Christian Geltner

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.

Multicenter, Prospective Clinical Evaluation of Respiratory Samples from Subjects at Risk for Pneumocystis jirovecii Infection by Use of a Commercial Real-Time PCR Assay

ABSTRACT 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.

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.

Invasive pulmonary mycosis due to Penicillium chrysogenum: a new invasive pathogen.

A New Invasive Pathogen In solid organ recipients, fungal infections contribute to significant morbidity and mortality. Candida spp. and Aspergillus spp. are the most common isolated molds, whereas non-Aspergillus filamentous fungi such as Glomeromycota, Fusarium, Pseudallescheria, and Penicillium species and many others gained more interest within the past years (1Y3). Filamentous fungi may simple colonize the bronchial system without any pathology or cause a variety of lung pathologies after lung transplantation ranging from simple to necrotizing bronchitis and invasive pulmonary mycoses. Penicillium spp. are rare human pathogens. Before the introduction of highly active antiretroviral therapy, Penicillium marneffei has been well studied as a cause of severe mycosis in HIV-infected individuals (4). Other Penicillium spp. are even less frequent human pathogens; however, they are commonly used in cheese fermentation and antibiotic production. Penicillium chrysogenum is a ubiquitous organism that can be found in soil with decaying plants as well as in sewage plants and in construction sites. The organism inhabits the human scalp and has been isolated as an important part of the microbiologic flora of the space station Mir and the International Space Station, demonstrating the extraordinary survival capabilities of this fungus (5, 6). P. chrysogenum produces various antifungal and antibacterial substances and is one of the most important fungi causing type I and III allergies, such as asthma (7) or hypersensitivity pneumonitis (8). Only a few cases of P. chrysogenum infections in humans have been described and involved both immunocompetent and immunosuppressed individuals. Clinical presentation differs depending on the source of infection. Airway infections are common and may include pneumonitis, pneumonia, pulmonary fibrosis, localized fungus balls, and pulmonary abscesses. Reported invasive infections include endocarditis, peritonitis associated with peritoneal dialysis, brain abscesses, endophthalmitis, and cutaneous infections (9). In lung transplant recipients, Penicillium sp. was described as benign colonizing mold (10). Penicillium spp. tend to be resistant to amphotericin B and amphotericin liposomal formulations (3). We report the first case of invasive pulmonary mycosis with P. chrysogenum in a lung transplant recipient. A 56-year-old Caucasian male underwent left single lung transplant for >1-antitrypsin deficiency with severe lung emphysema. The immunosuppressive regimen consisted of daclizumab induction, tacrolimus, mycophenolate mofetil, and tapered steroids. Postoperative course was complicated by pulmonary vein stenosis, pulmonary embolism, primary graft dysfunction (PGD 3) (11), and, 6 months later, a pulmonary nodule in his left upper lobe. Histologic specimen from Computed tomographyYguided biopsy revealed a polymorphic T-cell lymphoma (PTLD, CD20, CD52, EBV). Further treatment consisted of chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), alemtuzumab, reduction of immunosuppression, valganciclovir for cytomegalovirus, and posaconazole as antimycotic prophylaxis. Two months later, while still on posaconazole prophylaxis, he developed pulmonary infiltrates and nodules predominantly in the left lower lobe (Fig. 1). After completion of chemotherapy, antimycotic prophylaxis with posaconazole was continued. Bronchoalveolar lavage and transbronchial biopsy revealed diagnosis of invasive mycosis with microscopy being highly suggestive for non-Aspergillus filamentous fungus (Fig. 2BYD). Fungal culture remained sterile. Posaconazole was stopped, and combination therapy including voriconazole and caspofungin was started. Oxygenation and diffusion capacity deteriorated and the patient had increasing oxygen requirements. After further evaluation, the pathogen was deemed to be zygomycosis; therefore, liposomal amphotericin was added. Nevertheless, the patient’s condition worsened and his bilateral pulmonary infiltrates progressed. Another bronchoscopy with bronchoalveolar lavage was done. Galactomannan enzyme immunoassay and polymerase chain reaction for Aspergillus were negative (12), whereas microscopy was positive for hyphae and cultures revealed Penicillium spp. (Fig. 2A). For

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.

Successful management of postpneumonectomy Aspergillus pleural empyema by combined surgical and anti-fungal treatment with voriconazole and caspofungin.

Aspergillus pleural empyema is a rare but often fatal infection complicating thoracic surgery. Three men and one woman aged 23–47 years were diagnosed with Aspergillus pleural empyema after lung resection. Underlying diseases were lung cancer (n = 2), Hodgkin’s disease (n = 1) and thoracic trauma (n = 1). The treatment protocol consisted of systemic anti‐fungal treatment with caspofungin and voriconazole, intrapleural application of amphotericin B and surgical debridement with secondary closure of the leaking bronchial stump. Two patients with chronic Aspergillus pleural empyema had been pretreated with itraconazole and/or amphotericin B. Two patients were treated with a thoracostoma. Two patients had undergone pneumonectomy for previously diagnosed pulmonary aspergillosis. Caspofungin was given for 13–60 days, Voriconazole for up to 100 days. Surgical debridement was performed in all cases and in two cases the created thoracostoma was closed during a second surgical procedure. Aspergillus PCR using blood samples, bronchoalveolar lavage or aspiration fluid was used for monitoring. All four patients had complete clinical and microbiological remission. Our case series shows promising results and underscores the importance of a combined therapeutic approach for Aspergillus pleural empyema consisting of anti‐fungal treatment and surgery. Voriconazole and caspofungin seem to be a suitable combination for this infection.

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.

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.

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.

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.