Diagnosing filamentous fungal infections in immunocompromised patients applying computed tomography-guided percutaneous lung biopsies: a 12-year experience.

BACKGROUND: Invasive fungal diseases (IFD) are an important cause of morbidity and mortality in immunocompromised patients, and early diagnosis and management are a challenge. We evaluated the clinical utility of computed tomography (CT)-guided percutaneous lung biopsies in diagnosing IFD. METHODS: Between 2003 and 2014, we analyzed 2671 CT-guided lung biopsies, from which 157 were IFD associated; we aimed to determine microbiological-based diagnostic accuracy of calcofluor white staining (CFWS), culture, Aspergillus antigen detection (GM), broad-range fungal PCR, and Aspergillus PCR per sample. RESULTS: 127 (81%) specimens were microscopically positive for any fungal elements, 30 (19%) negative. Aspergillus and non-Aspergillus like hyphae were obtained in 85 (67%) and 42 (33%) specimens, respectively. CFWS positivity was defined as proof of infection. Sensitivity, specificity, and positive (PPV) and negative predictive (NPV) values for CT scan were 100, 44, 80, and 100%, for Aspergillus PCR 89, 58, 88, and 58%, for broad-range fungal PCR 90, 83, 95, and 90%, and for GM 94, 83, 95, and 90%. The most common CT features were patchy opacifications with central necrosis (78%) or cavern defects (50%), less common were air bronchograms (39%) or ground glass halos (39%), and all other features were rare. The overall pneumothorax rate subsequent to biopsy was 19%, but in only 2% of all cases the placement of a chest tube was indicated. One case of fatal air embolism occurred. CONCLUSIONS: CT-guided lung biopsies have high diagnostic accuracy in terms of microscopic examination, and complication rates are low. Molecular-based and antigen tests applied on fungal hyphae-positive specimens showed comparable results.

Use of Cidofovir for Cytomegalovirus Disease Refractory to Ganciclovir in Solid Organ Recipients.

BACKGROUND: Solid organ transplantation (SOT) frequently is complicated by cytomegalovirus (CMV) infections. Cidofovir (CDV) is active against CMV, including many ganciclovir (GCV)-resistant mutants, but often is considered to be too nephrotoxic for use after organ transplantation. PATIENTS AND METHODS: Seven males and two females (median age 50.1 years), including two kidney/pancreas, four lung, one small bowel, and two hand recipients, received CDV for refractory CMV disease. RESULTS: Three recipients were CMV seronegative, but all nine received grafts from CMV-seropositive donors. Five patients were given antithymocyte globulin, four received daclizumab induction, seven experienced rejection (five with multiple episodes), and one suffered from common variable immunodeficiency. Six presented with other infections (five invasive fungal and four bacterial). Eight patients had received prophylactic GCV, and eight had been treated for CMV infection/disease (GCV eight; CMV immunoglobulin three; foscarnet three). The indications for CDV were UL97 CMV mutation (n = 2), GCV-induced neutropenia with continued CMV disease (n = 4), and clinical resistance to GCV (n = 3). Seven patients cleared CMV, and two had a partial response. Four experienced CMV relapse requiring GCV (n = 2), repeat CDV (n = 1), or CMV immunoglobulin (n = 1). Four patients had mild nephrotoxicity, and three developed renal failure, all in association with additional factors. No patient died directly from CMV disease alone. Two patients died of uncontrolled infections and concurrent CMV disease, one with invasive aspergillosis and another with nocardiosis. CONCLUSIONS: Cidofovir was useful for the treatment of GCV-refractory CMV disease after SOT. Although nephrotoxicity was a common complication of CDV, several patients completed a course of therapy successfully and demonstrated effective treatment of CMV disease.

Management of Postintubational Tracheal Injury by Endoscopic Stent Placement: Case Report and Review of the Literature.

Endobronchial stent placement is a novel therapy for treatment of iatrogenic tracheal tears. A review of the available literature shows surgery and long-term intubation being the established treatment strategy. We describe the case of a 64-year-old woman with a tracheal rupture following endotracheal intubation for routine surgery. Pneumo-mediastinum and chest pain were the predominant symptoms. She was treated with a covered self-expandable metal stent that closed the tear and led to immediate symptom relief. After six weeks and complete healing of the trachea, the stent could be explanted. No stent complications occurred. A new algorithm for the treatment of these ruptures has been proposed.

