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Risk factors for invasive aspergillosis in lung transplant recipients.
... Universal risk factors for IFD amongst SOT recipients include environmental exposure and net state of immunosuppression [75, 76]. Overall, risk factors for early (<3 months post SOT) pulmonary IA include recurrent bacterial infection, a complicated post-operative period, renal failure requiring dialysis and CMV disease [6, 75, 77, 78]. In late onset IA (>3 months), risk factors have been identified to be advanced age (age >50 years), recurrent bacterial infection, increased immunosuppression , chronic graft rejection, immunosuppressionrelated lymphoma and renal failure [5, 6, 77]. ...
The onset of a pulmonary infiltrate in a solid organ transplant (SOT) recipient is both a challenging diagnostic and therapeutic challenge. We outline the potential aetiologies of a pulmonary infiltrate in a SOT recipient, with particular attention paid to fungal pathogens. A diagnostic and empirical therapy approach to a pulmonary infiltrate, especially invasive fungal disease (IFD) in SOT recipients, is provided.
... Multivariate analysis confirmed that the increased risk for candidemia was independent of colonization. CMV disease has been previously found to be associated with the development of pulmonary aspergillosis in lung transplant recipients [26] and with deep fungal infection (intra-abdominal infection and fungemia) in liver transplant recipients [18]. It is possible that other opportunistic infections, such as candidemia, are caused by CMV-associated shifts in the ratios of lymphocyte helpers and suppressors, as well as by overall lymphocyte function. ...
The prophylactic use of fluconazole is common in blood and marrow transplant (BMT) recipients. To evaluate how fluconazole
has influenced the development of azole resistance and candidemia, weekly mouthwashings were done, and fluconazole susceptibility
was determined for 1475 colonizing and invasive isolates obtained from patients undergoing BMT. Of 585 patients, 256 (44%)
were colonized with Candida species during the course of BMT. Of these, 136 patients (53%) had at least 1 mouthwashing sample that yielded Candida species other than C. albicans on culture. Only 4.6% of patients developed candidemia. Overall, C. albicans was the most common colonizing isolate, but it caused only 7% of cases of candidemia. About 5% of colonizing C. albicans strains and 100% (2 of 2) invasive C. albicans strains were fluconazole-resistant. Colonization, cytomegalovirus disease, and bacteremia are risk factors for the development
of candidemia. The use of prophylactic fluconazole is associated with a low incidence of candidemia and attributable mortality,
despite colonization with azole-resistant Candida species in BMT recipients.
... The effect of CMV on the respiratory burst in human macrophages has to our knowledge not previously been studied. In lung transplanted patients CMV has been associated with invasive aspergillosis [22], the control of which depends, at least in part, on superoxide production in phagocytic cells [23,24]. Furthermore, in an animal model Miller et al. [25] have demonstrated a decreased H 2 O 2 production in guinea pigs infected with CMV. ...
Infection of human monocyte-derived macrophages with CMV decreased the respiratory burst when cells were stimulated with opsonized zymosan or Pneumocystis carinii (P. carinii). Such an effect, though smaller, was also seen with heat-inactivated CMV, but only when triggered by zymosan. The effect was most pronounced in cells obtained from CMV antibody-negative donors. Dexamethasone further reduced the respiratory burst, both in uninfected and CMV-infected cells. Interferon-gamma increased the response in uninfected cells and, to a lesser extend, in cells treated with heat-inactivated CMV, whereas no effect was seen with infective CMV. No overt productive infection or cytopathology could be detected, however, the monocytes incubated with infective but also heat-inactivated CMV formed clusters, a phenomenon that was equally pronounced in cultures from CMV antibody positive and negative-donors. These results might help explain the worse prognosis of P. carinii pneumonia in patients coinfected with CMV and receiving dexamethasone.
