Objectives

1. To review the pulmonary complications in immunosuppressed patients using a clinical-radiologic approach to diagnosis and management.
2. To discuss the role of bronchoscopy in the diagnosis of pulmonary infiltrates in the immunocompromised host.
3. To discuss the role of bronchoscopy in the diagnosis of pulmonary nodules in the immunocompromised host.
4. To discuss the role of bronchoscopy in the diagnosis of Pneumocystis carinii pneumonia in the current era of prophylaxis.
5. To discuss the role of bronchoscopy in the diagnosis of cytomegalovirus in the current era of prophylaxis, cytomegalovirus antigenemia, and polymerase chain reaction.

Key words

BAL; bronchoscopy; cytomegalovirus; immunocompromised host; Pneumocystis carinii pneumonia; pneumonia

Abbreviations

BMT = bone marrow transplantation; BOOP = bronchiolitis obliterans with organizing pneumonia; CMV = cytomegalovirus; DAD = diffuse alveolar damage; OLB = open lung biopsy; PCP = Pneumocystis carinii pneumonia; PSB = protected specimen brush; TBBx = transbronchial biopsy

Over the last two decades, there has been a significant increase in the number patients living with acquired or induced immunosuppression. More aggressive treatments that are now available for chronic diseases involve the use of corticosteroids as well as other immunosuppressive agents; bone marrow transplantation (BMT) has become a standard treatment for many hematologic and some nonhematologic malignancies, and solid organ transplants are performed more frequently now as a result of better and stronger immunosuppressive drugs. Although these advances have had a significant impact on the management of many disorders, these therapies have been associated with multiple complications, including infectious and noninfectious pulmonary diseases.¹

Pulmonary disease in the immunosuppressed host may have an incidence as high as 50%, with a direct mortality approaching 30%.² Theoretically, the prompt and accurate diagnosis of potentially treatable pulmonary complications can have significant implications in these patients. The differential diagnosis is often broad and includes both opportunistic and nonopportunistic community-acquired or nosocomial infections, as well as noninfectious entities in up to 25% of cases. Examples of the latter include cardiogenic and noncardiogenic pulmonary edema, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP), alveolar hemorrhage, diffuse alveolar damage (DAD), malignancy, cytotoxic drug reactions, radiation damage, and pulmonary thromboembolism.^1,2

Bronchoscopy with BAL and/or transbronchial biopsy (TBBx) has traditionally been the preferred diagnostic modality used to evaluate these patients, with a diagnostic yield that varies greatly between 30 and 80%.^3-6 In the past, many of the diagnoses obtained from these procedures resulted in significant changes in therapy, especially with the demonstration of pathogens such as cytomegalovirus (CMV) and Pneumocystis carinii. However, recent publications have questioned the usefulness of bronchoscopic techniques, suggesting that the information provided does not significantly change treatment or improve survival and can be associated with significant complications.^3,7,8 Furthermore, prophylaxis for pathogens such as CMV and P carinii pneumonia (PCP) has become the standard of care. Treatment with multiple antibacterial, antiviral, and antifungal agents is frequently started after infectious pulmonary involvement is suspected, decreasing the yield of cultures obtained bronchoscopically.^9,10 The purpose of this paper is to review the common pulmonary complications in non-HIV immunosuppressed patients and to evaluate the most recent literature focusing on the role of bronchoscopy in the diagnosis and management of these patients.

Background on Pulmonary Complications in the Immunosuppressed Patient

The approach to determining the cause of pulmonary involvement in the immunocompromised host should be systematic, taking into consideration the major immune defect, the time period after the initiation of immunosuppression, and the radiographic findings (pulmonary nodules vs infiltrates).

The immune defect may be secondary to neutrophil dysfunction, which is more commonly associated with infections caused by bacteria as well as aspergillus and candidal organisms. The humoral defects are associated with infections with encapsulated organisms such as Haemophilus influenzae and Streptococcus pneumoniae. Cell-mediated immune defects are very frequently seen in transplant patients secondary to the immunosuppressive agents used. A number of organisms can cause infection in the host with impaired cell-mediated immunity, including bacterial infections with Nocardia, mycobacteria, Listeria, and legionella; fungal infections due to aspergillus, Candida, Coccidioides, Histoplasma, and Cryptococcus; viral infections, particularly with herpes simplex virus, varicella zoster virus, and CMV; and parasitic infections due to Pneumocystis, Toxoplasma, and Strongyloides.