Management of malignant pleural mesothelioma - part 1: epidemiology, diagnosis, and staging : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

Malignant pleural mesothelioma is a rare malignant disease that in the majority of cases is associated with asbestos exposure. The incidence in Europe is about 20 per million inhabitants and it is increasing worldwide. Initial symptoms are shortness of breath, pleural effusion, cough, and chest pain. The typical growth pattern is along the pleural surface; however, infiltration of the lung and/or mediastinal and chest wall structures can occur in a more advanced stage. Ultimately, distant metastases outside the chest can result. Several histological subtypes of pleural mesothelioma exist, which must be differentiated from either benign diseases or metastases in the pleural space by other tumor entities. This differential diagnosis can be very difficult and a large panel of immunohistochemical markers is required to establish the exact diagnosis. The standard procedure for confirming the disease and obtaining sufficient tissue for the diagnosis is videothoracoscopy. Full thickness biopsies are required, while transthoracic needle puncture of pleural fluid or tissue is considered to be insufficient for a cytological diagnosis. Complete and detailed staging is mandatory for categorization of the disease as well as for therapeutic decision making.

Management of malignant pleural mesothelioma-part 2: therapeutic approaches : Consensus of the Austrian Mesothelioma Interest Group (AMIG).

Treatment of malignant pleural mesothelioma (MPM) depends on performance status of the patient, tumor stage, and histological differentiation. Chemotherapy (CHT) can be administered as first- and second-line treatment in unresectable MPM or as neoadjuvant or adjuvant treatment before or after surgery. A combination of an antifolate and platinum-based CHT is the only approved standard of care. Several targeted and immunotherapies are in evaluation and further studies are warranted to determine the therapeutic value of these new treatment options. Radiotherapy (RT) can be considered either as adjuvant treatment after surgery or for palliation of pain-related tumor growth. Recent data support the use of RT in a neoadjuvant setting. Macroscopic complete resection by pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) is indicated in selected patients with good performance status. Surgery should only be applied as part of a multimodality treatment (MMT) in combination with chemo- and/or radiotherapy. In a large number of cases, palliative attempts are needed to improve quality of life and to achieve symptom control.

Management of malignant pleural mesothelioma - part 3 : Data from the Austrian Mesothelioma Interest Group (AMIG) database.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor originating from the pleural cavity with a strong link to previous asbestos exposure. In order to determine the demographics, diagnostics, therapeutic strategies, and prognosis of MPM patients in Austria, the Austrian Mesothelioma Interest Group (AMIG) was founded in 2011. In this report the data from the AMIG MPM database collected to date are reported. METHODS: A prospective observational registry was initiated, including patients with histologically verified MPM diagnosed and treated at specialized centers in Austria. Patient inclusion started in January 2011 and follow-up was completed until September 2015. RESULTS: A total number of 210 patients were included. There were 167 male and 43 female patients with a mean age of 67.0 years (SD ± 11.3) at the time of diagnosis. Asbestos exposure was confirmed in 109 (69.4 %) patients. The histological subtype was epithelioid in 141 (67.2 %), sarcomatoid in 16 (7.6 %), biphasic in 28 (13.3 %), and MPM not otherwise specified in 25 (11.9 %) patients. Of the patients, 30 (14.3 %) received best supportive care (BSC) only, 71 (33.8 %) chemotherapy (CHT) alone, four (1.9 %) radiotherapy (RT) alone, 23 (11.9 %) CHT/RT, two (0.9 %) surgery alone, and 76 (36.2 %) curative surgery within a multimodality treatment (MMT), which was more frequently performed for patients younger than 65 years and with early-stage disease (I + II). Median overall survival (OS) was 19.1 months (95 % CI 14.7-23.5). The 1­, 3­, and 5­year OS rates were 66 %, 30 %, and 23 %, respectively, and OS was significantly better in patients undergoing surgery within MMT (5-year survival 5 % vs. 40 %, p = 0.001). CONCLUSION: Patients with earlier disease stages, younger age, good performance status, and epithelioid histology were more likely to undergo MMT including surgery, which resulted in a more favorable outcome.