... The median time to onset of Aspergillus infections in lung transplant recipients is 120 days; 49% and 68% of the infections have occurred within 3 and 6 months of lung transplantation, respectively [6]. Risk factors for invasive aspergillosis in lung transplant recipients include CMV infection , obliterative bronchitis, rejection, and augmented immunosuppression [16,29]. Up to 86% of the lung transplant recipients can be colonized with Candida spp Locally invasive mucocutaneous infections, pneumonia, mediastinitis , and less frequently disseminated infection are the predominant manifestations of Candida infections in these patients [23]. ...
The advent of effective antibacterial and antiviral prophylatic and therapeutic strategies has led to the emergence of opportunistic mycoses as a principal cause of infection-related mortality in organ transplant recipients. Candida and Aspergillus species have accounted for most invasive fungal infections in organ transplant recipients. Epidemiologic trends within the last decade, however, are notable for the emergence of mycelial fungi other than Aspergillus as increasingly important pathogens in these patients. This article reviews the epidemiology, clinical manifestations, pathogenetic basis, diagnosis, and management of invasive fungal infections after organ transplantation in context of emerging trends and new developments in these areas.
... Lung and bone marrow transplant recipients are at particularly high risk for CMV pneumonia, which is among the most serious CMV disease manifestations (de Maar et al., 2003). Additionally, CMV infection in transplant recipients has been correlated with chronic rejection of the allograft (Lopez et al., 1974; Toupance et al., 2000; Paya, 1999) and increased susceptibility to severe microbial infections (Duncan et al., 1992; Falagas et al., 1996; George et al., 1997; Husni et al., 1998; van den Berg et al., 1996; Wagner et al., 1995). Current anti-viral treatments for CMV infection include ganciclovir, foscarnet and cidofovir (De Clercq, 2004) which, although effective, have high toxicity and adverse sideeffects . ...
Cytomegalovirus (CMV) infection can cause severe disease in immunocompromised individuals, with CMV pneumonia, most commonly seen in lung or bone marrow transplant recipients, carrying a particularly high fatality rate. Early and accurate diagnosis of CMV pneumonia is therefore critical.
Current diagnostic tests for CMV pneumonia in bronchoalveolar lavage (BAL) specimens are either insensitive or poor prognostic indicators of disease. We therefore examined nucleic acid sequence-based amplification (NASBA) assays for CMV transcripts in BAL for the prediction of CMV pneumonia and associated diseases.
A total of 220 BAL specimens from lung transplant recipients and other patients with suspected viral pneumonia were studied. Ninety-nine samples had previously tested positive for CMV by shell vial (SV) culture, while the other 121 had tested negative. All specimens were assayed for CMV pp67 and immediate early (IE) transcripts by NASBA. Results were correlated with evidence of concurrent or subsequent CMV pneumonia, rejection, and infection with other microbes.
From a total of 220 BAL specimens, 27 tested positive for pp67 mRNA, 25 tested positive for IE mRNA, and 17 tested positive for both. Only 10 specimens tested positive for CMV by either or both NASBA assays while testing negative by SV assay. However, 74 specimens were SV positive but negative in both NASBA assays. Detection of CMV by any of the three methods was associated with an increased prevalence of pneumonia (i.e., pulmonary interstitial inflammation with radiographic or clinical evidence of lung injury), but not with pulmonary CMV pathology. Detection of CMV by SV was associated with moderate to severe graft rejection. There was no evidence of increased bacterial or fungal pulmonary infections associated with a positive CMV result by any of the three assays.
Detection of either CMV pp67 or IE mRNA transcripts by NASBA in BAL specimens can occasionally identify CMV infections that are negative by conventional shell vial culture, but does not have sufficient sensitivity or positive predictive value to be employed routinely for pre emptive management of pulmonary CMV disease in transplant recipients.
The advent of modern immunosuppressive drugs, improvement in surgical technique, availability of rapid and reliable diagnostic assays, and advances in prophylactic strategies against a number of pathogens have collectively contributed towards a striking decline in infectious morbidity in transplant recipients in recent years. The epidemiologic trends in infectious diseases through the last decade have been most notable for a dramatic decrease in the incidence of several opportunistic infections, e.g. cytomegalovirus and Pneumocystis carinii, due largely to the advent of effective prophylaxis. However, recognition of novel microorganisms as potential pathogens and escalating rates of antimicrobial resistance, that largely parallels the more widespread national and global trends in nosocomially acquired infections, has altered the spectrum and therefore our approach towards the management of infections in transplant recipients.