The time periods in which the patient is immunosuppressed are also determinants of the infections that the patients are more likely to develop. One of the main determinants of the net state of immunosuppression is the level of sustained immunosuppression rather than the short-term effects of a particular immunosuppressive regimen. In transplantation, based on the usual course of intense immunosuppression initially followed by a subsequent reduction in immunosuppression, certain infections are more common in specific posttransplant periods (Fig 1).¹¹

Finally, the presentation and evolution of the abnormalities on chest radiography provide important clues to both the differential diagnosis of pulmonary complications, both infectious and noninfectious, and aid in formulating the diagnostic work-up. From the clinical standpoint, it is imperative to try to define the main abnormality on the chest radiograph as pulmonary infiltrates vs pulmonary nodules. In situations where this distinction is difficult or mixed infiltrates are present, the chest CT may be important in defining the major abnormality and also in deciding the best approach to diagnosis.

Pulmonary infiltrates are typically defined as lobar or multilobar patchy alveolar consolidation, usually involving multiple areas of the lungs. The differential diagnosis during the early period of immunosuppression in acutely ill patients is diverse and includes pulmonary edema, pneumonia, alveolar hemorrhage, atelectasis, and ARDS. In patients in a later period of immunosuppression who have acute symptoms, these infiltrates more frequently arise from acute bacterial infections; however, if the presentation is subacute, it is more common to find infections with fungi, viruses, Nocardia, mycobacteria, and P carinii.

Nodular infiltrates are defined as single or multiple focal defects that are > 1 cm in diameter on chest radiograph, have well-defined borders, and are surrounded by aerated lung. These abnormalities may develop acutely; they may represent infections with atypical bacteria or an atypical presentation of pulmonary edema. However, pulmonary nodules more frequently present as a subacute or chronic entity and, in the vast majority of cases, represent an opportunistic infection with fungi, Nocardia asteroides, tuberculosis, and rarely P carinii. As with pulmonary infiltrates, the time period following the beginning of immunosuppression is also important with pulmonary nodules. Early causes of pulmonary nodules include fungal infections such as aspergillus, which can be aggressive and fatal. After this period, patients become susceptible to more subacute infections, such as those due to Nocardia spp, Cryptococcus neoformans, Coccidioides immitis, and tuberculosis.^12,13 Various neoplastic diseases are more common in those patients who survive the early posttransplant period, including metastatic carcinoma, posttransplant lymphoproliferative disease, lymphoma, and metastatic disease.

The Role of Bronchoscopy in the Evaluation of Immunosuppressed Patients With Pulmonary Infiltrates and Nodules

Pulmonary Infiltrates

In the evaluation of immunocompromised patients with pulmonary infiltrates, it is very important to have a systematic approach as discussed above. A gold-standard test for the diagnosis of pneumonia in these patients has not been established. Even trying to define pneumonia has been controversial in some studies. The definitions most commonly used are histologic findings consistent with pneumonia, positive cultures in tissue, or high bacterial counts in quantitative cultures from BAL or protected specimen brush (PSB) samples. It is important to remember that prior antibiotic therapy can decrease the yield of quantitative bacterial counts obtained by PSB, BAL, or lung biopsy cultures.^9,10,14,15 This is very relevant to immunosuppressed patients with pulmonary infiltrates, as antibiotics are almost universally initiated before any diagnostic testing is performed.

Because studies for the diagnosis of pneumonia in immunosuppressed patients have the limitations outlined above, many clinicians have extrapolated findings from studies examining bronchoscopy in patients requiring mechanical ventilation. Recently, Torres et al¹⁴ published their results in 20 patients who died with a clinical diagnosis of ventilator-associated pneumonia based on pulmonary infiltrates and leukocytosis or increased purulent tracheal secretions. Immediately after death, bilateral thoracotomies were performed and multiple lung biopsies were sent for histologic and microbiologic examination. The results of the thoracotomy specimens were considered the reference gold standard and were compared with specimens obtained from tracheobronchial aspirates, PSBs, and conventional BAL. All of the diagnostic sampling techniques had poor correlation when histologic reference standards were used alone, ie, when histology demonstrated pneumonia, no organism was detected in the nonsurgical specimens. When histologic and microbiologic results obtained from thoracotomy specimens were used together as a reference test, the diagnostic yield of the nonsurgical techniques improved but remained limited. The only subgroup in which the sampling techniques being studied had high diagnostic accuracy for detecting organisms were cases in which there was clear histologic confirmation of pneumonia followed by cultures with very high concentrations of bacteria in tissue (>103 cfu/g of lung tissue) [Table 1].