Long term complications following 54 consecutive lung transplants.

BACKGROUND: Due to the complex therapy and the required high level of immunosuppression, lung recipients are at high risk to develop many different long term complications. METHODS: From 1993-2000, a total of 54 lung transplantation (LuTx) were performed at our center. Complications, graft and patient survival of this cohort was retrospectively analyzed. RESULTS: One/five and ten-year patient survival was 71.4%, 41.2% and 25.4%; at last follow up (4/2010), twelve patients were alive. Of the 39 deceased patients, 26 died from infectious complications. Other causes of death were myocardial infarction (n=1), progressive graft failure (n=1), intracerebral bleeding (n=2), basilary vein thrombosis (n=1), pulmonary emboli (n=1), others (n=7). Surgical complication rate was 27.7% during the first year and 25% for the 12 long term survivors. Perioperative rejection rate was 35%, and 91.6% for the 12 patients currently alive. Infection incidence during first hospitalization was 79.6% (1.3 episodes per transplant) and 100% for long term survivors. Commonly isolated pathogens were cytomegalovirus (56.8%), Aspergillus (29.4%), RSV (13.7%). Other common complications were renal failure (56.8%), osteoporosis (54.9%), hypertension (45%), diabetes mellitus (19.6%). CONCLUSIONS: Infection and rejection remain the most common complications following LuTx with many other events to be considered.

Invasive pulmonary Aspergillosis in organ transplants--Focus on lung transplants.

Infections with filamentous fungi are common in transplant recipients. The risk for aspergillosis and other invasive pulmonary mycosis (IPM) is high in patients undergoing stem cell and lung transplantations. The mortality rates range from 20% to 60% and depend on a number of risk factors. The typical manifestations of IPM are lung infiltrates, consolidations, and fungal tracheobronchitis. The most common infectious agent is Aspergillus fumigatus. Infections caused by non-Aspergillus molds are more frequent for various reasons. The species distribution of non-Aspergillus molds varies in different locations. Furthermore, infections caused by Mucor and Penicillium are increasing, as are infections caused by species resistant to azoles and amphotericin B. Most centers use antifungal prophylaxis with inhaled amphotericin B or oral azoles. Early diagnosis and therapy is crucial. Reliable information on the local microbiological spectrum is a prerequisite for the effective treatment of molds with primary or secondary resistance to antimycotic drugs.

Necrotizing mycosis due to Verruconis gallopava in an immunocompetent patient.

Verruconis gallopava is a dematiaceous mould usually causing saprophytic infection in immunosuppressed host. Only a few cases have been published even in immunocompromised states. We present a rare case of pulmonary involvement in an immunocompetent patient with recurrent disease. The mid-aged woman had no evidence of any disease causing impaired immune response. Recurrent disease shows pulmonary infiltrates and symptoms of allergic bronchopulmonary mycosis. We describe an emerging pathogen that has been found in an immunocompetent host. Eradication was not possible despite the use of several different antifungal drugs. Further recurrence of infection in the described patient is probable.

Immune reconstitution syndrome-like entity in lung transplant recipients with invasive aspergillosis.

BACKGROUND: Incidence, characteristics, and risk-factors for invasive aspergillosis (IA)-associated immune reconstitution syndrome (IRS) in lung transplant recipients are not known. METHODS: Patients comprised 68 lung transplant recipients with proven/probable IA followed for 12 months. IRS was defined based on previously proposed criteria. RESULTS: In all, 7.3% (5/68) of the patients developed IRS based on aforementioned criteria, a median of 56 days after initiation of antifungal therapy. This entity was associated with heart-lung transplantation (p=0.006), anti T-cell agent use (p=0.003), discontinuation of calcineurin inhibitor agent (p=0.002), and disseminated IA (p=0.069). In a risk assessment model, IRS developed in 0% (0/55) of the patients with none of the aforementioned factors, 28.6% (2/7) with one, 33.3% (1/3) with two, and in 1/1 patient with 3 factors (X(2) for trend p=0.0001). Three out of 5 patients with IRS died and 2 of 3 deaths in this group were due to chronic rejection. CONCLUSIONS: Overall 7% of the lung transplant recipients with IA appear to develop an IRS-like entity. Clinically assessable factors can identify patients at risk for post-transplant IA-associated IRS. Deaths due to chronic rejection were significantly higher in patients with IRS than those without IRS.