Human cytomegalovirus (CMV) continues to be a major threat against solid-organ transplant recipients despite significant advancements in its prophylaxis and therapy. Primary CMV infection or reactivation of latent CMV in the transplant recipients may cause CMV diseases such as flu-like viral syndrome and tissue-invasive CMV disease. In addition, CMV infection in the recipients is associated with graft rejection and higher risk of other opportunistic infections, which are collectively known as the "indirect effects" of CMV infection. Prevention strategies with antiviral drugs including ganciclovir remarkably decreased CMV disease and the "indirect effects". Two commonly employed strategies are universal prophylaxis and preemptive therapy. However, gangciclovir-resistant CMV has emerged due to mutations in CMV UL97 and UL54 genes, now requiring alternative therapeutic options to be developed. This review provides an overview of CMV infection and disease, "indirect effects" on hosts, prevention strategies, and drug resistance in solid-organ transplant recipients.
The guidelines on the treatment of invasive fungal disease by Aspergillus spp. and other fungi issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) are presented. These recommendations are focused on four clinical categories: oncology-haematology patients, solid organ transplant recipients, patients admitted to intensive care units, and children. An extensive review is made of therapeutical advances and scientific evidence in these settings. These guidelines have been prepared according the SEIMC consensus rules by a working group composed of specialists in infectious diseases, clinical microbiology, critical care medicine, paediatrics and oncology-haematology. Specific recommendations on the prevention of fungal infections in these patients are included.
The purpose of this study was to evaluate the epidemiology and investigate the impact of colonization and pulmonary fungal infections (PFIs).
In this investigation we performed a retrospective analysis of 55 pediatric lung transplant recipients from 2002 to 2007 at a single institution. Associations between risk factors and time to post-transplant colonization, PFI, and other outcomes were assessed using Cox proportional hazard models.
Although 29 patients had positive pre-transplant colonization, 33 (60%) were colonized post-transplant and 20% (11 subjects) developed proven or probable PFI. In a multivariate model, post-transplant fungal colonization was associated with older age (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1 to 7.6), cytomegalovirus (CMV) prophylaxis (HR 5.6, 95% CI 1.3 to 24.6) and respiratory viral infection prior to fungal colonization (HR 2.9, 95% CI 1.0 to 8.3).
Neither fungal colonization nor PFI was associated with the development of chronic allograft rejection or death.
Invasive aspergillosis is a disease typically related with prolonged neutropenia or the use of corticosteroids. However, the increased use of new therapeutic modalities such as biologic agents that act by blocking specific immune pathways have put more patients at risk for invasive aspergillosis. Most cases of aspergillosis in patients taking monoclonal antibodies have been associated with the use of tumour necrosis factor (TNF)-alpha blockers. However, many more drugs have been implicated, including interleukin-2 inhibitors, and CD52 and CD20 blockers. In this manuscript we review the pathophysiology associated with an increased risk for aspergillosis in these patients, in addition to diagnostic and therapeutic considerations.