Table 1. Sensitivity and Specificity of PSB, BAL, and Tracheal Aspirates in Patients With Ventilator-Associated Pneumonia*

The conclusions of this study concur with those of other animal and human studies: defining pneumonia based on quantitative cultures by PSB or BAL may not be a valid method.^16-19 These studies suggested that no technique can be used to definitively diagnose pneumonia and that treatment decisions as well as the adjustment of antimicrobial therapy should not rely exclusively on the results of quantitative cultures in an individual patient.

Sanchez-Nieto et al⁹ conducted an open, prospective, randomized clinical trial in 51 patients receiving mechanical ventilation for >72 h in order to evaluate the impact of using PSB and BAL as compared with noninvasive quantitative endotracheal aspirates in patients with possible ventilator-associated pneumonia. Antibiotic changes were more frequent in the group undergoing bronchoscopy, but this did not result in a change in mortality, ICU stay, or total duration of mechanical ventilation.

The pulmonologist evaluating an immunocompromised patient with pulmonary infiltrates must therefore decide on the initial diagnostic procedure of choice given the limitations of the procedures described above. The choice should balance both the diagnostic yield and the potential complications. The early studies in BMT patients with pulmonary infiltrates had suggested that BAL alone is the best and safest procedure to obtain a diagnosis.⁶ After undergoing BMT, patients frequently have hematologic disturbances including low or dysfunctional platelets, and often the risk of bleeding outweighs the benefits of transbronchial biopsy (TBBx). In the few reports where TBBx and BAL were both performed, the diagnosis of pneumonia was rarely made only by TBBx, but the complications were clearly more frequent in that group.³ BAL seems to be the best initial test in these patients as the differential diagnosis may include alternative conditions that may not require a TBBx, such as pulmonary alveolar proteinosis or alveolar hemorrhage.

Feinstein et al² published the results of bronchoscopy in 61 BMT patients who underwent 76 bronchoscopies. At least one positive diagnosis was made after 42% of the bronchoscopies. The bronchoscopic findings resulted in at least one change in management in 32% of the cases. The most common changes were to add antibiotics (18%), stop antibiotics (13%), and add corticosteroids (1%). Current management was continued in 68% of the patients. Five patients in whom bronchoscopy was nondiagnostic underwent open lung biopsy (OLB). The OLB was diagnostic in four of these patients. The most common diagnoses obtained by OLB were CMV, BOOP, and DAD. The 28-day survival tended to be higher in patients who had either a diagnostic bronchoscopy (66 vs 62%) or a change in management (76 vs 69%), but this was not statistically significant.

White et al³ evaluated their results in BMT patients with pulmonary infiltrates. Their protocol was designed to exclude patients with pulmonary edema on clinical grounds and to initiate empiric antibiotics and antifungal agents. If there was no prompt improvement, then bronchoscopy was performed. In this study, 52 patients underwent 68 bronchoscopies (42 BAL + TBBx, 26 BAL only). Thirty-one percent of bronchoscopies yielded a diagnosis (CMV, 10 cases; PCP, 2; invasive pulmonary aspergillosis, 3; candida, 2; bacterial pneumonia, 2; DAD, 2; BOOP, 1; and bronchiolitis obliterans, 1). Bronchoscopy resulted in a change in therapy in 24% of the patients (11 with diagnostic and 6 with nondiagnostic bronchoscopies). Four patients with nondiagnostic bronchoscopies underwent OLB, which was diagnostic in three patients (BOOP, 2 cases; pulmonary veno-occlusive disease, 1). After 6 months of follow-up, there was no difference in survival rates in patients with or without diagnostic bronchoscopies or changes in therapy.³

Dunagan et al⁷ reported similar data. In their series, 30% of BMT patients underwent bronchoscopy to evaluate respiratory complications; 94% of the patients were receiving antibiotics at the time of bronchoscopy. Again, there was no survival difference between patients with diagnostic or nondiagnostic bronchoscopies.