Risk factors and outcomes in lung transplant recipients with nodular invasive pulmonary aspergillosis.

BACKGROUND: Whether nodular lesions have specific risk-factors or influence outcomes in lung transplant recipients with invasive aspergillosis, is not fully known. METHODS: The study population consisted of 64 consecutive lung transplant recipients with proven or probable invasive aspergillosis. Nodules, with or without halo/air crescent-sign were considered nodular presentations. Outcomes assessed were response rate (successful versus unsuccessful outcome) and all-cause mortality at 12 weeks. RESULTS: Overall, 34 patients had nodular and 30 had non-nodular lesions. Presence of nodular lesions was less likely to be associated with renal failure at baseline (adjusted OR 0.21, 95% CI, 0.04-0.97, p = 0.047), CMV infection (adjusted OR 0.18, 95% CI 0.04-0.75, p = 0.019) and receipt of antifungal prophylaxis (adjusted OR 0.22, 95% CI, 0.06-0.88, p = 0.032). Successful outcome and mortality rates in the study patients were 64.0% (41/64) and 25.0% (16/64), respectively. Nodular aspergillosis was associated with significantly higher successful outcome (adjusted OR 3.35, 95% CI, 1.06-10.54, p = 0.039) and lower mortality at 12 weeks (adjusted OR 0.20, 0.05-0.78, p = 0.021). CONCLUSIONS: Lung transplant recipients with nodular lesions due to invasive aspergillosis had better outcomes than those without such lesions.

Multicentre European study for the treatment of advanced emphysema with bronchial valves.

This multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bronchial valve therapy using a bilateral upper lobe treatment approach without the goal of lobar atelectasis. Patients with upper lobe predominant severe emphysema were randomised to bronchoscopy with (n = 37) or without (n = 36) IBV Valves for a 3-month blinded phase. A positive responder was defined as having both a ≥ 4-point improvement in St George's Respiratory Questionnaire (SGRQ) and a lobar volume shift as measured by quantitative computed tomography. At 3 months, there were eight (24%) positive responders in the treated group versus none (0%) in the control group (p = 0.002). Also, there was a significant shift in volume in the treated group from the upper lobes (mean ± SD -7.3 ± 9.0%) to the non-treated lobes (6.7 ± 14.5%), with minimal change in the control group (p<0.05). Mean SGRQ total score improved in both groups (treatment: -4.3 ± 16.2; control: -3.6 ± 10.7). The procedure and devices were well tolerated and there were no differences in adverse events reported in the treatment and control groups. Treatment with bronchial valves without complete lobar occlusion in both upper lobes was safe, but not effective in the majority of patients.

Airborne fungus exposure prior to hospitalisation as risk factor for mould infections in immunocompromised patients.

The aim of this study was to investigate the relationship between fungal exposure prior to hospitalisation and ensuing onset of invasive mould infections (IMI) in patients at risk. Patients admitted to the Department of Haematology, Oncology and Transplant Surgery of the Medical University Innsbruck received a questionnaire regarding fungal exposure prior to hospital stay. Questions inquired heavy fungal exposures up to 5 days before hospitalisation. A total of 234 patients were enrolled in this study. Multiple fungus exposures were associated with the onset of community-acquired IMI in patients with haematological malignancies. In univariate analysis, haematological malignancies (P = 0.013) and allergy to dust, pollen or moulds (P = 0.015) were significantly associated with fungal infections. In multivariate analysis, logistic regression showed that haematological patients (P = 0.015) and patients with allergy (P = 0.015) were significantly more frequently infected with fungi. Hospital-independent fungal sources highlight risk-factors for IMI in severe immunocompromised patients and the rate of community-acquired IMI does increase.

Multicenter, prospective clinical evaluation of respiratory samples from subjects at risk for Pneumocystis jirovecii infection by use of a commercial real-time PCR assay.

