patients was temporally related to the rash, diarrhea, and liver function abnormalities characteristic of the observed GVHD; and (3) lymphocytic bronchitis was not seen in the two autologous BMT recipients evaluated or in 74 cases of pulmonary disease not related to BMT.

Yousem²² has described a constellation of histopathologic findings that he believes are consistent with GVHD affecting the airways and lungs of patients after BMT. These include lymphocytic bronchitis, lymphocytic bronchiolitis, diffuse alveolar damage, bronchiolitis obliterans, and BOOP. Other investigators have suggested that lymphocytic interstitial pneumonitis, diffuse alveolar damage, and nonclassifiable interstitial pneumonitis are immunologic forms of posttransplant lung injury related to GVHD of the lung. Palmas and colleagues²³ have described a similar spectrum of noninfectious pulmonary complications in 18 of 179 patients (approximately 10%) within the first 6 months after BMT.

Outcome of Patients Requiring Mechanical Ventilation

Several studies have indicated that patients with hematologic malignancies and, in particular, bone marrow or stem cell recipients have a poor prognosis if a pulmonary event precipitates respiratory failure and the need for mechanical ventilation. Survival rates of 0 to 17% have been previously described in such patients. In a retrospective review by Ewig et al,²⁴ the overall mortality was 70/89 (79%) and 47/52 (90%) for BMT patients admitted to a respiratory ICU with hematologic malignancies. Mortality was worse in those BMT patients admitted to the ICU > 90 days after transplantation. Huaringa et al²⁵ have recently reported an 18% ICU survival rate and 5% 6-month survival in 60 of 619 BMT patients who developed a pulmonary complication that necessitated mechanical ventilation. Although duration of mechanical ventilation did not differ significantly between survivors and nonsurvivors, the longer the duration of mechanical ventilation the poorer the outcome, with a mortality rate of 95% for patients mechanically ventilated for > 15 days.²⁵ Underlying disease and the specific cause of respiratory failure were important predictors for survival. Patients with breast cancer and a less toxic conditioning regimen had the best prognosis, their respiratory failure being induced by cardiogenic pulmonary edema. In contrast, the presence of subsequent GVHD in patients receiving allogeneic marrow or stem cells was a strong independent predictor of poor survival. In this review, the late development of respiratory failure after 30 days was associated with a poorer prognosis. Thus, factors that affect survival should be carefully considered in BMT patients requiring mechanical ventilation so as to help guide ethical decisions regarding life support measures in these individuals.

Open Lung Biopsy and the Bone Marrow Patient

Despite improved recognition and earlier diagnosis of pulmonary complications after BMT, occasionally patients with progressive pulmonary disease and respiratory dysfunction evade a definitive diagnosis. Subjecting such an individual to open lung biopsy (OLB) for a histologic diagnosis can be a problematic task that needs to be examined in light of several considerations. First, immunosuppressed patients undergoing OLB may be compromised by their pulmonary disease to the extent that they require mechanical ventilation and other forms of intensive support. Because the collective information from several studies indicates that the prognosis is poor for BMT recipients who require these intensive measures, a patient in such a scenario may not be a suitable candidate for OLB based on his or her likelihood of surviving hospitalization. Second, although OLB is widely viewed as the definitive procedure for those with undiagnosed pulmonary infiltrates, even after necropsy a conclusive diagnosis can not be established for diffuse lung abnormalities in 15 to 20% of immunosuppressed patients. Finally, even if a definitive diagnosis is secured through OLB, there is no guarantee that such a diagnosis will subsequently affect the patient’s management and short-term survival.

Snyder and colleagues²⁶ retrospectively reviewed morbidity, mortality, and therapeutic outcome in 87 bone marrow recipients who underwent OLB by limited anterolateral thoracotomy. Bronchoscopy was performed in 37 patients, and at least one definitive diagnostic result was obtained in 30 of the 37 individuals. Ninety-four diagnostic OLBs were performed, with concordant results between bronchoscopy and OLB in 67% of the patients and conflicting information in 11 patients who underwent both procedures. In 15 patients, there were negative findings from both bronchoscopy and OLB. The most common histopathologic diagnosis from OLB was interstitial pneumonia/fibrosis, followed by diffuse alveolar damage and then various pulmonary infections, with CMV being the most common pathogen. Diagnostic OLB prompted no change in treatment in 37% of cases, and in only 18% of cases did OLB clearly lead to a beneficial therapeutic change. No intraoperative complications were recorded, but the perioperative mortality rate was 45% in patients undergoing OLB. These authors compared their results with a review of the literature and found that a specific diagnosis was rendered after OLB in 45 to 83% (average, 67%) of the cases reviewed. Furthermore, results from OLB invoked therapeutic changes 30 to 100% of the time, with a mean complication rate of 23% and a mean mortality rate of 34% for the 625 patients in the various series.

There is little information about the relative advantage of performing OLB by VATS compared with small-incision anterolateral thoracotomy in BMT patients. In the study by Habicht et al,²⁷ 18 diagnostic OLBs, including four VATS wedge biopsies and 24 therapeutic lung resections, were performed in 41 patients with pulmonary disease and concurrent leukemia or aplastic anemia. Early postoperative mortality was 26.8% and was significantly related to whether patients required preoperative mechanical ventilation, the presence of diffuse vs localized radiographic patterns, and whether a diagnostic OLB or a therapeutic lung resection was performed. The authors stressed that although it would seem self-evident to distinguish between OLB and lung resection, in their study lobectomies had a significantly lower mortality (4.3%) compared with VATS and thoracotomy-derived lung biopsies (55.6%).²⁷ Considering that thrombocytopenia or coagulation defects did not correlate with mortality, whereas diffuse pulmonary disease and mechanical ventilation did, this study suggests that neither the risk of bleeding nor the extent of lung resection are early predictors of mortality after these procedures.²⁷ Unfortunately, in only 51% of the biopsies performed did a directed change in therapy follow OLB. Lung biopsy in these patients may not always alter clinical course and thus the decision of whether to perform an OLB must be made on an individual basis. Furthermore, it remains controversial whether VATS or thoracotomy should be the procedure of choice for lung biopsy in these patients. Regardless of which procedure is used, however, careful consideration should be given to the patient’s preoperative respiratory status including need for impending mechanical ventilation.

Summary

Although progress has been made in the diagnosis and management of respiratory complications after BMT, such complications are still frequent and are a major cause of morbidity and mortality. The use of serial ELISA and DNA amplification techniques may allow an earlier detection of Aspergillus infections, while resection of localized IPA and antifungal chemotherapy may improve survival in those patients. The specialist should be familiar with early-onset noninfectious events such as SIRS or capillary leak syndrome. Early recognition of alveolar hemorrhage not caused by infection may result in improved survival after treatment with high-dose corticosteroids. Physicians should be aware that late-onset noninfectious complications, including bronchiolitis obliterans and BOOP, occur 2 to 10% of the time after BMT. Finally, consideration for OLB should include the patient’s degree of preoperative respiratory impairment as this may relate to early postoperative survival.

References

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