The use of TBBx in the diagnosis and management of immunocompromised patients is more controversial and there is a significant lack of data. Cazzadori et al20 retrospectively evaluated 157 bronchoscopies in 142 immunocompromised patients; both BAL and TBBx were performed in every case. In the non-HIV immunocompromised host, the yield of TBBx compared with BAL was 55 vs 23%. The complication rate with TBBx was low (2.5%). They concluded that in patients without contraindications, TBBx had a definitive role in documenting invasive tissue involvement with opportunistic fungi and viruses and for the diagnosis of noninfectious etiologies; however, they also recognized that the impact of changes in therapy were not clear.²⁰

In patients who are coagulopathic and thrombocytopenic, OLB might be the preferred technique because of better direct hemostasis; however, it is not uncommon for these patients to be too ill to undergo this procedure. Although the yield of an OLB is known to be higher than that of other invasive pulmonary procedures, it is not clear if the benefit justifies the risk of general anesthesia and surgery in all cases. A recent study by White et al²¹ evaluated the use of OLB in patients with hematologic malignancy and pulmonary disease, and confirmed that OLB can be done safely in this population. A specific diagnosis was made in 62% of the biopsies, with a change in therapy in 57% of the patients. Survival was also improved in those patients with a specific diagnosis. OLB may still play an important role for the diagnosis of some noninfectious etiologies; OLB is now rarely needed to diagnose PCP or CMV.^21,24,25

Studies comparing OLB with BAL also have yielded conflicting results, including some with a very good correlation between both tests and others with a very poor correlation. A small pilot study examined 13 immunosuppressed, febrile, neutropenic patients with pulmonary infiltrates undergoing OLB and BAL; the authors found that a specific diagnosis was made more often by OLB than BAL. OLB provided one or more definitive diagnoses in 12 of these 13 patients (92%) [CMV, 2 cases; Pneumocystis, 3; fungal infection, 1; bacterial pneumonia, 1; pulmonary hemorrhage, 4; and pulmonary embolism, 1], whereas BAL provided a definitive diagnosis in 4 of 13 patients (31%). In addition, there was a poor correlation between the findings found on BAL and OLB.²⁶

In small series of patients who died secondary to their pulmonary pathology, autopsies have yielded diagnoses missed despite the use of multiple invasive or noninvasive diagnostic methods, implying that changes in therapy are not always the correct approach owing to the underdiagnosis of many potentially lethal infections.^3,4

In summary, studies in immunosuppressed patients with pulmonary infiltrates have demonstrated that the use of noninvasive and bronchoscopic procedures can result in a specific diagnosis in many cases with a resultant change in therapy. However, it should be emphasized that none of these studies has demonstrated that these practices have resulted in improvement in survival.

Pulmonary Nodules

The incidence of pulmonary nodules in BMT or solid organ transplant recipients has ranged from 7 to 13%. In contrast to pulmonary infiltrates (in which the differential diagnosis includes multiple benign, noninfectious etiologies), pulmonary nodules in immunosuppressed patients are more commonly secondary to life-threatening neoplastic diseases or to opportunistic infections.^12,27,30 The diagnostic approach includes a chest radiograph almost invariably followed by a CT scan, which is very useful in defining the characteristics of the nodule, evaluating the existence of other pulmonary nodules, and defining adenopathy or subtle pleural effusions.³¹ Because the differential diagnosis is so broad, a definitive diagnosis is mandatory. The symptoms and history are usually nonspecific and there appears to be little role for observation of a nodule, as might be done in the immunocompetent patient.¹²

Bronchoscopic evaluation with biopsy and BAL appears less useful in the diagnosis of pulmonary nodules. Although there are no studies comparing the different diagnostic modalities as there are with pulmonary infiltrates, some of the principles commonly used for pulmonary nodules in nonimmunosuppressed patients apply to these patients.^13,30 If the pulmonary nodules are in the periphery of the lung and <2 cm in size, the chances of obtaining a diagnostic sample via bronchoscopy are <20%. In larger nodules with a more central distribution and mediastinal involvement, bronchoscopy offers an alternative for diagnosis.³² However, with these limitations in mind, and the concern for opportunistic infections as the main pathogen, CT- or sonographic-guided fine needle aspiration or thoracoscopic biopsy is frequently recommended.^13,27