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection. Microscopic diagnosis, including diagnosis using the Merifluor-Pneumocystis direct fluorescent antigen (MP-DFA) test, has limitations. Real-time PCR may assist in diagnosis, but no commercially validated real-time PCR assay has been available to date. MycAssay Pneumocystis is a commercial assay that targets the P. jirovecii mitochondrial large subunit (analytical detection limit, ≤ 3.5 copies/µl of sample). A multicenter trial recruited 110 subjects: 54 with transplants (40 with lung transplants), 32 with nonmalignant conditions, 13 with leukemia, and 11 with solid tumors; 9 were HIV positive. A total of 110 respiratory samples (92% of which were bronchoalveolar lavage [BAL] specimens) were analyzed by PCR. Performance was characterized relative to investigator-determined clinical diagnosis of PCP (including local diagnostic tests), and PCR results were compared with MP-DFA test results for 83 subjects. Thirteen of 14 subjects with PCP and 9/96 without PCP (including 5 undergoing BAL surveillance after lung transplantation) had positive PCR results; sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were 93%, 91%, 59%, and 99%, respectively. Fourteen of 83 subjects for whom PCR and MP-DFA test results were available had PCP; PCR sensitivity, specificity, PPV, and NPV were 93%, 90%, 65%, and 98%, respectively, and MP-DFA test sensitivity, specificity, PPV, and NPV were 93%, 100%, 100%, and 98%. Of the 9 PCR-positive subjects without PCP, 1 later developed PCP. The PCR diagnostic assay compares well with clinical diagnosis using nonmolecular methods. Additional positive results compared with the MP-DFA test may reflect low-level infection or colonization.

Primary mediastinal synovial sarcoma: a case report and review of the literature.

Primary mediastinal synovial sarcoma is a rare malignancy with only a few cases reported so far. A 56-year-old woman was admitted to our hospital for an investigation of a nodule in the left middle lung on chest radiography. Computed tomography revealed a mediastinal mass first described as a solitary fibrous tumor. The diagnosis of synovial sarcoma was established by computed tomography-guided percutaneous needle biopsy. Work up showed no metastasis to distant organs or contralateral pleural cavity. The mass was surgically resected; pathological and immunohistochemical analyses confirmed the diagnosis of a monophasic spindle cell synovial sarcoma probably originating from phrenic nerve. The patient received adjuvant chemotherapy and radiation and is free of recurrence after a follow up of 16 months.

Infections caused by Candida krusei in five transplant and two surgical patients.

BACKGROUND: Candida krusei (Ck) may cause severe infections in immunocompromised hosts and is innately resistant to fluconazole. PATIENTS AND METHODS: During an 18-month period, seven patients with Ck infection were identified at our center. All were treated in the transplant intensive care unit. Candida isolates were grown on Sabouraud agar, and chromosomal DNA was extracted; clonality was investigated using random amplified polymorphic DNA-polymerase chain reaction with primers M13, OPA-18, and OPE-18. RESULTS: Among the patients with Ck infection, there were three pancreas recipients with intra-abdominal infection, one liver recipient with cholangitis, one lung recipient with pleural empyema, one patient with pleural empyema after esophageal perforation, and one case of pneumonia in a patient with a ventricular assist device. Treatment consisted of caspofungin (n = 3), voriconazole (n = 1), or a combination of the two (n = 2) together with surgery (n = 3) or pigtail catheter drainage (n = 3). One patient underwent drainage without antifungal treatment, and one patient did not have drainage. The infection was controlled in all cases. The patient with the assist device died from multiple organ dysfunction, the lung recipient died after four months from graft failure, and one pancreas graft was lost. Four patients (57%) harbored the same Ck strain. CONCLUSION: Solid organ recipients seem to be at particular risk for Ck infections; clonal outbreaks may occur in intensive care units.

Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients.

Fungi cause severe infections in solid organ transplant (SOT) recipients. Recently, a shift towards non-Aspergillus filamentous fungal infections (nAFFI) was noticed. In a series of 2878 SOTs (kidney, pancreas, islets, liver, heart, lung, and bowel) performed between January 1995 and December 2006 at the Innsbruck medical university, eleven cases of nAFFI were diagnosed. The encountered species included Zygomyzetes (n = 8), and Alternaria alternate, Pseudallescheria boydii, Trichoderma spp. (one each); there were three liver and three heart, one intestinal, pancreas, lung, bilateral forearm and renal recipient each. Five patients died from nAFFI (zygomycosis: 4, Pseudallerichia boydii: 1); four were diagnosed postmortem. In five cases infection was surgically treated in combination with antifungals. Risk factors for nAFFI were renal failure (73%) and intensified immunosuppression (73%); two cases were associated with post-transplant lymphoproliferative disorder, one with graft versus host disease. An increase in the incidence of nAFFI was observed parallel to introduction of caspofungin and voriconazole (three cases until 12/2003, seven cases thereafter). NAFFI are increasingly found in SOT recipients. If diagnosed in time, the outcome seems acceptable. Intensified immunosuppression and exposure to antifungals not active against zygomycetes may be risk factors. Surgical therapy may play an important role in these infections.