Aspergillosis is a potential, severe, and usually early complication of liver transplantation. New promising strategies, such as detecting Aspergillus antigenemia, have been used for the diagnosis of aspergillosis in immunosuppressed patients, but the impact in solid organ transplantation is not well known. A case-control study in 260 adults who underwent liver transplantation from January 1994 to June 2000 was performed. A case was defined as any liver transplant recipient with a proven or probable diagnosis of invasive aspergillosis. Controls were defined as a liver transplant recipient without aspergillosis infection with a survival longer than two months after transplantation. Clinical and analytical variables, including Aspergillus antigenemia, were compared. A special analysis was performed in patients in whom late aspergillosis developed (after day 100 posttransplantation). Among 260 patients, invasive aspergillosis developed in 15 (5.6%). Median time from transplantation to aspergillosis in 13 patients with sufficient data for analysis was 126 days (range, 22 to 1117). Seven (54%) developed the infection after day 100 posttransplantation. Thirty-eight patients were used as controls. Antigenemia was available in nine of 13 cases and in 33 of 38 controls. By multivariate analysis, retransplantation (OR, 29.9 [95% CI, 2.1 to 425.1]), dialysis requirements after transplantation (OR, 24.5 [95% CI, 1.25 to 354]), and the presence of Aspergillus antigenemia in serum at any time point after transplantation (OR, 50.0 [95% CI, 3.56 to 650]) were independently associated to aspergillosis. In the subgroup of patients that developed late aspergillosis, cytomegalovirus infection (OR, 6.7 [95% CI, 1.0 to 42.5]) was the only independent factor associated. Hepatic and renal dysfunction predispose to Aspergillus infection in liver transplant recipients. Cytomegalovirus infection and increased immunosuppression favor invasive aspergillosis during the late posttransplantation period. Aspergillus antigenemia seems to be a good predictor of invasive aspergillosis.
Invasive aspergillosis is a serious opportunistic infection in lung transplant recipients. It has not been fully discerned whether there are differences in the characteristics, risk factors and outcome of Aspergillus infection in single as compared with bilateral lung transplant recipients.
English-language articles identified by a MEDLINE search through December 2000 and bibliographies were used as data sources to identify cases of Aspergillus infections in lung transplant recipients. The studies selected had to have provided a definition of invasive aspergillosis to distinguish colonization from infection.
The median incidence of Aspergillus infections in lung transplant recipients was 6.2%. In total, 58% (45 of 78) of the Aspergillus infections were tracheobronchitis or bronchial anastomotic infections, 32% (25 of 78) were invasive pulmonary, and 22% (25 of 78) were disseminated infections. Single lung transplant recipients with Aspergillus infections were significantly older (p = 0.006), more likely to have had chronic obstructive pulmonary disease as an underlying illness (p = 0.05), more likely to have developed Aspergillus infections later after transplantation (p = 0.019), and tended to have a higher incidence of invasive aspergillosis (p = 0.11) than all other lung transplant recipients. Overall mortality in lung transplant recipients with Aspergillus infections was 52%. Single lung transplant recipients (p = 0.03), and patients with late-onset infections (occurring at least 3 months after transplantation ([p = 0.045]) infections had significantly higher mortality.
Single lung transplant recipients with Aspergillus infections had an overall greater morbidity and poorer outcome than other types of lung transplant recipients. Recognition of the unique characteristics of Aspergillus infections in single lung (vs bilateral or heart-lung) transplant recipients has implications relevant for the management of lung transplant recipients with aspergillosis.
The aim of the present study is to evaluate the epidemiology, etiology and prognosis of pneumonia in lung transplant (LT) recipients. This is a prospective, multicenter study of a consecutive cohort of LT recipients in Spain. From September 2003 to November 2005, 85 episodes of pneumonia in 236 LT recipients were included (incidence 72 episodes per 100 LT/year). Bacterial pneumonia (82.7%) was more frequent than fungal (14%) and viral pneumonia (10.4%). The most frequent microorganisms in each etiological group were Pseudomonas aeruginosa (n = 14, 24.6%), CMV (n = 6, 10.4%) and Aspergillus spp. (n = 5, 8.8%). Incidence of Aspergillus spp. and CMV pneumonia is lower than previously reported, probably due to the spread of universal prophylaxis. Pneumonia caused by viruses appeared significantly later than pneumonia due to gram-negative bacilli, fungi and those without known etiology (p < 0.01, p = 0.03 and p = 0.02, respectively). The routine use of ganciclovir has changed the natural history of CMV infection, so that pneumonia appears later, once prophylaxis is suspended. The probability of survival during the first year of follow-up was significantly higher in the multivariate analysis in LT recipients who did not have a pneumonia episode compared with those that had at least one episode (p < 0.01).
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