PCP and CMV Infections

PCP and CMV infections are a common complication in patients receiving high doses of corticosteroids or other immunosuppressive agents. The diagnosis of any of these conditions has significant implications for both management and prognosis of the immunosuppressed patient. Traditionally the diagnosis of these infections required invasive tests, of which bronchoscopy had been most frequently used. With more familiarity with these infections and their pulmonary manifestations, different approaches to diagnosis and management have been adopted. Prophylaxis and treatment for PCP is now almost universal.^2,33

CMV infections are approached very aggressively with prophylaxis or preemptive therapy based on surveillance samples from blood, urine, or throat cultures. More recently, CMV antigenemia and the polymerase chain reaction were added to the armamentarium of diagnostic tests available to document CMV infections, and these studies now play a significant role in screening and monitoring for disease in at-risk patients. The role of bronchoscopy in patients who are receiving prophylaxis for PCP and/or CMV or being monitored for CMV infection has been evaluated in several small clinical studies.

In BMT patients, surveillance bronchoscopy followed by preemptive therapy with ganciclovir was associated with a decreased incidence of CMV disease in a recent study.³⁴ More recently, the same group in Toronto evaluated this strategy in a randomized trial comparing CMV antigenemia assay vs screening bronchoscopy for the early detection and prevention of disease in allogeneic bone marrow and peripheral blood stem-cell transplant recipients.³³ The two groups were similar at baseline. After positive findings of antigenemia, patients were treated with ganciclovir for 2 weeks or until the antigenemia was negative. In patients in whom CMV was recovered via bronchoscopy, ganciclovir treatment continued for 10 weeks. Active CMV developed in 7 of 58 patients (12%) in the bronchoscopy arm vs 1 of 60 (1.6%) in the CMV antigenemia arm. Of the 60 patients in the antigenemia arm of the study, 29 (48.3%) had at least one positive antigenemia screening and therefore received preemptive ganciclovir therapy, compared with 8 of 58 (13.8%) in the bronchoscopy arm. The authors concluded that preemptive therapy for CMV using antigenemia screening is superior to screening with bronchoscopy.

Preemptive therapy also has the potential for minimizing the occurrence of late CMV disease because these patients have the opportunity to develop specific anti-CMV cytotoxic T cell immunity, a process that may be delayed by universal ganciclovir prophylaxis. In a study by Ibrahim et al³⁵ comparing CMV blood antigenemia with BAL in BMT patients, both tests were positive in only 35% of the cases. In 65% of the cases, only one of the two screening tests was positive. In 8 of 63 patients (13%), only the BAL results were positive for CMV.

Feinstein et al² recently reviewed their experience in 61 BMT patients who underwent 76 bronchoscopies for evaluation of pulmonary infiltrates from 1977 to 1999. Results for the spectrum of bacterial infections and therapeutic outcomes were similar to those reported in the studies described above; however, CMV was the most commonly diagnosed infection, with a positive BAL in 11 patients. Of the 11 patients in this series in whom CMV was diagnosed at bronchoscopy, 9 patients also had a positive CMV antigen in the serum and were already receiving antiviral medications. It is too early to draw firm conclusions about the current role of bronchoscopy in CMV detection; however, it seems that the combination of BAL and antigenemia is an accurate and sensitive test for the diagnosis of CMV disease.

Conclusions

The management of immunosuppressed patients in whom pulmonary complications develop is challenging for the health-care provider. Noninvasive testing should be done initially using blood and sputum samples and microbiologic and cytologic examination of tracheal aspirates. In the future, more advanced noninvasive tests relying on molecular and immunologic methods, such as CMV antigenemia and polymerase chain reaction, and better prophylactic and preemptive regimens may help to decrease the incidence, morbidity, and mortality of pulmonary infections in the immunosuppressed patient. Unfortunately, until such testing is more widely available, invasive testing will continue to be the best option for the diagnosis of pulmonary complications in the immunosuppressed patient. Clinical studies currently available continue to support the use of bronchoscopy with BAL, with or without TBBx depending on the risk of this diagnostic modality, but do not show significant improvement in end points including mortality; when TBBx is performed, it may be associated with a significant incidence of complications. Although bronchoscopy should not be expected to significantly alter the prognosis of these patients, it may offer some guidance to the physician as well as to the patient and his or her family, by establishing the diagnosis and providing prognostic information.

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