Single time point measurement by C2 or C3 is highly predictive in cyclosporine area under the curve estimation immediately after lung transplantation.

BACKGROUND: The two h post-dose cyclosporine (CsA) concentration has been advocated as the optimal time point measurement for CsA area under the curve (AUC) estimation after solid organ transplantation. The aim of the study was to investigate whether intensified CsA monitoring is necessary, or if a single time point measurement is accurate to estimate the AUC in the very early period following lung transplantation (LuTX). METHODS: Within the first two wk following transplantation, daily AUCs were calculated by serial CsA measurements at zero, one, two, three, four, and six h (C0-C6) in 12 consecutive lung transplant recipients. Correlation of single CsA measurements and AUC as well as linear regression analysis was performed to evaluate the most predictive single CsA blood level regarding the AUC. RESULTS: A total of 606 CsA concentration measurements were performed and the 101 corresponding AUCs were calculated for each patient. Mean AUC was 3443 +/- 1451 microg/L. C0: 361 +/- 118 microg/L, C1: 481 +/- 231 microg/L, C2: 682 +/- 314 microg/L, C3: 715 +/- 347 microg/L, C4: 658 +/- 271 microg/L, C6: 571 +/- 260 microg/L. The correlation of CsA serum levels with AUC was the lowest at trough levels (C0) with a correlation coefficient (r = 0.31) and highest at three h (C3: r = 0.89) and two h (C2: r = 0.88). CONCLUSIONS: Similar to a stable post-transplant period, CsA trough levels turned out to have poor correlation with the corresponding AUC early after LuTX. The highest correlation of C3 with the AUC may be explained by delayed intestinal resorption immediately post-operative, however C2 is a peer parameter. Optimum AUCs and corresponding C2 or C3 levels in the immediate post-operative phase however remain to be determined.

Combined CMV prophylaxis improves outcome and reduces the risk for bronchiolitis obliterans syndrome (BOS) after lung transplantation.

BACKGROUND: The benefit of cytomegalovirus (CMV) hyperimmune globuline in preventing CMV infection after lung transplantation still remains unclear. The aim of this study was to investigate the effect of combined prophylaxis using ganciclovir (GAN) and CMV hyperimmune globulin (CMV-IG) on CMV infection, CMV disease, survival and its role in preventing Bronchiolitis obliterans syndrome (BOS). METHODS: A consecutive series of 68 CMV high-risk lung transplant recipients (D+/R-, D+/R+), who had a minimum follow-up of 1 year posttransplant were analyzed. Thirty patients (44.1%) received single GAN prophylaxis for 3 months (control group) and 38 recipients (55.9%) received GAN together with CMV-IG 7 times during the first postoperative month (study group). Median follow-up was 16.5 months in the control and 23.8 months in the study group (P = 0.54). RESULTS: Five CMV-related deaths (16.7%) occurred in the control group (P = 0.014). Fifteen recipients suffered from CMV pneumonitis and three patients had CMV syndrome. In the control group, 13 recipients (43.3%) suffered from clinically manifested CMV disease compared to 5 (13.2%) in the study group (P = 0.007). Additionally, recipient survival was significantly better in the study group (P = 0.01). One year freedom from CMV affection was 52.1% in the control and 71.5% in the study group (P = 0.027). Three-year freedom from BOS was significantly higher in the study group (54.3% vs. 82%, P = 0.024). CONCLUSIONS: In CMV high risk patients, additional CMV-IG administration seems to be effective to reduce CMV-related morbidity and to avoid CMV-related mortality. Reduced incidence of BOS may result from improved CMV prevention, although randomized trials are warranted.