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Dr. Rizk is Professor of Medicine and Dr. Faul is a Fellow in Pulmonary and Critical Care Medicine, Stanford University Medical Center.
Correspondence to: Norman W. Rizk, MD, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, 300 Pasteur Dr, RM H3142, Stanford, CA 94305-5236
Over the past 20 years, opportunistic lung infections have become a serious clinical problem for solid organ and bone marrow transplant (BMT) recipients, because of their immunosuppressive therapy intended to prevent allograft rejection. Without prophylactic antimicrobial therapy, transplant recipients may suffer life-threatening pulmonary infections, including Pneumocystis carinii pneumonia (PCP) and cytomegalovirus (CMV) pneumonitis. With the advent of newer immunosuppressive agents, like mycophenolate mofetil, tacrolimus, and rapamycin, the nature of immunosuppression and the accompanying susceptibility to opportunistic infection have continued to evolve. Each transplant population is unique, especially in terms of differing immunosuppressive therapies and antimicrobial prophylaxis. In general, the severity and number of serious opportunistic infections, and the consequent need for prophylaxis, are proportional to the degree of immunosuppression. When infections do occur in the absence of or despite prophylaxis, enough data now exist to make some general comments about their management.
In transplant recipients, the new onset of respiratory symptoms, or new infiltrates by chest radiography, should prompt an early and definitive diagnosis. Diagnostic tests should ideally be as noninvasive as possible. When invasive diagnostic approaches are required, the consensus approach is now increasingly clear. For diffuse pulmonary infiltrates, as in PCP or CMV pneumonitis, the initial invasive diagnostic test should be fiberoptic bronchoscopy (FB) with BAL. This can be performed safely even in patients with coagulopathy or receiving mechanical ventilation, as reported by Torres et al in this issue of CHEST (see page 494). For focal, subsegmental, or nodular disease, fine-needle aspiration with CT guidance and video-assisted thoracoscopy are the most accurate diagnostic tools. Many focal lesions are due to fungal infection, particularly due to Aspergillus species. Open thoracotomy is rarely required, except for the patient with coagulopathy in whom BAL was nondiagnostic, and in whom the bleeding tendency cannot be corrected. Controversy still surrounds the exact role of protected brush specimens and quantitative BAL sampling to obtain bacterial colony counts. In this scheme, the main role of thoracic CT is to improve the sensitivity and localization of lesions seen on chest radiograph. Even relatively characteristic images, like the angiocentric nodule with a hemorrhagic halo seen in invasive aspergillosis, always require biopsy, because the specificity of radiographic images is limited.1 Use of this decision tree for establishing a definitive diagnosis is successful in the majority of cases, depending on the prior probability of a specific diagnosis established by chest radiography, the type of immunosuppression, and the clinical status of the patient.
Antimicrobial prophylaxis plays an important role in organ transplantation. Daily or thrice-weekly trimethoprim sulfamethoxazole has reduced PCP from 10 to 12% to almost nil at most centers.2 In addition nocardia, Toxoplasma gondii, and Listeria species infections have also been markedly curtailed by its use.3 Because of the complex interaction between viral infection and allograft rejection, recipient immunosuppression, and posttransplant lymphoproliferative disorders, the importance of antiviral, particularly CMV, prophylaxis is becoming increasingly evident. Some patients, like heart and liver transplant recipients, should probably receive routine ganciclovir prophylaxis if they are at risk for primary infection. BMT recipients, who may suffer prolonged neutropenia, may be better served by surveillance for CMV and preemptive therapy only if necessary. Prophylaxis against Aspergillus species continues to be problematic. Some workers have reported successful prevention of infection with inhaled amphotericin4 ; however, repeated exposure to inhaled ambient conidia makes infection difficult to prevent, even when in-hospital environmental controls are implemented.
Recent research has focused on the development of more effective surveillance methods and prophylaxis. Accurate surveillance, although expensive and labor-intensive, permits treatment of infection only when and if it is necessary. This preemptive strategy works. At Stanford and the City of Hope, for example, the mortality rate of CMV pneumonitis in allogeneic BMT recipients declined from historical levels of about 15% to < 1% after surveillance BAL at day 35 posttransplant and preemptive therapy were instituted.5 Commercial molecular assays are currently available for detecting CMV DNA in plasma; these assays may replace surveillance bronchoscopy by establishing even higher levels of sensitivity and specificity.6 Just as quantitative BAL counts have been correlated with ventilator-associated pneumonia, quantitative polymerase chain reactions (PCR) assays for plasma DNA can be correlated with a variety of infections, including HIV and CMV. These novel amplification techniques can provide not only rapid diagnosis and monitoring of the response to therapy, but also might be able to distinguish between colonization and disease in those disorders (like CMV) in which this distinction can be important.7 Similarly, the examination of sputum or BAL by PCR has been useful to screen for Mycobacterium tuberculosis, but the quantitative aspects of these assays and their standardization need to be validated.3
In this context, Torres et al report in this issue of CHEST their findings from the diagnostic workup of pulmonary infiltrates in orthotopic liver transplant recipients. A definite infectious etiology was found in 48% by FB with BAL and protected brush specimen. The study reconfirms the utility of FB in this patient population. In the future, noninvasive diagnostic tests, relying on molecular and immunologic methods, and the use of more effective surveillance and prophylaxis regimens for the immunosuppressed patient should help to prevent the development of serious pulmonary opportunistic infections.
References
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